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Non-digestible long chain beta-glucans as novel prebiotics
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Non-digestible long chain beta-glucans as novel prebiotics (Review) Ka-Lung Lam, Peter Chi-Keung Cheung
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To appear in: Bioactive Carbohydrates and Dietary Fibre
Received date:10 July 2013 Revised date: 3 September 2013 Accepted date: 4 September 2013 Cite this article as: Ka-Lung Lam, Peter Chi-Keung Cheung, Nondigestible long chain beta-glucans as novel prebiotics (Review), Bioactive Carbohydrates and Dietary Fibre, http://dx.doi.org/10.1016/j.bcdf.2013.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ͳ
Non-digestible long chain beta-glucans as novel prebiotics (Review)
ʹ ͵
Ka-Lung Lam and Peter Chi-Keung Cheung*
Ͷ
Food and Nutritional Sciences, School of Life Sciences, The Chinese University of Hong
ͷ
Kong, Shatin, Hong Kong SAR, China
*Corresponding author:
ͺ
Peter C.K. Cheung, University Science Centre, School of Life Sciences, The Chinese
ͻ
University of Hong Kong, Shatin, New Territory, HKSAR, China
ͳͲ ͳͳ
Email: [email protected]
ͳʹ
Tel.: 852-3943 6272
ͳ͵
Fax: 852-2603 5745
ͳ
ͳͶ
Abstract
ͳͷ
As our understanding of host gut microbiome increases, research interests in the fields of
ͳ
prebiotics, probiotics and synbiotics are growing rapidly. Currently, the majority of
ͳ
prebiotics in the markets are derived from non-digestible oligosaccharides. Very few
ͳͺ
investigations have been focused on non-digestible long chain complex
ͳͻ
carbohydrates/polysaccharides for their potential as novel prebiotics. One of the reasons
ʹͲ
behind this is the unavailability of non-digestible polysaccharides that can fulfil the
ʹͳ
criteria as prebiotics. Beta-glucans that exist as non-digestible polysaccharides derived
ʹʹ
from different food sources have demonstrated not only health promoting effects, but also
ʹ͵
the potential as a novel source of prebiotics. This review commences with the current
ʹͶ
trends in the research fields of prebiotics, probiotics and synbiotics. This is followed by a
ʹͷ
discussion of the potential of long chain beta-glucans to serve as novel prebiotics based
ʹ
on current knowledge on their sources, preparation, fermentation characteristics, and the
ʹ
plausible mechanisms involved in their utilization. Some future research directions with
ʹͺ
emphasis on new approaches using molecular biology, genetics and genomics are also
ʹͻ
discussed.
͵Ͳ ͵ͳ ͵ʹ ͵͵ ͵Ͷ
Keywords: Beta-glucans, complex carbohydrates, non-digestiblity, polysaccharides,
͵ͷ
prebiotics, probiotics, synbiotics
ʹ
͵
Abbreviations
͵
ABC
ATP-binding cassette
͵ͺ
CAZymes
carbohydrate-active enzymes
͵ͻ
CBM
carbohydrate-binding module
ͶͲ
DB
degree of branching
Ͷͳ
DP
degree of polymerization
Ͷʹ
EPS
exo-polysaccharides
Ͷ͵
EI
enzyme E I
ͶͶ
EIIA
enzyme E II A
Ͷͷ
EIIBC
enzyme E II B & C
Ͷ
FOS
fructo-oligosaccharides
Ͷ
GOS
galacto-oligosaccharide
Ͷͺ
GH
glycosyl hydrolases
Ͷͻ
HITS
high-throughput insertion tracking by deep sequencing
ͷͲ
HPr
histidine protein/heat-stable protein
ͷͳ
IMO
isomaltooligosaccharides
ͷʹ
INSeq
insertion sequencing
ͷ͵
MW
molecular weight
ͷͶ
P
a phosphate group
ͷͷ
PEP
phosphoenolpyruvate
ͷ
PI
prebiotic index
ͷ
PTS
phosphotransferase system
ͷͺ
RT-PCR
reverse transcription polymerase chain reaction
͵
ͷͻ
SCFAs
short chain fatty acids
Ͳ
Tnಣseq
transposon sequencing
ͳ
TraDIS
transposonಣdirected insertion site sequencing
ʹ
XOS
xylooligosaccharides
Ͷ
͵
1. Introduction
Ͷ
Gut microbiome and host interaction is getting more attention nowadays and it is
ͷ
estimated that each individual harbors at least 160 microbial species from a consortium of
1000 to 1150 prevalent bacterial species (Ley et al., 2006; Qin et al., 2010; Marchesi,
2011). Moreover, it is accepted that this “small world within” provides important
ͺ
metabolic functions that cannot be performed by our human metabolic processes (Jia et
ͻ
al., 2008). In 2011, a review coined the term “MicrObesity” (Microbes and Obesity),
Ͳ
demonstrating the importance of gut microbiome to humans (Cani & Delzenne, 2011). In
ͳ
order to reestablish the bacterial homeostasis, one common approach is to employ the use
ʹ
of prebiotics, probiotics, and synbiotics (Vyas & Ranganathan, 2012). There have been a
͵
number of recent reviews on the effects of pre- and pro-biotics on human and animal
Ͷ
health (Ogueke et al., 2010; Ohimain & Ofongo, 2012; Chauhan and Chorawala, 2012;
ͷ
Licht et al., 2012: Ganguly et al, 2013; Saad et al., 2013).
Nowadays, the majority of prebiotics sold in the market are non-digestible
ͺ
oligosaccharides. Inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS),
ͻ
lactulose and polydextrose are recognized as the well established prebiotics, whereas
ͺͲ
isomaltooligosaccharides (IMO), xylooligosaccahrides (XOS), and lactitol are
ͺͳ
categorized as emerging prebiotics (Sabater-Molina et al., 2009; Femia et al., 2010; Xu et
ͺʹ
al., 2009). Other non-digestible oligosaccharides and sugar alcohols such as mannitol,
ͺ͵
maltodextrin, raffinose, and sorbitol have also demonstrated prebiotic properties and
ͺͶ
health benefits (Yeo and Liong, 2010; Vamanu and Vamanu, 2010; Mandal et al., 2009).
ͺͷ
However, there are few investigations on non-digestible long chain complex
ͷ
ͺ
carbohydrates as potential prebiotics. Resistant starch-rich whole grains can be
ͺ
considered as having prebiotic action since they are not absorbed in the small intestine of
ͺͺ
healthy individuals but are later fermented by gut microflora to produce short chain fatty
ͺͻ
acids (SCFAs) (Vaidya and Sheth, 2010). However, resistant starch is more regarded as a
ͻͲ
colonic food instead of a typical prebiotics because of its non-selective fermentation by
ͻͳ
all colonic bacteria and not just by probiotic bacteria (Ogueke et al., 2010). Colonic foods
ͻʹ
are defined as foods that are capable to reach the large intestine and also serve as
ͻ͵
substrate for the endogenous microorganisms (Gibson and Roberfroid, 1995).
ͻͶ
Nevertheless, there are still some non-digestible long chain complex carbohydrates that
ͻͷ
are candidates as potential prebiotics. Longer chain prebiotics can sometimes be referred
ͻ
as “slowly fermentable” substrates. Previous studies on potential slow fermentable
ͻ
substrates include long chain inulin (Van de Wiele et al., 2007), psyllium (Morita et al.,
ͻͺ
1999), arabinoxylan, an alkali-soluble polymeric fraction of corn bran (Rose et al., 2010),
ͻͻ
and long chain beta-glucan (Hughes et al., 2008). Fermentation studies of beta-glucans
ͳͲͲ
can indeed shed light on the possible use of beta-glucans as a novel source of long chain
ͳͲͳ
prebiotics. For example, the fermentability of oat beta-glucan to produce SCFAs points to
ͳͲʹ
their potential application as a prebiotic in promoting human health (Lin et al., 2011).
ͳͲ͵ ͳͲͶ
Therefore, the aims of this review were to summarize the latest findings on prebiotic
ͳͲͷ
research; to explore the potential of non-digestible long chain beta-glucans as a new
ͳͲ
source of prebiotics, to unravel the mechanism of their utilization by probiotic bacteria;
ͳͲ
and to suggest some future research directions.
ͳͲͺ
ͳͲͻ
2. Current research on probiotics, prebiotics and synbiotics
ͳͳͲ
2.1 Probiotics
ͳͳͳ
Probiotics are defined as “preparations of or products containing viable, defined
ͳͳʹ
microorganisms in sufficient numbers, which alter the microflora (by implantation or
ͳͳ͵
colonization) in a compartment of the host and by that exert beneficial health effects in
ͳͳͶ
this host” (Schrezenmeir & De Vrese, 2001). A microorganism to be qualified as a
ͳͳͷ
probiotic, a number of selection criteria have to be met. Firstly, it has to be safe for
ͳͳ
human consumption, not conferring any pathogenic or toxic effects; secondly, it would be
ͳͳ
better to be originated from the intestinal tract of healthy persons so that such
ͳͳͺ
microorganisms are regarded safe for humans and best adapted to the ecology of the gut;
ͳͳͻ
thirdly, it has to be tolerant to gastric and bile acids as well as sufficiently resistant to
ͳʹͲ
digestive enzymes to enable its survival after passing the intestinal tract; and lastly,
ͳʹͳ
allowing the detection of parameters confirming a positive influence on the intestinal
ͳʹʹ
flora such as viability, adhesion to intestinal epithelial cells, and capability of
ͳʹ͵
reproduction in the human intestine (De Vrese & Schrezenmeir, 2008). A permanent
ͳʹͶ
colonization of probiotic bacteria in the large bowel is not required for attaining their
ͳʹͷ
probiotic effects, as far as there is a daily or regular bacteria supplementation (De Vrese
ͳʹ
& Schrezenmeir, 2008). Several microorganisms have been considered or used as
ͳʹ
probiotics including fungi (particularly mushroom), yeast, bacteria or mixed
ͳʹͺ
combinations. Two genera of bacteria that are mostly reported as probiotics include lactic
ͳʹͻ
acid bacteria of the genus Lactobacllus and Bifodobacterium (Ohimain & Ofongo, 2012).
ͳ͵Ͳ
ͳ͵ͳ
Generally, probiotic cultures must be consumed at a level of at least 107 CFU/mL to
ͳ͵ʹ
provide the therapeutic benefits mentioned above (Lourens-Hattingh and Viljoen, 2001).
ͳ͵͵
The beneficial effects of regular consumption of probiotics include disease fighting and
ͳ͵Ͷ
prevention, nutrients absorption enhancement and other health promoting consequences
ͳ͵ͷ
(De Vrese & Schrezenmeir, 2008), with validity of scientific proofs being summarized.
ͳ͵
Sekhon and Jairath updated a list of all common probiotics and proven probiotic strains
ͳ͵
with brand name and producer in their recent review (Sekhon & Jairath, 2010).
ͳ͵ͺ
Moreover, there is an increasing diversity of probiotics being investigated in different
ͳ͵ͻ
fields. For instance, Vyas and Ranganathan presented an emerging field of probiotic
ͳͶͲ
investigation on myocardial infarction, the influence of gut microbiota alternation on
ͳͶͳ
brain and behavior, genetic disorders such as Familial Mediterranean Fever, and in
ͳͶʹ
psychological studies such as autism (Vyas & Ranganathan, 2012).
ͳͶ͵ ͳͶͶ
2.2 Prebiotics
ͳͶͷ
Prebiotics are defined as “non-digestible food ingredients that beneficially affect the host
ͳͶ
by selectively stimulating the growth and/or activity of one or a limited number of
ͳͶ
bacteria in the colon” (Gibson and Roberfroid, 1995). Recently, bioactive long chain
ͳͶͺ
complex carbohydrates (polysaccharides) from various plant materials, such as cereal,
ͳͶͻ
mushrooms, herbs, chicory root, citrus, soybeans, and potatoes, are gaining attention as
ͳͷͲ
new prebiotic alternatives (Chou et al., 2013; Gullón et al, 2013). Apart from plant origin,
ͳͷͳ
prebiotics can be synthesized by some microorganisms, mainly the exo-polysaccharides
ͳͷʹ
(EPS) from probiotic strains (Patterson & Burkholder, 2003; Patel et al., 2010; Stack et
ͳͷ͵
al., 2010). Furthermore, many research studies have indicated that polysaccharides
ͺ
ͳͷͶ
obtained from mushrooms such as Pleurotus sp. (Synytsya et al, 2009), Lentinus edodes,
ͳͷͷ
Tremella fuciformis (Guo et al, 2004), and Agaricus bisporus (Giannenas et al., 2011)
ͳͷ
have prebiotic activity. The active component is believed to be the long chain beta-
ͳͷ
glucans, including homo- and hetero-glucans with Ǫ (1ψ3), Ǫ (1ψ4), and Ǫ (1ψ6)
ͳͷͺ
glucosidic linkages (Manzi & Pizzoferrato, 2000).
ͳͷͻ ͳͲ
Current research on prebiotics has demonstrated their diverse health implications
ͳͳ
including gut health maintenance, colitis prevention, cancer inhibition, immune-
ͳʹ
potentiation, cholesterol removal, reduction of cardiovascular disease, prevention of
ͳ͵
obesity and constipation, restoration of vaginal ecosystem, bacteriocin production as well
ͳͶ
as food applications including starter culture formulations as well as in pet food and fish,
ͳͷ
poultry, pig, and cattle feed (Patel & Goyal, 2012). Nakamura and Omaye reviewed the
ͳ
potential of the involvement of intestinal bacteria in host metabolism and the preventative
ͳ
and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases
ͳͺ
such as obesity and Type II diabetes (Nakamura & Omaye, 2012). Shen and others
ͳͻ
recently have reviewed the potential of prebiotic intervention in gestational diabetes
ͳͲ
(Shen et al., 2013). Macfarlane and others focused on the prebiotic effects on human gut
ͳͳ
functions and concluded that oligofructose, galacto-oligosaccharides and lactulose could
ͳʹ
significantly alter the large bowel microbiota by increasing the population of
ͳ͵
Bifidobacterium sp. and Lactobacillus sp. (Macfarlane et al, 2006). A most recent review
ͳͶ
on the effects of the intake of prebiotics on human health with evidence-based clinical
ͳͷ
studies and the mechanisms behind their beneficial effects has been published (Slavin,
ͳ
2013). More importantly, all these authors have pointed out that research on prebiotics is
ͻ
ͳ
still at its infancy and the potential for them to modify the gut microbial balance in such a
ͳͺ
way as to bring health benefits inexpensively and safely to humans is emerging.
ͳͻ ͳͺͲ
The conventional methodologies for the production of non-digestible oligosaccharides by
ͳͺͳ
extraction and purification procedures are summarized in a review by Mussatto and
ͳͺʹ
Manciha (Mussatto & Mancilha, 2007). In addition to these traditional methods, some
ͳͺ͵
novel biotechnological approaches using recombinant enzymes, enzyme/cell
ͳͺͶ
immobilization or recombinant bacterial strains for the production of different prebiotics
ͳͺͷ
have been reviewed recently (Panesar et al., 2012). When probiotics are incorporated into
ͳͺ
food products, culture viability often decreases as a result of pH reduction, temperature
ͳͺ
lowering, nutrients inadequacy, and oxidative stress. These challenges could be
ͳͺͺ
ameliorated by the addition of prebiotics into the food matrix (Bruno et al., 2002;
ͳͺͻ
Corcoran et al., 2004; Capela et al., 2006). Further details of the technological application
ͳͻͲ
of prebiotics in this respect can be referred to a recent review by Mohammadi &
ͳͻͳ
Mortazavian (2011). Using probiotic-fermented milks as example, issues on the effects of
ͳͻʹ
the viability of probiotics, sensory attributes, physicochemical and rheological
ͳͻ͵
characteristics of the fermented milks have been addressed (Mohammadi & Mortazavian
ͳͻͶ
2011).
ͳͻͷ ͳͻ
The recommended doses of fifteen different prebiotics for healthy individuals and
ͳͻ
patients, ranging from 1-15g/day, have been suggested recently (Singh et al., 2012). To
ͳͻͺ
further evaluate the prebiotic effect, a ‘‘prebiotic index’’ (PI = E/A), which is defined as
ͳͻͻ
‘‘The increase in bifidobacteria expressed as the absolute number of “new” cfu/g of feces
ͳͲ
ʹͲͲ
(E) divided by the daily dose (g) of prebiotic ingested (A)” has been proposed
ʹͲͳ
(Roberfroid, 2007). PI is commonly used as a standard for the comparison of different
ʹͲʹ
prebiotic effects among different prebiotic carbohydrates.
ʹͲ͵ ʹͲͶ
2.3 Synbiotics
ʹͲͷ
The term synbiotics refers to products containing both probiotics and prebiotics. This
ʹͲ
term should be reserved for products in which the prebiotic substances are selectively
ʹͲ
utilized by the probiotic bacteria (Schrezenmeir & De Vrese, 2001). It has been pointed
ʹͲͺ
out in a recent review that the health effects, including modulation of intestinal flora,
ʹͲͻ
cancer prevention, immunomodulation, prevention of sepsis and bacterial translocation of
ʹͳͲ
certain potential synbiotics on animals and humans did show that the combinations of
ʹͳͳ
prebiotics and probiotics were more effective than placebo products (De Vrese &
ʹͳʹ
Schrezenmeir, 2008).
ʹͳ͵ ʹͳͶ
Based on previous clinical investigations, the applications of synbiotics in integrative
ʹͳͷ
medicine and human health include the restoration of the immune function, reduction in
ʹͳ
systemic inflammation, alleviation in irritable bowel disease and acute pancreatitis, etc.
ʹͳ
(Bengmark, 2012). A recent new concept derived from synbiotics is known as
ʹͳͺ
metabiotics, which refers to the “structural components of probiotic microorganisms
ʹͳͻ
and/or formulation of and/or signaling molecules with a determined (known) chemical
ʹʹͲ
structure that can optimize host-specific physiological functions and regulate metabolic
ʹʹͳ
and/or behavior reactions connected with the activity of host indigenous microbiota”
ʹʹʹ
(Shenderov, 2012). It is thus observed that new concepts are being proposed in the area of
ͳͳ
ʹʹ͵
pre-, pro- and synbiotics, and these products are of great potential as functional food
ʹʹͶ
ingredients (Bigliardi & Galati, 2013).
ʹʹͷ ʹʹ
3. Long chain beta-glucans as potential prebiotics
ʹʹ
3.1 Background
ʹʹͺ
Beta-glucans are polysaccharides of D-glucose monomers linked by beta-glycosidic
ʹʹͻ
linkages. It is one source of valuable dietary fiber found in cereals, yeast, mushrooms,
ʹ͵Ͳ
seaweeds and some bacteria. Chemically, beta-glucans are non-starch polysaccharides
ʹ͵ͳ
with repeating glucose residues in either linear chains or multiply branched structures
ʹ͵ʹ
with the glucose units being branched in several ways depending upon the source of
ʹ͵͵
origin. For cereal beta-glucans the chains are completely linear, consisting of
ʹ͵Ͷ
consecutively linked (via beta 1-3 linkages) of cellulosic oligomers; i.e. segments of beta
ʹ͵ͷ
1-4 linked glucose residues (Lazaridou & Biliaderis, 2007). Instead, for microbial beta-
ʹ͵
glucans, the beta-D-glucopyranose units are linked together through beta -(1,3) linkages
ʹ͵
to form a long backbone, whereas side chains mostly arise through beta -(1,6) linkages
ʹ͵ͺ
(Ahmad et al., 2012a). Beta-D-glucans can form large cylindrical molecules containing
ʹ͵ͻ
up to 250,000 glucose units (Vannucci et al., 2013).
ʹͶͲ ʹͶͳ
In 1941, there was the first discovery of a pharmaceutical insoluble yeast crude product
ʹͶʹ
called ‘Zymosan,’ which is composed of 50% glucan and other polysaccharides (Pillemer
ʹͶ͵
& Ecker, 1941). Beta-glucans are major structural components of the cell walls of
ʹͶͶ
brewers’ yeast Saccharomyces cerevisiae, fungi and some bacteria. Depending on the
ʹͶͷ
source, there are clear differences between beta-glucans in their solubility, molecular
ͳʹ
ʹͶ
mass, tertiary structure, degree of branching, polymer charge and solution conformation,
ʹͶ
all of which in turn alter their immune modulating effects (Bohn & BeMiller, 1995;
ʹͶͺ
Eccles, 2005). Accordingly, beta-glucans having a beta-(1, 3) chain with beta-(1, 6)
ʹͶͻ
branching are more effective than beta-(1, 3) linear chain alone (Bohn & BeMiller, 1995).
ʹͷͲ ʹͷͳ
The macromolecular structure of beta-glucans depends on both their sources and isolation
ʹͷʹ
methods, affecting mainly the distribution and the length of side chains, forming complex
ʹͷ͵
tertiary structures stabilized by inter-chain hydrogen bonds (Mantovani et al., 2008).
ʹͷͶ
Parameters such as primary structure, solubility, degree of branching (DB), molecular
ʹͷͷ
weight (MW), polymer charge and conformation in aqueous media are involved in
ʹͷ
biological activity that beta-glucan exhibits (Zekovic et al., 2005). Beta-glucans with 0.2
ʹͷ
DB 0.33, 100 MW 200 kDa, and a triple-helix structure have greater biological
ʹͷͺ
activities than linear beta-glucan molecules (Zekovic et al., 2005). The solubility of beta-
ʹͷͻ
glucans is associated with the degree of polymerization (DP). Beta-glucans are
ʹͲ
completely insoluble in water when DP > 100.
ʹͳ ʹʹ
Cereal beta-glucans have been demonstrated to have prebiotic properties owing to their
ʹ͵
ability to pass undigested through the gastro-intestinal tract (GIT), where they act as a
ʹͶ
substrate for microbial fermentation and selectively stimulate the growth and activity of a
ʹͷ
small number of beneficial bacteria (Gibson, 2004). The use of beta-glucans derived from
ʹ
cereals as a source of fermentable substrates for the growth of probiotic microorganisms
ʹ
has been reviewed recently (Bigliardi & Galati, 2013). The beta-glucans extracted from
ʹͺ
the fruiting body of Pleurotus mushrooms. (pleuran) have also been used as food
ͳ͵
ʹͻ
supplements due to their immunosuppressive activity and stimulation of probiotics (Patel
ʹͲ
& Goyal, 2012). Similar beta-glucan extracts from Pleurotus species including P.
ʹͳ
ostreatus and P. eryngii, have been explored for their effects on human health (Synytsya
ʹʹ
et al. 2009). The use of beta-glucans from different mushroom species as a potential
ʹ͵
source of prebiotics was firstly published 5 years ago (Aida et al., 2009).
ʹͶ ʹͷ
Furthermore, beta-glucans have been well investigated in other fields. Recently, the
ʹ
applications of beta-glucans in cosmetics (Du et al., 2013) and food industries (Ahmad et
ʹ
al., 2012b) have been reviewed. Some beta-glucan products such as Ceapro from oat
ʹͺ
(Morgan & Ofman, 1998; Tomasik & Tomasik, 2003), Glucagel from barley (Morgan &
ʹͻ
Ofman, 1998), and Betamune from Yeast (Vetvicka et al., 2008) have been
ʹͺͲ
commercialized. More recently, the application of beta-glucans as an immune-stimulant
ʹͺͳ
in aquaculture to enhance productivity has been published (Meena et al., 2013).
ʹͺʹ ʹͺ͵
3.2 Health benefits of beta-glucans
ʹͺͶ
Cumulative evidence obtained from animal models and human intervention studies
ʹͺͷ
strongly suggest the immunostimulatory effect of beta-glucans and the relevant
ʹͺ
knowledge has been summarized in several recent reviews (Volman et al, 2008; Ramberg
ʹͺ
et al., 2010; Di Bartolomeo et al., 2012; Licht et al., 2012; Daou & Zhang, 2012). Most
ʹͺͺ
recently, the effect of consumption of brewers’ yeast beta-(1, 3)-(1, 6)- D-glucan on the
ʹͺͻ
number of common cold episodes in healthy subjects was investigated using a placebo-
ʹͻͲ
controlled, double-blind, randomized, multicentric clinical trial which demonstrated that
ͳͶ
ʹͻͳ
yeast beta-glucan preparation increased the human potential to defend against invading
ʹͻʹ
pathogens (Auinger et al, 2013).
ʹͻ͵ ʹͻͶ
Structure-function relationships have been studied among different beta-glucans, which
ʹͻͷ
offer plausible explanations of their different potency in health promoting effects as they
ʹͻ
relate to molecular structure of the polysaccharides. A recent review has summarized the
ʹͻ
beneficial influence of beta-glucans with different structures and the related potency in
ʹͻͺ
different biological functions (Zhang et al., 2007; Ahmad et al., 2012b; Du et al., 2013).
ʹͻͻ
For example, glucans with beta-(1, 3) (1, 6) linkages are found to have stronger anti-
͵ͲͲ
tumor property (Chan et al, 2009) and both beta-glucans with beta-(1, 3) (1, 4) and beta-
͵Ͳͳ
(1, 3) (1, 6) linkages are found to have greater immune-modulating potency (Rieder &
͵Ͳʹ
Samuelsen, 2012) and blood cholesterol lowering capacity (Chen & Seviour, 2007). Both
͵Ͳ͵
barley and oat kernel derived beta-glucans were found in vitro to inhibit cytokine-induced
͵ͲͶ
protein expression of adhesion molecules in human aortic endothelial cells in a
͵Ͳͷ
concentration- and molecular structure-dependent manner (Lazaridou et al., 2011); i.e.
͵Ͳ
the experimental data suggested that soluble cereal beta-glucans could act beneficially in
͵Ͳ
inhibiting the early stages of atherosclerosis, with the barley polysaccharides showing
͵Ͳͺ
greater physiological potency than the respective oat beta-glucans of similar molecular
͵Ͳͻ
weight. Anti-tumor property is another light-spotting field of interests on beta-glucans
͵ͳͲ
research. Recent scientific research in Japan and China has been focused more on the
͵ͳͳ
anti-tumor potentials and showed the effects of these specific beta-glucans to be
͵ͳʹ
comparable to chemotherapy and radiation, but without the side effects of the latter
͵ͳ͵
treatments (Tzianabos, 2000; Chung et al., 2010). The characteristics of beta-glucans
ͳͷ
͵ͳͶ
from fungal mycelial walls as modulators of the immunity and their possible use as
͵ͳͷ
antitumor agents have been summarized most recently (Vannucci et al., 2013). The
͵ͳ
beneficial effects of beta-glucans are not only limited in immunomodulation and
͵ͳ
anticancer activities. The effects of pleuran (a type of beta-glucans from Pleurotus
͵ͳͺ
ostreatus) supplementation on cellular immune response and respiratory tract infections
͵ͳͻ
in athletes have been reported (Bergendiova et al., 2011), depicting the possible
͵ʹͲ
association between beta-glucan consumption and enhanced performance in sports.
͵ʹͳ ͵ʹʹ
Beta-glucans activity was studied mainly in human cell culture and animal models with
͵ʹ͵
comparatively fewer human studies (Wasser, 2011). It was revealed that stronger anti-
͵ʹͶ
tumor activity was observed with beta-glucans linked with proteins compared to pure
͵ʹͷ
beta-glucans in clinical trials (Jeurink et al., 2008). However, the molecular mechanism
͵ʹ
behind this is still not yet understood in spite of increasing evidence from phenotypic
͵ʹ
studies. Results from human studies are accumulating rapidly. The applications of beta-
͵ʹͺ
glucans in cancer therapy, based on clinical trials and epidemiological data assessing the
͵ʹͻ
efficacy and safety of mushroom-derived beta-glucans in cancer treatment and
͵͵Ͳ
prevention, have been recently reviewed (Aleem, 2013).
͵͵ͳ ͵͵ʹ
Apart from exerting the health-related benefits mentioned above, beta-glucans may also
͵͵͵
provide their health promoting effects by their action as potential prebiotics. Details of
͵͵Ͷ
the recent studies in this aspect will be discussed later. However, it is worth mentioning
͵͵ͷ
that since beta-glucans are fermented in the colon by the gut microbiome, it is certain that
͵͵
their consumption could cause flatulence, bloating, and abdominal cramps if their dietary
ͳ
͵͵
intake is suddenly increased. Based on some human intervention studies, it has been
͵͵ͺ
concluded that the consumption of a daily dose of up to 10 g of beta-glucans by humans
͵͵ͻ
is well tolerated and even a higher consumption level of beta-glucans might not be
͵ͶͲ
harmful for human health (Cloetens et al, 2012). It should be also emphasized that a dose
͵Ͷͳ
higher than 10 g/day is uncommon in a single meal (Cloetens et al, 2012). Due to its
͵Ͷʹ
health promoting effects, there is an increasing trend of consumption of beta-glucans as
͵Ͷ͵
dietary supplements in the functional food markets.
͵ͶͶ ͵Ͷͷ
3.3 Sources and preparations of beta-glucans
͵Ͷ
3.3.1 Sources
͵Ͷ
Sources for beta-glucans are quite diversified (Ahmad et al, 2012a). The major sources
͵Ͷͺ
for beta-glucans are from cereals, especially oat and barley, which have very high beta-
͵Ͷͻ
glucan content (Lazaridou & Biliaderis, 2007). Beta-glucans can also be extracted from
͵ͷͲ
rye and rice, with the latter being marketed in the name of ‘NutrimXe’ (Inglett et al.,
͵ͷͳ
2004). Among these sources, the content of beta-glucans differs from cultivar to cultivar
͵ͷʹ
(Zhang et al., 2002) and varies in different parts of the plant such as the kernels and bran
͵ͷ͵
in barley (Wirkijowska et al., 2012).
͵ͷͶ ͵ͷͷ
During the extraction of beta-glucans, the extraction yield varies and depends upon on the
͵ͷ
botanical sources, temperature, and pH (Zhang et al., 2002; Temelli, 1997). Extraction
͵ͷ
yield of beta-glucans from oat can be 50 to 80%, while that of barley ranges from 70 to
͵ͷͺ
80% (Freimund et al., 2003). Extraction of beta-glucans from Saccharomyces cerevisiae
͵ͷͻ
could give up to 87% -glucans (Freimund et al., 2003).
ͳ
͵Ͳ ͵ͳ
Recently, beta-glucans obtained from edible mushrooms (or edible fungi) have attracted
͵ʹ
much research interest because mushrooms are a good source of beta-glucans. The most
͵͵
renowned edible mushroom sources include Agaricus brasiliensis (Kodama et al, 2003),
͵Ͷ
Pleurotus tuberregium (Zhang et al, 2004), Grifola frondosa (Kodama et al., 2003),
͵ͷ
Lentinus edodes (Chihara, 1993), Pleurotus eryngii (Synytsya et al., 2009) and Pleurotus
͵
ostreatus (Carbonero et al., 2006; Yoshioka et al., 1985; Synytsya et al., 2009; Tong et
͵
al., 2009). A review on the beta-glucans content of these mushrooms has been published
͵ͺ
recently (Aida et al., 2009). The pharmacological effects of beta-glucans including
͵ͻ
antimicrobial, antiviral, antitumor, antiallergic, immunomodulating, anti-inflammatory,
͵Ͳ
antiatherogenic, hypoglycemic, and hepatoprotective have also been reported (Lindequist
͵ͳ
et al., 2005). A few fungal sources that are not used for edible purpose can also be used
͵ʹ
for extraction of beta-glucans including Termitomyces eurhizus (Chakraborty et al.,
͵͵
2006), Penicillium chrysongenum (Wang et al, 2002). Table 1 summarizes the source and
͵Ͷ
chemical structure of some native and modified beta-glucans available in the current
͵ͷ
market.
͵ ͵
3.3.2 Preparations
͵ͺ
The most direct method to obtain beta-glucans is to extract them from natural sources.
͵ͻ
However, isolation and purification of beta-glucans are complicated involving different
͵ͺͲ
extraction procedures using acids, alkalis and enzymes. Generally, extraction of beta-
͵ͺͳ
glucans relies on the solubility of beta-glucans in hot water or in alkaline solutions and
͵ͺʹ
the removal of non-targeted contaminants such as proteins. For example, dissolved
ͳͺ
͵ͺ͵
proteins can be removed by isoelectric precipitation, and then beta-glucans can be
͵ͺͶ
precipitated by ammonium sulphate, 2-propanol, or ethanol (Wood et al., 1978).
͵ͺͷ
Repeated precipitations and enzymatic hydrolysis of residual starch and proteins have
͵ͺ
been demonstrated to yield beta-glucans isolates with purity greater than 90% (Wood et
͵ͺ
al., 1991; Westerlund et al., 1993; Lazaridou & Biliaderis, 2007).
͵ͺͺ ͵ͺͻ
Alkaline extraction of beta-glucans has also been widely employed. Extraction with
͵ͻͲ
distilled water, by adjusting the pH to 10 with 20% sodium carbonate, was used to extract
͵ͻͳ
beta-glucans from oat bran, with a yield of 61% of crude beta-glucans. A beta-glucan
͵ͻʹ
isolate with a 84% purity was obtained by centrifugation, termamyl addition and alcohol
͵ͻ͵
precipitation after acidification using 2M hydrochloric acid to pH 4.5 (Bhatty, 1993).
͵ͻͶ
Similar methodologies have been further developed to improve the yield of beta-glucans
͵ͻͷ
extraction by alcohol precipitation (Beer et al., 1996). Another method to extract beta-
͵ͻ
glucans from the fruiting bodies of Pleurotus sajorcaju using cell wall-degrading
͵ͻ
enzymes (xylanase and cellulose) was developed to produce beta-glucans with a purity of
͵ͻͺ
up to 90.2% with enhanced immunostimulatory activity in a macrophage cell culture
͵ͻͻ
model (Satitmanwiwat et al., 2012). When comparing extraction methods using acids,
ͶͲͲ
alkalis, or enzymes, it was reported that enzymatic extraction was the best because it did
ͶͲͳ
not only give the highest yield but also removed most residual starch, fat, and pentosans
ͶͲʹ
during the extraction process (Ahmad et al., 2010). In a recent review, a comprehensive
ͶͲ͵
list of all recent extraction and purification processes of beta-glucans with their sources,
ͶͲͶ
salient features of the extraction process has been given (Ahmad et al., 2012b). This
ͳͻ
ͶͲͷ
review also summarizes the differences in the molecular weight of beta-glucans obtained
ͶͲ
by the different methods and from different sources (Ahmad et al., 2012b).
ͶͲ ͶͲͺ
In addition to the conventional production of beta-glucans by extraction from natural
ͶͲͻ
sources, beta-glucans can also be synthesized from microorganisms. The synthesis of
ͶͳͲ
beta-(1, 3)-D-glucans by lactic acid bacteria using a recombinant probiotic strain
Ͷͳͳ
Lactobacillus paracasei NFBC 338, which contains the Pediococcus parvulus
Ͷͳʹ
glycosyltransferase gene responsible for beta-glucans production was reported recently
Ͷͳ͵
(Kearney et al., 2011). Such synthesized beta-glucan could increase the viability of
ͶͳͶ
probiotic bacteria and did not alter the functional properties of the food products
Ͷͳͷ
(Kearney et al., 2011).
Ͷͳ Ͷͳ
3.4 Recent studies on the beta-glucans as prebiotics
Ͷͳͺ
Beta-glucans can show prebiotic characteristics when incorporated into food products.
Ͷͳͻ
There is growing market for food products having probiotics and prebiotics in their
ͶʹͲ
formulations. Such products are available in large food stores across the world in the
Ͷʹͳ
form of fresh and fermented milk products (e.g., yoghurts, kefir), fruit juices and so on
Ͷʹʹ
(Tomasik & Tomasik, 2003).
Ͷʹ͵ ͶʹͶ
In the 1990s, many studies have pointed out the phenotypic response of beta-glucans as
Ͷʹͷ
fermentation substrate. Lichenase hydrolysates of oat beta-glucans and xylans were also
Ͷʹ
studied as selective substrates for Bifidobacterium sp. and Lactobacillus sp. strains
Ͷʹ
(Jaskari et al, 1998). In this study, low molecular weight oat beta-glucooligomers and
ʹͲ
Ͷʹͺ
xylooligomers both enhanced the growth of probiotic strains, but not to a significant level
Ͷʹͻ
compared to raffinose and fructooligomers (Jaskari et al, 1998). In another study, glucans
Ͷ͵Ͳ
with beta-(1, 4) linkages were shown to be cleaved more slowly by beta-galactosidase of
Ͷ͵ͳ
B. bifidum compared to beta-(1, 3) and beta-(1, 6) linkages (Dumortier et al, 1994). The
Ͷ͵ʹ
beta-(1, 3) and beta-(1, 6) linkages have also been described as being more selectively
Ͷ͵͵
hydrolyzed by the enzymic systems of Bifidobacterium sp. (Rowland & Tanaka, 1993).
Ͷ͵Ͷ Ͷ͵ͷ
In the late 1990s and early 2000s, beta-glucans have been reported as a potential
Ͷ͵
prebiotic, selectively promoting the growth of beneficial intestinal microorganisms such
Ͷ͵
as lactobacilli and bifidobacteria according to some in vitro studies (Jaskari et al., 1998;
Ͷ͵ͺ
Kontula et al., 1998b) and animal experiments (Dongowski et al., 2002; Drzikova et al.,
Ͷ͵ͻ
2005; Snart et al., 2006). Beta-glucans (Su et al., 2007), and especially their oligomeric
ͶͶͲ
fragments (Grootaert et al., 2007; Kontula et al., 1998a; Lee et al., 2002; Manderson et
ͶͶͳ
al., 2005; Olano-Martin et al., 2002) have been also proposed as prebiotics. In 2009,
ͶͶʹ
Synytsya and others (2009) have used different extraction methods to obtain beta-glucans
ͶͶ͵
from Pleurotus sp. (pleuran) and demonstrated their prebiotic effects using nine probiotic
ͶͶͶ
strains of Lactobacillus, Bifidobacterium and Enterococcus, showing different substrate
ͶͶͷ
dependency of their growth and strain specificity.
ͶͶ ͶͶ
At present, active research on beta-glucans as potential source of prebiotics is still going
ͶͶͺ
on. The most updated research studies have been summarized in Table 2, involving both
ͶͶͻ
basic research and clinical studies. Currently, research on beta-glucans as a potential
ͶͷͲ
source of prebiotics is shifting from basic studies towards human clinical work. For basic
ʹͳ
Ͷͷͳ
research studies, there is also an increasing effort to unravel the molecular mechanism
Ͷͷʹ
behind the selective fermentation of beta-glucans by different probiotic bacterial strains.
Ͷͷ͵ ͶͷͶ
4. Structure–function relationships
Ͷͷͷ
4.1 Pathways for bacterial fermentation of beta-glucans
Ͷͷ
There is detailed structural information on beta-glucans from different sources obtained
Ͷͷ
by modern analytical techniques (Satitmanwiwat et al., 2012). For example, enzymic
Ͷͷͺ
digestion (lichenase) combined with high performance liquid chromatography (HPLC)
Ͷͷͻ
analysis of the oligosaccharides in the hydrolyzate as well as nuclear magnetic resonance
ͶͲ
(NMR) analysis of beta-glucans from oat and other cereal grains revealed that cello-
Ͷͳ
oligosaccharides are joined by beta-(1,3) linkages and that the main components of cereal
Ͷʹ
beta-glucans are cellotri- and cellotetrasaccharides (95% of the whole beta-glucan)
Ͷ͵
(Wood et al., 1991; Johansson et al., 2000; Lazaridous & Biliaderis, 2007). Although
ͶͶ
there has been some research interest in the structure-function relationships of prebiotics
Ͷͷ
such as FOS and GOS in terms of specific enzymes or transporters that are present in the
Ͷ
bacteria for their utilization (Rastall & Maitin, 2002; Van den Broek et al., 2008a; Van
Ͷ
Den Broek & Voragen, 2008b), it is clear that more work is needed to fully elucidate the
Ͷͺ
roles of cell-associated enzymes and prebiotic transport systems. Besides the differences
Ͷͻ
in fermentation selectivity among the various strains of probiotic microorganisms, there
ͶͲ
are some key studies on oligosaccharides, comparing the structural characteristics with
Ͷͳ
their fermentation selectivity, primarily in relation to the monosaccharide composition,
Ͷʹ
glycosidic linkage, and molecular mass of the prebiotics (Sarbini & Rastall, 2011).
Ͷ͵
ʹʹ
ͶͶ
Our current understanding of prebiotic substances is that low-molecular-mass
Ͷͷ
oligosaccharides are more rapidly and more selectively fermented by bifidobacteria and
Ͷ
lactobacilli than their high-molecular-weight counterparts. This property may be due to
Ͷ
the fact that the low molecular mass substrates have more non-reducing ends per unit
Ͷͺ
mass, which favors a more rapid attack by the exo-acting enzymes produced by probiotic
Ͷͻ
organisms (Gibson, 2004). However, the detailed mechanism on bacterial selective
ͶͺͲ
fermentation of beta-glucans remains unclear and there are many research challenges for
Ͷͺͳ
further study in this area.
Ͷͺʹ Ͷͺ͵
In our laboratory, beta-glucans obtained from barley, seaweed, bacteria, and mushroom
ͶͺͶ
sclerotia were incubated with pure cultures of Bifidobacterium infantis, Bifidobacterium
Ͷͺͷ
longum, and Bifidobacterium adolescentis for a 24-hour batch fermentation in order to
Ͷͺ
evaluate their bifidogenic effect with inulin as the positive control (Zhao & Cheung,
Ͷͺ
2011). The results showed that the utilization of all the beta-glucans isolated from
Ͷͺͺ
different sources regardless of their differences in glycosidic linkages and molecular
Ͷͺͻ
weight by all three bifidobacteria was comparable to that of inulin (Zhao & Cheung,
ͶͻͲ
2011). A plausible explanation for these observations might be the similarity of enzymic
Ͷͻͳ
and transporter systems of the different bifidobacterial species investigated.
Ͷͻʹ Ͷͻ͵
In the last decade, “omics approaches” have inuenced tremendously the way of studying
ͶͻͶ
the biology of microorganisms including probiotics. The “omics approach” is a powerful
Ͷͻͷ
tool to reveal the molecular mechanism behind (Mozzi et al, 2012). A recent review
Ͷͻ
summarized different “omics approaches” in the microbiological field and suggested the
ʹ͵
Ͷͻ
requirement of systematic omic measurements at different areas and at different time-
Ͷͻͺ
points can help resolved different omics profiles (genomics, transcriptomics, proteomics
Ͷͻͻ
and metabolomics) of samples, employing a discovery-driven approach instead of
ͷͲͲ
traditional targeted investigation (Muller et al., 2013). Recently, Van de Guchte and
ͷͲͳ
others reviewed different proteomics-based methods to gain understanding of the
ͷͲʹ
mechanisms underlying the characteristics of probiotic bacteria, such as gel
ͷͲ͵
electrophoresis, mass spectrometry based proteomics, stable isotope labeling with amino
ͷͲͶ
acids in cell culture, shaving (the use of bead-anchored trypsin to digest cell surface
ͷͲͷ
proteins, followed by mass spectrometry analysis and comparison with computer
ͷͲ
stimulated trypsin digestion of selected proteins in database), proteome fractionation and
ͷͲ
in silico proteomics (Van de Guchte et al, 2012). Siciliano & Mazzeo (2012) also
ͷͲͺ
summarized the different microbial proteomics strategies that can be possibly employed
ͷͲͻ
to investigate molecular mechanisms underlying the probiotic effects. These proteomic
ͷͳͲ
approaches allow us to better understand how probiotic bacteria can adapt to the harsh
ͷͳͳ
physical–chemical environment of the gastro-intestinal tract, adhere to host epithelial
ͷͳʹ
cells and intestinal mucosa and exert immunomodulatory properties (Siciliano & Mazzeo,
ͷͳ͵
2012).
ͷͳͶ ͷͳͷ
Most recently, our group elucidated the metabolic pathway of beta-glucan catabolism in
ͷͳ
the widely used probiotic B. longum subsp. infantis using a comparative proteomic
ͷͳ
analysis along with two-dimensional gel electrophoresis, real-time reverse transcription-
ͷͳͺ
polymerase chain reaction (real-time RT-PCR) for validation, and enzyme activity assay
ͷͳͻ
on samples obtained from cultures grown on beta-glucans derived from barley, seaweed,
ʹͶ
ͷʹͲ
and mushroom (Zhao & Cheung, 2013). On the basis of the above results, a model for
ͷʹͳ
catabolism of beta-glucans in B. infantis is proposed as follows (Figure 1): beta-glucan
ͷʹʹ
molecules in the medium are transported into the cell through the ABC (ATP-binding
ͷʹ͵
cassette) transport system and PTS (phosphotransferase system) proteins followed by
ͷʹͶ
hydrolysis through the action of intracellular glucanase to glucose, which is subsequently
ͷʹͷ
incorporated into the central fermentative pathway ‘bifid shunt’. This study for the first
ͷʹ
time reveals the possible degradation pathway of beta-glucans by B. infantis, which has
ͷʹ
implications for potential use of these beta-glucans as novel prebiotics in development of
ͷʹͺ
synbiotic formulations (Zhao & Cheung, 2013).
ͷʹͻ ͷ͵Ͳ
The proposal of biochemical pathways with relevant enzymes and transporters
ͷ͵ͳ
participating in beta-glucans catabolism can be regarded as the first step to elucidate the
ͷ͵ʹ
mechanism. However, validation of pathways by employing genetic manipulation of
ͷ͵͵
probiotic organisms must be performed. In addition, the use of novel meta-omics
ͷ͵Ͷ
approaches (Sánchez et al., 2013) including metagenomics, metaproteomics and
ͷ͵ͷ
metatranscriptomics, as well as focus on the analysis of the biological molecules in
ͷ͵
complex microbial communities, are worth mentioning (Del Chierico et al., 2012;
ͷ͵
McNulty et al., 2011; Wu, et al., 2011) Although these approaches are still nascent
ͷ͵ͺ
disciplines, they are expected to gain a deeper insight into the role of probiotics and their
ͷ͵ͻ
relationships with our bacterial community and human physiology.
ͷͶͲ ͷͶͳ
4.2 New approaches for pathways validations
ʹͷ
ͷͶʹ
The carbohydrates uptake, transport, and substrate utilization capability of a probiotic
ͷͶ͵
bacterium is considered as a competitive edge in the host gut for microbial adaptation.
ͷͶͶ
For example, more than 10% of bifidobacterial genome encodes related enzymes and
ͷͶͷ
transporters (Schell et al. 2002). Different probiotic bacteria show capabilities of
ͷͶ
utilization of different sources of carbohydrates. For instance, Lactobacillus plantarum
ͷͶ
adapts to many different environments and thus it encodes a large number of enzymes for
ͷͶͺ
utilization of many different carbohydrates (Kleerebezem et al. 2003). Furthermore, most
ͷͶͻ
carbohydrate-digesting genes are present as gene clusters or as operons. The L.
ͷͷͲ
acidophilus msm operon is an example for FOS metabolism (Barrangou et al. 2003).
ͷͷͳ
Similar response might take place for probiotic organisms fermenting beta-glucans.
ͷͷʹ ͷͷ͵
The “omics approach” is a powerful tool to construct possible pathways from the
ͷͷͶ
knowledge of relative expression of particular biomolecules of interests. Omics
ͷͷͷ
methodologies comprise high-throughput techniques directed to understand the cell
ͷͷ
metabolism as one integrated system, rather than merely a collection of independent
ͷͷ
parts, by using information about the relationships between different molecules (Zhang et
ͷͷͺ
al., 2010). However, validation of any proposed metabolic pathways for prebiotic
ͷͷͻ
fermentation is the direct evidence and it is essential to confirm the function of all the
ͷͲ
participating biomolecules involved in the proposed pathways.
ͷͳ ͷʹ
In molecular biology, the golden standard method to determine the function of predicted
ͷ͵
genes and establish which genes are essential under specific environmental conditions is
ͷͶ
to disrupt the candidate genes and determine the phenotypic changes. However, in order
ʹ
ͷͷ
to perform such functional genomic investigations, it will be necessary to develop
ͷ
effective genetic tools such as highly efficient transformation protocols and to implement
ͷ
effective gene knockout methodologies for probiotics (Law et al., 1995; Serafini et al.,
ͷͺ
2012). Such reverse genetic approach can be exemplified by a recent review on lactic
ͷͻ
acid bacteria engineering (Bron & Kleerebezem, 2011).
ͷͲ ͷͳ
Recently, there is an increasing number of studies on the forward genetics investigation
ͷʹ
of probiotic bacteria, especially bifidobacteria by bacterial conjugation (Dominguez &
ͷ͵
O’Sullivan, 2013) with the machinery composed of an oriT sequence and tra genes
ͷͶ
(Smillie et al., 2010). There is also an earlier review on bacterial conjugation for Gram-
ͷͷ
positive bacteria (Schröder & Lanka, 2005). Other approaches including transformation,
ͷ
reporter systems, heterologous gene expression and mutagenesis, using bifidobacteria as
ͷ
an example, have been reviewed (Cronin et al., 2011). Most recently, a group of scientists
ͷͺ
described the generation of transposon insertion mutants in two bifidobacterial strains, B.
ͷͻ
breve UCC2003 and B. breve NCFB2258 and reported the creation of the first transposon
ͷͺͲ
mutant library in a bifidobacterial strain, using the B. breve UCC2003 and a Tn5- based
ͷͺͳ
transposome strategy (Ruiz et al., 2013). The usefulness of this library to perform
ͷͺʹ
phenotypic screenings was confirmed through identification and analysis of mutants
ͷͺ͵
defective in D-galactose, D-lactose or pullulan utilization abilities (Ruiz et al., 2013). The
ͷͺͶ
same group of scientists have also developed an efficient and reproducible conjugation-
ͷͺͷ
based gene transfer system for bifidobacteria based on the RP4 conjugative machinery in
ͷͺ
the Escherichia coli strain WM3064 (pBB109) and this novel conjugative gene transfer
ͷͺ
protocol can be used for the introduction of genetic material into Bifidobacterium species
ʹ
ͷͺͺ
and is particularly useful for strains that are recalcitrant to electroporation (Dominguez &
ͷͺͻ
O’Sullivan, 2013). With so many genetic tools being developed by different scientists,
ͷͻͲ
the function of particular genes or proteins can be elucidated with ease.
ͷͻͳ ͷͻʹ
In addition, massively parallel sequencing has been combined with traditional transposon
ͷͻ͵
mutagenesis (Van Opijnen & Camilli, 2013). These techniques can be referred to as
ͷͻͶ
transposon sequencing (Tnಣseq), highಣthroughput insertion tracking by deep sequencing
ͷͻͷ
(HITS), insertion sequencing (INSeq) and transposonಣdirected insertion site sequencing
ͷͻ
(TraDIS), making it possible to identify putative gene functions in a highಣthroughput
ͷͻ
manner (Van Opijnen & Camilli, 2013).
ͷͻͺ ͷͻͻ
4.3 Molecular mechanism of beta-glucan fermentation at protein level
ͲͲ
Carbohydrates are biomolecules involved in many life processes such as metabolism,
Ͳͳ
structural support, energy storage, antibiosis, immunological recognition, targeting,
Ͳʹ
attachment, etc. To exert these multiple cellular functions, several carbohydrate-active
Ͳ͵
proteins have acquired non-catalytic modules that interact very specifically with mono-,
ͲͶ
oligo-, and polysaccharides. In general, these carbohydrate-binding modules (CBM) are
Ͳͷ
auxiliary domains with autonomous folding and skilled recognition of the heterogeneous
Ͳ
and complex carbohydrate arrangement (Boraston et al. 2004).
Ͳ Ͳͺ
In carbohydrate-active enzymes (CAZymes) like glycoside hydrolases or glycosyl
Ͳͻ
transferases, CBMs can be localized at the N- or C-terminal end of these proteins (Abe et
ʹͺ
ͳͲ
al. 2004; Juge et al. 2002). Certainly, the main function of CBMs is to recognize and bind
ͳͳ
specifically to carbohydrates. The biological consequences of this event result in different
ͳʹ
functions, such as increased hydrolysis of insoluble substrates, bringing the catalytic
ͳ͵
domain in close proximity to the substrate, substrate structure disruption, and so on
ͳͶ
(Guillén et al., 2010). Relevant information on CBM, focusing on the biological
ͳͷ
importance of CBMs–ligand interactions, including the basis of modern classification and
ͳ
the function of these versatile proteins, can be found in a comprehensive review (Guillén
ͳ
et al., 2010). Enzymes that are believed to function against beta-glucans include
ͳͺ
endoglucanases and exoglucanases (Boraston et al. 2002; Cosgrove 2005; Barral et al.
ͳͻ
2005). CBMs have been classified based on amino acid similarity. In the latest update of
ʹͲ
the CAZY database (July 3rd, 2013), a total of 30,581 CBMs were grouped into 67
ʹͳ
families (http://www.cazy.org). The information in this database is continuously updated
ʹʹ
so that new families are frequently added (Cantarel et al. 2009). Among all the different
ʹ͵
types of CBMs, Type B CBMs is responsible for the recognition of substrates like beta-
ʹͶ
(1, 3)- glucans, mixed beta-(1,3)(1,4)-glucans, beta-1,4-mannan, glucomannan, and
ʹͷ
galactomannan (Boraston et al, 2002; Guillén et al., 2010).
ʹ ʹ
A very good example of beta-glucan catabolic enzymes is the Family 3 of glycosyl
ʹͺ
hydrolases (GH3), which consists of nearly 44 beta-glucosidases and hexosaminidases
ʹͻ
from bacteria, molds, and yeasts. Most of the fungal beta-glucosidases studied belong to
͵Ͳ
GH3. Structural data on representatives of GH3 are still scarce, since only three of their
͵ͳ
structures are known and only one of them has been thoroughly characterized, which is
͵ʹ
the beta-D-glucan-(exo1-3, 1-4)-glucanase (Exo 1) from Hordeum vulgare, which
ʹͻ
͵͵
catalyzes the hydrolysis of cell-wall polysaccharides (Bhatia et al., 2002). The enzyme
͵Ͷ
consists of N-terminal (alpha/beta) 8 trans-membrane barrel domain and a C-terminal
͵ͷ
domain of six stranded beta sandwich. The non-homologous region, a helix-like strand of
͵
16 amino acid residues, connects the two domains (Bhatia et al., 2002). The catalytic
͵
center is located in the pocket at the interface of the two domains with Asp285 in the N-
͵ͺ
terminal domain acting as a catalytic nucleophile, while Glu491 in the C-terminal domain
͵ͻ
acting as a proton donor (Varghese et al., 1999). A more detailed discussion on glycosyl
ͶͲ
hydrolases (GH) such as classification, different structure isoforms and cloning
Ͷͳ
approaches, can be found in a recent review by Singhania and others (Singhania et al,
Ͷʹ
2013). Moreover, an earlier review on the carbohydrate-binding module (CBM) for
Ͷ͵
alpha-glucans might shed light on the future studies on beta-glucans CBM using similar
ͶͶ
approaches such as in silico prediction (such as the prediction of the CBMs from the
Ͷͷ
amino acid sequence of proteins, based on homology of conserved sequences),
Ͷ
evolutionary analysis, three-dimensional structure analysis, docking, determination of the
Ͷ
binding constants, stoichiometry, and thermodynamics (Christiansen et al, 2009).
Ͷͺ Ͷͻ
Further studies on the roles played by particular enzymes or transporters in probiotics
ͷͲ
especially at a protein level during fermentation of beta-glucans are required.
ͷͳ ͷʹ
5. Conclusion and future perspectives
ͷ͵
The introduction of functional compounds like prebiotics in the diet seems to be an
ͷͶ
attractive alternative to ameliorate the quality of life ridden with obesity, cancer,
ͷͷ
hypersensitivity, vascular diseases and degenerative ailments. For example, beta-glucans
͵Ͳ
ͷ
have demonstrated beneficial effects to human health especially due to their immune-
ͷ
stimulatory effects. There is also an accumulating evidence suggesting beta-glucans as
ͷͺ
potential source of prebiotics. However, the molecular mechanism behind how the beta-
ͷͻ
glucans are being utilized by specific probiotics is still not fully understood. The
Ͳ
employment of the “omics approach”, forward or reverse genetic approach and deeper
ͳ
understanding of the mechanism at a protein level may shed light to the detailed function
ʹ
of the beta-glucans as prebiotics.
͵ Ͷ
Also, modification of the chemical structure of prebiotics might alter their bioactivities.
ͷ
Modification of beta-glucans has not yet received much attention in the field of prebiotic
research. Physical (reduction in molecular mass, branching), chemical (addition of
functional groups), and biochemical (enzymatic treatment) modifications might enhance
ͺ
the probiogenic property of beta-glucans. It is anticipated that the potential use of beta-
ͻ
glucans as prebiotics will continue to draw much attention in the near future.
Ͳ
͵ͳ
ͳ
Figure captions
ʹ
Figure 1: Schematic representation of the proposed catabolic pathway of beta-glucans
͵
by B. infantis. Enzymes involved in the carbohydrate catabolism are denoted by numbers:
Ͷ
1, glucokinase; 2, glucose-6-phosphate isomerase; 3, fructose-6-phosphate
ͷ
phosphoketolase; 4, transaldolase; 5, transketolase; 6, ribose 5-phosphate isomerase; 7,
ribulose 5-phosphate epimerase; 8, xylulose-5-phosphate phosphoketolase; 9, acetate
kinase; 10, glyceraldehyde-3-phosphate dehydrogenase; 11, phosphoglycerate kinase; 12,
ͺ
phosphoglycerate mutase; 13, enolase; 14, pyruvate kinase; 15, lactate dehydrogenase,
ͻ
16, pyruvate formate lyase. Numbers circled in red denote the proteins identified in this
ͺͲ
study with different abundances among treatments (adapted from Zhao & Cheung, 2013).
ͺͳ
EPS: exo-polysaccharides; E I: enzyme E I; EIIA: enzyme E II A; EIIBC: enzyme E II B
ͺʹ
& C; HPr: histidine protein/heat-stable protein; P: a phosphate group; PEP:
ͺ͵
phosphoenolpyruvate.
͵ʹ
ͺͶ
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ͳ͵͵
ͷ
ͳ͵Ͷ
Figures and Tables
ͳ͵ͷ ͳ͵
Figure 1
ͳ͵ Source
Genetically engineered,
beta-(1, 3)-D-glucan with beta-(1, 6) branching, at
Yeast, Saccharomyces cerevisiae
Seaweed: Laminaria species
PGG (betafectin),
pharmaceutical grade
Laminarin
Betafectin is a soluble
20-25 glucose units
zymocel
little beta-(1, 6) branching
cerevisiae
zymosan
Crude beta-glucan extract
high beta-(1, 6) branching
beta-(1, 3)-D-glucan with
Yeast, Saccharomyces
Zymocel, purified
& Fiore, 1958;
non-uniform branches
Read et al., 1996;
Kuda et al., 1992 ;
al., 1998
1998; Michalek et
Kernodle et al.,
2008;
Volman et. al
Suzuki et al, 1996;
Miura et al., 1999
1941; Di Carlo
Pillemer & Ecker,
Reference
beta-glucan and mannan
hydrolysis product from
little beta-(1, 6) branching
cerevisiae
Crude extract with
Remarks
beta-(1, 3)-D-glucan with
beta-(1, 3)-D-glucan with
Zymosan
Yeast, Saccharomyces
Structure
Source and chemical structure of some native and modified beta-glucans
Beta-glucans from plant and yeast/fungi
Beta-glucans
Table 1
cerevisiae
zymosan, OX-ZYM
Yeast, Saccharomyces
(1, 6-)-linked glucan
beta-(1, 3)-linked and beta-
glucan
Gram negative bacteria, Alcaligenes faecalis
Unbranched beta-(1, 3)-D-
beta-(1, 3)-D-glucan
Exopolysaccharide of
(a Basidiomycetes sp.)
sclerotia of Poria cocos
Hypochlorite oxidized
Modified beta-glucans
Curdlan
Pachyman
the 3:1 ratio
moiety about 10–50,
DP of beta-(1, 6)-glucan
ͺ
Ohno et al., 2001
Miura et al., 1996;
Zhan et al., 2012
& Cheung, 2011;
et. al 2008; Zhao
al., 2001; Volman
1968; Shimizu et
Harada et al.,
Bian et al., 2010
Wong et al., 2005;
Ding et al., 1998;
Cheung, 2011
1974; Zhao &
Nelson & Lewis,
DS about 0.28-0.54 using
Sclerotia of Pleurotus tuber-regium
Same as pachyman
Sulphated beta-glucans
(pleuran)
Carboxymethylated
curdlan
Carboxymethylated
pachyman
Same as curdlan
(1, 3)-D-glucan
cerevisiae
al., 1995; Volman
(C6H10O5)7·PO3H2
1979; Sasaki et al., 1978; Na et
chloroacetic acid for carboxymethylation
Sasaki et al.,
Stone, 1969
carboxymethylation DS about 0.4 to 0.65 using
1962; Barras &
ͻ
Clarke & Stone,
Zhao et al., 2006
et. al 2008
1991; Müller et
William et al.,
formula is
Repeating-unit empirical
chloroacetic acid for
DS about 0.2 to 0.4 using
pyridine complex
with chlorosulfonic acid –
Synthetic modified, beta-
Yeast, Saccharomyces
Glucan phosphate, GluP
oxidation
solubility increased after
residues, every 4th being substituted with single Dglucopyranosyl groups
P. tuberregium, and P. pulmonarius
600,000 and 700,000 Da
ostreatus or genus Pleurotus, linked D-glucopyranosyl
name: Imunoglukan) P. eryngii, P. ostreatoroseus,
Molecular mass between
Backbone of beta-(1, 3)-
Oyster mushroom Pleurotus
Pleuran (commercial
combination of these
al., 2010;
2006; Baggio et
ͺͲ
Carbonero et al.,
Zhang et al., 2003;
Kuniak, 1994;
Karácsonyi &
& Miller, 1994
glycerol, succinic acid, methylmalonic acid, or a
1996; Breedveld
with sn-1-phospho-
Gonzalez et al.,
Roset et al., 2006;
Brucella sp.
and cyclic beta-(1, 2)-
Cogez et al., 2002;
backbones substituted
cyclic beta-(1, 2)-glucan
Rhizobium,
17–25 glucose residues;
Sinorhizobium, and
Heterogeneously sized
Agrobacterium,
Beta-glucans from macrofungi/mushrooms
Cyclic beta-(1, 2)-glucans
al., 2000
frondosa
name: GRN)
Maitake mushroom Grifola
stranded helix form bears
beta-(1, 3) linkages, triple
Mao et al., 2007;
ͺͳ
approximately 450,000 Da Tada et al., 2009
Molecular mass of
2013
structure
Grifolan, (common
2007; Zhang et al.,
Van & Teramoto,
residue, triple helical
450,000 Da
Van et al., 1984;
1982; Kony et al.,
beta-(1, 6) branching at
commune
sizofiran, SPG
Molecular mass of about
approximately every third
Beta-(1, 3)-D-glucan with
Fungus, Schizophyllum
linkages
linked by beta-(1, 6)
al., 2011
2000; Brauer et
to 2 molecules of glucose
molecular mass
Ooi and Liu,
al., 2010; Zhang et
backbone linked by beta-
Lentinula edodes
Have great divergence in
(1, 3) linkages connected
5 molecules of glucose in
Shiitake mushroom
Schizophyllan,
Lentinan, LNT
2011
Bergendiov et al.,
20K, PSG, Gl-1)
Ganoderan, (MW
beta-(1, 3)-glucan
al., 2008; Rop et al., 2009
immunomodulatory proteins) and GPP
ͺʹ
2007; Volman et
(fungal
(Ganoderma
2000; Zhou et al.,
Ooi and Liu,
al., 2007
2000; Moradali et
Ooi and Liu,
proteins, known as FIMs
Consists of 4% of
Da
molecular mass is 100,000
Ganoderma lucidum
Proteoglucan that contains
K)
beta-(1, 3)-D-glucan
2008
beta-(1, 6) branches
25–38% of proteins,
Coriolus versicolor
Crestin, (common
Volman et. al
beta-(1, 3)-D-glucan with
name: polysaccharide
Glomerella cingulata
Glomerellan
curdlan
(1, 3)-glucans such as
resemblance to other beta-
ͳ͵ͻ
ͳ͵ͺ
Chaga extract beta-(1, 6) branches
polysaccharide of Inonotu obliquus
beta-(1, 3)-D-glucans with
Mycelial endoWater soluble
polysaccharides peptide)
ͺ͵
Rhee et al., 2008
Chen et al., 2007;
Zjawiony, 2004;
ͳͶͳ
ͳͶͲ
Recent studies of beta-glucans as prebiotics in the last 4 years.
elucidated, including ABC transporter for sugars, enolase, and phosphotransferase
different beta-glucans with pure culture of Bifidobacterium infantis (JCM 1222) for a 24 h followed by 2 dimensional gel electrophoresis and MALDI-TOF analysis, validated by real-time RT-PCR & enzyme activity assay
(Laminarin), barley
beta-glucan,
mushroom beta-
glucan prepared from
the sclerotia of
Pleurotus tuber-
native liquid form of the extract, not the
liquid/spray-dried fucoidan and laminarin extract, studied the effects on
Laminaria digitata
were higher in the ileum of pigs fed the
Supplementing animal feed with a
Counts of lactobacilli and bifidobacteria
beta-glucans in B. infantis is proposed
Laminarin from
regium
Enzymes and transporters participated are
in vitro batch fermentation of the 3
Seaweed beta-glucan
system protein; a model for catabolism of
Major findings
Method
Source
Basic research studies
Table 2
2013
Murphya et al,
2013
Zhao & Cheung,
Reference
ͺͶ
Low concentration (0.1% to 0.5%) of polysaccharides enhance the survival rate of
Mushroom polysaccharides with different concentration incubated with probiotics bacteria and check vability after cold storage of 28 days
Mixture of
polysaccharides from
Lentinula edodes,
Pleurotus eryngii, and
significant decrease of number of Enterobacteriaceae decreased, both in a dose-dependent manner
groups of 40 rats each, control group fed with saline, and 4 groups fed with oat & barley derived beta-glucans intragastric gavaged at a dose of 0.35 g/
commercial oat bran
or naked barley
based animal feed with endogenous
based diets vs. oats
Supplementing barley based & oat-
Formulated barley-
for 6 weeks
kg of body weight and 0.70 g/kg daily
Significant increase of population of
200 male rats were divided into 5
Oat & barley from
populations of lactobacilli, higher counts of
Oat based diet gave most diverse
Lactobacillus and Bifidobacterium &
longum during cold storage
Flammulina velutipes
casei, and Bifidobacterium longum subsp.
Lactobacillus acidophilus, Lactobacillus
spray-dried one
the porcine gastrointestinal microbiota
ͺͷ
Murphy et al., 2012
Shen et al., 2012
Chou et al., 2013
diets
beta-glucanase and endo-1, 4-beta-
Bifidobacterium genus with 0.3- 0.7 log10 cells/ml increase & Lactobacillus 0.7 to 1 log10 cells/ml increase
carbon sources in the 1L batch fermentation with Bifidobacterium pseudocatenulatum G4, B. longum BB536 and B. breve ATCC 15700 for 24h in 37oC with glucose used as
Ganoderma lucidum
(including beta-D-
glucans,
heteropolysaccharides
and glycoproteins)
glucans of bacterial origin & all the
WCFS1, L. acidophilus strain NCFM,
(EPS), mainly beta-
Demonstrated prebiotic action of a beta-
Growth kinetics of L. plantarum strain
Exo-polysaccharides
control
growth of probiotics with population of
Crude polysaccharides were used as
Polysaccharides from
explored Polysaccharide mixtures supported the
caecum and colon than the barley-based
enzyme supplementation (endo-1, 3-
xylanase) in both diets was also
Bifidobacterium counts in the ileum,
gastrointestinal microbiota, effect of
intrinsic beta-glucans
Lactobacillus in the caecum and colon and
beta-glucans on the 28 porcine
based diets with
ͺ
Russo et al., 2012
Yamin et al., 2012
Bifidobacterium longum, and
a relatively larger increase in populations
Bifidobacterium infantis,
mushroom sclerotia
2011
three bifidobacteria with B. infantis, having
were incubated with pure cultures of
bacteria, and
storage.
Bulgaricus)
All beta-glucans supported the growth of the Zhao & Cheung,
high viability (>108 cfu/mL) during 28 days
and Lactobacillus delbrueckii ssp.
strain
Beta-glucans from different sources
recombinant probiotic strain maintaining
cultures (Streptococcus thermophilus
paracasei NFBC 338
ͺ
Kearney et al., 2011
Barley, seaweed,
yoghurt cultures were found, with the
synergistic effect
glucose, EPS or both
Lactobacillus strain and 2 other yoghurt
into stationary phase, suggesting a
supplementing the same medium with
Lactobacillus
EPS as carbon sources delayed the entry
absence of carbon source or
No effect on growth and viability of the
simultaneous availability of D-glucose and
WCFS1-gal) were evaluated either in
Yoghurt with beta-glucan producing
consume beta-glucans for growth;
the -galactosidase gene (L. plantarum
Pediococcus parvulus
Recombinant
investigated bacterial strains were able to
recombinant strain that overexpresses
glucan, produced by
but later fermented rapidly with little remaining in the final half of the fermentation period
dietary fibers, including long-chain inulin, psyllium, the alkali-soluble fraction of corn bran arabinoxylan and
Barley & oat
Oat fiber
gas and short chain fatty acid production,
various purported slowly fermentable
beta-glucan type & exogenous enzyme
Endogenous beta-glucans had higher
of probiotic bacteria
starch and probiotics (B. breve & B. longum)
Addition beta-glucan improve the survival
Yogurt with beta-glucan, modified corn
long-chain beta-glucan
slower fermenting with comparatively low
of starch-entrapped microspheres, with
flour
Long-chain beta-glucan initially appeared
Comparison of fermentation properties
Corn bran and barley
positive control
bifidogenic effect with inulin as the
batch fermentation to evaluate their
Bifidobacterium adolescentis for a 24 h
Reilly et al, 2010
ͺͺ
Rosburg et al, 2010
Kaur et al., 2011
intervention but no significant increase in Bifidobacteria and Lactobacilli
(placebo group), for 3 months to determine the effect of barley-derived beta-glucans in the gut microbiota of
Barley
concentration on the 90th day of the
beta-glucans (3 g/d), or without
Zurich, Switzerland
Daily intake of food containing barley betaglucan is well-tolerated and barley beta-
in vivo prebiotic efficacy of barley betaglucans in human fecal microbiota
polypectomized patients
decrease of Clostridium perfringens
consume 125 g of bread per day with
Switzerland Ltd.,
on the 30th day of the trial & significant
20 subjects were randomly assigned to
and mineral metabolism in pigs
Significant decrease in total coliform counts
commercial purified beta-glucans
concentrations, nutrient digestibility,
Barley, DKSH
Clinical studies
pigs offered diets supplemented with
populations, volatile fatty acid
indole and skatole levels in the digesta
populations of Bifidobacterium compared to
supplementation on microbial
ͺͻ
Mitsou et al., 2010
Turunen et al., 2011
ͳͶ͵
ͳͶʹ
volunteers
clinical trial in 52 human healthy
double-blinded, placebo-controlled
specimen by conducting a randomized,
glucan induced a strong bifidogenic effect
ͻͲ
Non-digestible long chain beta-glucans as novel prebiotics (Review) Ka-Lung Lam, Peter Chi-Keung Cheung
www.elsevier.com/locate/bcdf
PII: DOI: Reference:
S2212-6198(13)00032-6 http://dx.doi.org/10.1016/j.bcdf.2013.09.001 BCDF24
To appear in: Bioactive Carbohydrates and Dietary Fibre
Received date:10 July 2013 Revised date: 3 September 2013 Accepted date: 4 September 2013 Cite this article as: Ka-Lung Lam, Peter Chi-Keung Cheung, Nondigestible long chain beta-glucans as novel prebiotics (Review), Bioactive Carbohydrates and Dietary Fibre, http://dx.doi.org/10.1016/j.bcdf.2013.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ͳ
Non-digestible long chain beta-glucans as novel prebiotics (Review)
ʹ ͵
Ka-Lung Lam and Peter Chi-Keung Cheung*
Ͷ
Food and Nutritional Sciences, School of Life Sciences, The Chinese University of Hong
ͷ
Kong, Shatin, Hong Kong SAR, China
*Corresponding author:
ͺ
Peter C.K. Cheung, University Science Centre, School of Life Sciences, The Chinese
ͻ
University of Hong Kong, Shatin, New Territory, HKSAR, China
ͳͲ ͳͳ
Email: [email protected]
ͳʹ
Tel.: 852-3943 6272
ͳ͵
Fax: 852-2603 5745
ͳ
ͳͶ
Abstract
ͳͷ
As our understanding of host gut microbiome increases, research interests in the fields of
ͳ
prebiotics, probiotics and synbiotics are growing rapidly. Currently, the majority of
ͳ
prebiotics in the markets are derived from non-digestible oligosaccharides. Very few
ͳͺ
investigations have been focused on non-digestible long chain complex
ͳͻ
carbohydrates/polysaccharides for their potential as novel prebiotics. One of the reasons
ʹͲ
behind this is the unavailability of non-digestible polysaccharides that can fulfil the
ʹͳ
criteria as prebiotics. Beta-glucans that exist as non-digestible polysaccharides derived
ʹʹ
from different food sources have demonstrated not only health promoting effects, but also
ʹ͵
the potential as a novel source of prebiotics. This review commences with the current
ʹͶ
trends in the research fields of prebiotics, probiotics and synbiotics. This is followed by a
ʹͷ
discussion of the potential of long chain beta-glucans to serve as novel prebiotics based
ʹ
on current knowledge on their sources, preparation, fermentation characteristics, and the
ʹ
plausible mechanisms involved in their utilization. Some future research directions with
ʹͺ
emphasis on new approaches using molecular biology, genetics and genomics are also
ʹͻ
discussed.
͵Ͳ ͵ͳ ͵ʹ ͵͵ ͵Ͷ
Keywords: Beta-glucans, complex carbohydrates, non-digestiblity, polysaccharides,
͵ͷ
prebiotics, probiotics, synbiotics
ʹ
͵
Abbreviations
͵
ABC
ATP-binding cassette
͵ͺ
CAZymes
carbohydrate-active enzymes
͵ͻ
CBM
carbohydrate-binding module
ͶͲ
DB
degree of branching
Ͷͳ
DP
degree of polymerization
Ͷʹ
EPS
exo-polysaccharides
Ͷ͵
EI
enzyme E I
ͶͶ
EIIA
enzyme E II A
Ͷͷ
EIIBC
enzyme E II B & C
Ͷ
FOS
fructo-oligosaccharides
Ͷ
GOS
galacto-oligosaccharide
Ͷͺ
GH
glycosyl hydrolases
Ͷͻ
HITS
high-throughput insertion tracking by deep sequencing
ͷͲ
HPr
histidine protein/heat-stable protein
ͷͳ
IMO
isomaltooligosaccharides
ͷʹ
INSeq
insertion sequencing
ͷ͵
MW
molecular weight
ͷͶ
P
a phosphate group
ͷͷ
PEP
phosphoenolpyruvate
ͷ
PI
prebiotic index
ͷ
PTS
phosphotransferase system
ͷͺ
RT-PCR
reverse transcription polymerase chain reaction
͵
ͷͻ
SCFAs
short chain fatty acids
Ͳ
Tnಣseq
transposon sequencing
ͳ
TraDIS
transposonಣdirected insertion site sequencing
ʹ
XOS
xylooligosaccharides
Ͷ
͵
1. Introduction
Ͷ
Gut microbiome and host interaction is getting more attention nowadays and it is
ͷ
estimated that each individual harbors at least 160 microbial species from a consortium of
1000 to 1150 prevalent bacterial species (Ley et al., 2006; Qin et al., 2010; Marchesi,
2011). Moreover, it is accepted that this “small world within” provides important
ͺ
metabolic functions that cannot be performed by our human metabolic processes (Jia et
ͻ
al., 2008). In 2011, a review coined the term “MicrObesity” (Microbes and Obesity),
Ͳ
demonstrating the importance of gut microbiome to humans (Cani & Delzenne, 2011). In
ͳ
order to reestablish the bacterial homeostasis, one common approach is to employ the use
ʹ
of prebiotics, probiotics, and synbiotics (Vyas & Ranganathan, 2012). There have been a
͵
number of recent reviews on the effects of pre- and pro-biotics on human and animal
Ͷ
health (Ogueke et al., 2010; Ohimain & Ofongo, 2012; Chauhan and Chorawala, 2012;
ͷ
Licht et al., 2012: Ganguly et al, 2013; Saad et al., 2013).
Nowadays, the majority of prebiotics sold in the market are non-digestible
ͺ
oligosaccharides. Inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS),
ͻ
lactulose and polydextrose are recognized as the well established prebiotics, whereas
ͺͲ
isomaltooligosaccharides (IMO), xylooligosaccahrides (XOS), and lactitol are
ͺͳ
categorized as emerging prebiotics (Sabater-Molina et al., 2009; Femia et al., 2010; Xu et
ͺʹ
al., 2009). Other non-digestible oligosaccharides and sugar alcohols such as mannitol,
ͺ͵
maltodextrin, raffinose, and sorbitol have also demonstrated prebiotic properties and
ͺͶ
health benefits (Yeo and Liong, 2010; Vamanu and Vamanu, 2010; Mandal et al., 2009).
ͺͷ
However, there are few investigations on non-digestible long chain complex
ͷ
ͺ
carbohydrates as potential prebiotics. Resistant starch-rich whole grains can be
ͺ
considered as having prebiotic action since they are not absorbed in the small intestine of
ͺͺ
healthy individuals but are later fermented by gut microflora to produce short chain fatty
ͺͻ
acids (SCFAs) (Vaidya and Sheth, 2010). However, resistant starch is more regarded as a
ͻͲ
colonic food instead of a typical prebiotics because of its non-selective fermentation by
ͻͳ
all colonic bacteria and not just by probiotic bacteria (Ogueke et al., 2010). Colonic foods
ͻʹ
are defined as foods that are capable to reach the large intestine and also serve as
ͻ͵
substrate for the endogenous microorganisms (Gibson and Roberfroid, 1995).
ͻͶ
Nevertheless, there are still some non-digestible long chain complex carbohydrates that
ͻͷ
are candidates as potential prebiotics. Longer chain prebiotics can sometimes be referred
ͻ
as “slowly fermentable” substrates. Previous studies on potential slow fermentable
ͻ
substrates include long chain inulin (Van de Wiele et al., 2007), psyllium (Morita et al.,
ͻͺ
1999), arabinoxylan, an alkali-soluble polymeric fraction of corn bran (Rose et al., 2010),
ͻͻ
and long chain beta-glucan (Hughes et al., 2008). Fermentation studies of beta-glucans
ͳͲͲ
can indeed shed light on the possible use of beta-glucans as a novel source of long chain
ͳͲͳ
prebiotics. For example, the fermentability of oat beta-glucan to produce SCFAs points to
ͳͲʹ
their potential application as a prebiotic in promoting human health (Lin et al., 2011).
ͳͲ͵ ͳͲͶ
Therefore, the aims of this review were to summarize the latest findings on prebiotic
ͳͲͷ
research; to explore the potential of non-digestible long chain beta-glucans as a new
ͳͲ
source of prebiotics, to unravel the mechanism of their utilization by probiotic bacteria;
ͳͲ
and to suggest some future research directions.
ͳͲͺ
ͳͲͻ
2. Current research on probiotics, prebiotics and synbiotics
ͳͳͲ
2.1 Probiotics
ͳͳͳ
Probiotics are defined as “preparations of or products containing viable, defined
ͳͳʹ
microorganisms in sufficient numbers, which alter the microflora (by implantation or
ͳͳ͵
colonization) in a compartment of the host and by that exert beneficial health effects in
ͳͳͶ
this host” (Schrezenmeir & De Vrese, 2001). A microorganism to be qualified as a
ͳͳͷ
probiotic, a number of selection criteria have to be met. Firstly, it has to be safe for
ͳͳ
human consumption, not conferring any pathogenic or toxic effects; secondly, it would be
ͳͳ
better to be originated from the intestinal tract of healthy persons so that such
ͳͳͺ
microorganisms are regarded safe for humans and best adapted to the ecology of the gut;
ͳͳͻ
thirdly, it has to be tolerant to gastric and bile acids as well as sufficiently resistant to
ͳʹͲ
digestive enzymes to enable its survival after passing the intestinal tract; and lastly,
ͳʹͳ
allowing the detection of parameters confirming a positive influence on the intestinal
ͳʹʹ
flora such as viability, adhesion to intestinal epithelial cells, and capability of
ͳʹ͵
reproduction in the human intestine (De Vrese & Schrezenmeir, 2008). A permanent
ͳʹͶ
colonization of probiotic bacteria in the large bowel is not required for attaining their
ͳʹͷ
probiotic effects, as far as there is a daily or regular bacteria supplementation (De Vrese
ͳʹ
& Schrezenmeir, 2008). Several microorganisms have been considered or used as
ͳʹ
probiotics including fungi (particularly mushroom), yeast, bacteria or mixed
ͳʹͺ
combinations. Two genera of bacteria that are mostly reported as probiotics include lactic
ͳʹͻ
acid bacteria of the genus Lactobacllus and Bifodobacterium (Ohimain & Ofongo, 2012).
ͳ͵Ͳ
ͳ͵ͳ
Generally, probiotic cultures must be consumed at a level of at least 107 CFU/mL to
ͳ͵ʹ
provide the therapeutic benefits mentioned above (Lourens-Hattingh and Viljoen, 2001).
ͳ͵͵
The beneficial effects of regular consumption of probiotics include disease fighting and
ͳ͵Ͷ
prevention, nutrients absorption enhancement and other health promoting consequences
ͳ͵ͷ
(De Vrese & Schrezenmeir, 2008), with validity of scientific proofs being summarized.
ͳ͵
Sekhon and Jairath updated a list of all common probiotics and proven probiotic strains
ͳ͵
with brand name and producer in their recent review (Sekhon & Jairath, 2010).
ͳ͵ͺ
Moreover, there is an increasing diversity of probiotics being investigated in different
ͳ͵ͻ
fields. For instance, Vyas and Ranganathan presented an emerging field of probiotic
ͳͶͲ
investigation on myocardial infarction, the influence of gut microbiota alternation on
ͳͶͳ
brain and behavior, genetic disorders such as Familial Mediterranean Fever, and in
ͳͶʹ
psychological studies such as autism (Vyas & Ranganathan, 2012).
ͳͶ͵ ͳͶͶ
2.2 Prebiotics
ͳͶͷ
Prebiotics are defined as “non-digestible food ingredients that beneficially affect the host
ͳͶ
by selectively stimulating the growth and/or activity of one or a limited number of
ͳͶ
bacteria in the colon” (Gibson and Roberfroid, 1995). Recently, bioactive long chain
ͳͶͺ
complex carbohydrates (polysaccharides) from various plant materials, such as cereal,
ͳͶͻ
mushrooms, herbs, chicory root, citrus, soybeans, and potatoes, are gaining attention as
ͳͷͲ
new prebiotic alternatives (Chou et al., 2013; Gullón et al, 2013). Apart from plant origin,
ͳͷͳ
prebiotics can be synthesized by some microorganisms, mainly the exo-polysaccharides
ͳͷʹ
(EPS) from probiotic strains (Patterson & Burkholder, 2003; Patel et al., 2010; Stack et
ͳͷ͵
al., 2010). Furthermore, many research studies have indicated that polysaccharides
ͺ
ͳͷͶ
obtained from mushrooms such as Pleurotus sp. (Synytsya et al, 2009), Lentinus edodes,
ͳͷͷ
Tremella fuciformis (Guo et al, 2004), and Agaricus bisporus (Giannenas et al., 2011)
ͳͷ
have prebiotic activity. The active component is believed to be the long chain beta-
ͳͷ
glucans, including homo- and hetero-glucans with Ǫ (1ψ3), Ǫ (1ψ4), and Ǫ (1ψ6)
ͳͷͺ
glucosidic linkages (Manzi & Pizzoferrato, 2000).
ͳͷͻ ͳͲ
Current research on prebiotics has demonstrated their diverse health implications
ͳͳ
including gut health maintenance, colitis prevention, cancer inhibition, immune-
ͳʹ
potentiation, cholesterol removal, reduction of cardiovascular disease, prevention of
ͳ͵
obesity and constipation, restoration of vaginal ecosystem, bacteriocin production as well
ͳͶ
as food applications including starter culture formulations as well as in pet food and fish,
ͳͷ
poultry, pig, and cattle feed (Patel & Goyal, 2012). Nakamura and Omaye reviewed the
ͳ
potential of the involvement of intestinal bacteria in host metabolism and the preventative
ͳ
and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases
ͳͺ
such as obesity and Type II diabetes (Nakamura & Omaye, 2012). Shen and others
ͳͻ
recently have reviewed the potential of prebiotic intervention in gestational diabetes
ͳͲ
(Shen et al., 2013). Macfarlane and others focused on the prebiotic effects on human gut
ͳͳ
functions and concluded that oligofructose, galacto-oligosaccharides and lactulose could
ͳʹ
significantly alter the large bowel microbiota by increasing the population of
ͳ͵
Bifidobacterium sp. and Lactobacillus sp. (Macfarlane et al, 2006). A most recent review
ͳͶ
on the effects of the intake of prebiotics on human health with evidence-based clinical
ͳͷ
studies and the mechanisms behind their beneficial effects has been published (Slavin,
ͳ
2013). More importantly, all these authors have pointed out that research on prebiotics is
ͻ
ͳ
still at its infancy and the potential for them to modify the gut microbial balance in such a
ͳͺ
way as to bring health benefits inexpensively and safely to humans is emerging.
ͳͻ ͳͺͲ
The conventional methodologies for the production of non-digestible oligosaccharides by
ͳͺͳ
extraction and purification procedures are summarized in a review by Mussatto and
ͳͺʹ
Manciha (Mussatto & Mancilha, 2007). In addition to these traditional methods, some
ͳͺ͵
novel biotechnological approaches using recombinant enzymes, enzyme/cell
ͳͺͶ
immobilization or recombinant bacterial strains for the production of different prebiotics
ͳͺͷ
have been reviewed recently (Panesar et al., 2012). When probiotics are incorporated into
ͳͺ
food products, culture viability often decreases as a result of pH reduction, temperature
ͳͺ
lowering, nutrients inadequacy, and oxidative stress. These challenges could be
ͳͺͺ
ameliorated by the addition of prebiotics into the food matrix (Bruno et al., 2002;
ͳͺͻ
Corcoran et al., 2004; Capela et al., 2006). Further details of the technological application
ͳͻͲ
of prebiotics in this respect can be referred to a recent review by Mohammadi &
ͳͻͳ
Mortazavian (2011). Using probiotic-fermented milks as example, issues on the effects of
ͳͻʹ
the viability of probiotics, sensory attributes, physicochemical and rheological
ͳͻ͵
characteristics of the fermented milks have been addressed (Mohammadi & Mortazavian
ͳͻͶ
2011).
ͳͻͷ ͳͻ
The recommended doses of fifteen different prebiotics for healthy individuals and
ͳͻ
patients, ranging from 1-15g/day, have been suggested recently (Singh et al., 2012). To
ͳͻͺ
further evaluate the prebiotic effect, a ‘‘prebiotic index’’ (PI = E/A), which is defined as
ͳͻͻ
‘‘The increase in bifidobacteria expressed as the absolute number of “new” cfu/g of feces
ͳͲ
ʹͲͲ
(E) divided by the daily dose (g) of prebiotic ingested (A)” has been proposed
ʹͲͳ
(Roberfroid, 2007). PI is commonly used as a standard for the comparison of different
ʹͲʹ
prebiotic effects among different prebiotic carbohydrates.
ʹͲ͵ ʹͲͶ
2.3 Synbiotics
ʹͲͷ
The term synbiotics refers to products containing both probiotics and prebiotics. This
ʹͲ
term should be reserved for products in which the prebiotic substances are selectively
ʹͲ
utilized by the probiotic bacteria (Schrezenmeir & De Vrese, 2001). It has been pointed
ʹͲͺ
out in a recent review that the health effects, including modulation of intestinal flora,
ʹͲͻ
cancer prevention, immunomodulation, prevention of sepsis and bacterial translocation of
ʹͳͲ
certain potential synbiotics on animals and humans did show that the combinations of
ʹͳͳ
prebiotics and probiotics were more effective than placebo products (De Vrese &
ʹͳʹ
Schrezenmeir, 2008).
ʹͳ͵ ʹͳͶ
Based on previous clinical investigations, the applications of synbiotics in integrative
ʹͳͷ
medicine and human health include the restoration of the immune function, reduction in
ʹͳ
systemic inflammation, alleviation in irritable bowel disease and acute pancreatitis, etc.
ʹͳ
(Bengmark, 2012). A recent new concept derived from synbiotics is known as
ʹͳͺ
metabiotics, which refers to the “structural components of probiotic microorganisms
ʹͳͻ
and/or formulation of and/or signaling molecules with a determined (known) chemical
ʹʹͲ
structure that can optimize host-specific physiological functions and regulate metabolic
ʹʹͳ
and/or behavior reactions connected with the activity of host indigenous microbiota”
ʹʹʹ
(Shenderov, 2012). It is thus observed that new concepts are being proposed in the area of
ͳͳ
ʹʹ͵
pre-, pro- and synbiotics, and these products are of great potential as functional food
ʹʹͶ
ingredients (Bigliardi & Galati, 2013).
ʹʹͷ ʹʹ
3. Long chain beta-glucans as potential prebiotics
ʹʹ
3.1 Background
ʹʹͺ
Beta-glucans are polysaccharides of D-glucose monomers linked by beta-glycosidic
ʹʹͻ
linkages. It is one source of valuable dietary fiber found in cereals, yeast, mushrooms,
ʹ͵Ͳ
seaweeds and some bacteria. Chemically, beta-glucans are non-starch polysaccharides
ʹ͵ͳ
with repeating glucose residues in either linear chains or multiply branched structures
ʹ͵ʹ
with the glucose units being branched in several ways depending upon the source of
ʹ͵͵
origin. For cereal beta-glucans the chains are completely linear, consisting of
ʹ͵Ͷ
consecutively linked (via beta 1-3 linkages) of cellulosic oligomers; i.e. segments of beta
ʹ͵ͷ
1-4 linked glucose residues (Lazaridou & Biliaderis, 2007). Instead, for microbial beta-
ʹ͵
glucans, the beta-D-glucopyranose units are linked together through beta -(1,3) linkages
ʹ͵
to form a long backbone, whereas side chains mostly arise through beta -(1,6) linkages
ʹ͵ͺ
(Ahmad et al., 2012a). Beta-D-glucans can form large cylindrical molecules containing
ʹ͵ͻ
up to 250,000 glucose units (Vannucci et al., 2013).
ʹͶͲ ʹͶͳ
In 1941, there was the first discovery of a pharmaceutical insoluble yeast crude product
ʹͶʹ
called ‘Zymosan,’ which is composed of 50% glucan and other polysaccharides (Pillemer
ʹͶ͵
& Ecker, 1941). Beta-glucans are major structural components of the cell walls of
ʹͶͶ
brewers’ yeast Saccharomyces cerevisiae, fungi and some bacteria. Depending on the
ʹͶͷ
source, there are clear differences between beta-glucans in their solubility, molecular
ͳʹ
ʹͶ
mass, tertiary structure, degree of branching, polymer charge and solution conformation,
ʹͶ
all of which in turn alter their immune modulating effects (Bohn & BeMiller, 1995;
ʹͶͺ
Eccles, 2005). Accordingly, beta-glucans having a beta-(1, 3) chain with beta-(1, 6)
ʹͶͻ
branching are more effective than beta-(1, 3) linear chain alone (Bohn & BeMiller, 1995).
ʹͷͲ ʹͷͳ
The macromolecular structure of beta-glucans depends on both their sources and isolation
ʹͷʹ
methods, affecting mainly the distribution and the length of side chains, forming complex
ʹͷ͵
tertiary structures stabilized by inter-chain hydrogen bonds (Mantovani et al., 2008).
ʹͷͶ
Parameters such as primary structure, solubility, degree of branching (DB), molecular
ʹͷͷ
weight (MW), polymer charge and conformation in aqueous media are involved in
ʹͷ
biological activity that beta-glucan exhibits (Zekovic et al., 2005). Beta-glucans with 0.2
ʹͷ
DB 0.33, 100 MW 200 kDa, and a triple-helix structure have greater biological
ʹͷͺ
activities than linear beta-glucan molecules (Zekovic et al., 2005). The solubility of beta-
ʹͷͻ
glucans is associated with the degree of polymerization (DP). Beta-glucans are
ʹͲ
completely insoluble in water when DP > 100.
ʹͳ ʹʹ
Cereal beta-glucans have been demonstrated to have prebiotic properties owing to their
ʹ͵
ability to pass undigested through the gastro-intestinal tract (GIT), where they act as a
ʹͶ
substrate for microbial fermentation and selectively stimulate the growth and activity of a
ʹͷ
small number of beneficial bacteria (Gibson, 2004). The use of beta-glucans derived from
ʹ
cereals as a source of fermentable substrates for the growth of probiotic microorganisms
ʹ
has been reviewed recently (Bigliardi & Galati, 2013). The beta-glucans extracted from
ʹͺ
the fruiting body of Pleurotus mushrooms. (pleuran) have also been used as food
ͳ͵
ʹͻ
supplements due to their immunosuppressive activity and stimulation of probiotics (Patel
ʹͲ
& Goyal, 2012). Similar beta-glucan extracts from Pleurotus species including P.
ʹͳ
ostreatus and P. eryngii, have been explored for their effects on human health (Synytsya
ʹʹ
et al. 2009). The use of beta-glucans from different mushroom species as a potential
ʹ͵
source of prebiotics was firstly published 5 years ago (Aida et al., 2009).
ʹͶ ʹͷ
Furthermore, beta-glucans have been well investigated in other fields. Recently, the
ʹ
applications of beta-glucans in cosmetics (Du et al., 2013) and food industries (Ahmad et
ʹ
al., 2012b) have been reviewed. Some beta-glucan products such as Ceapro from oat
ʹͺ
(Morgan & Ofman, 1998; Tomasik & Tomasik, 2003), Glucagel from barley (Morgan &
ʹͻ
Ofman, 1998), and Betamune from Yeast (Vetvicka et al., 2008) have been
ʹͺͲ
commercialized. More recently, the application of beta-glucans as an immune-stimulant
ʹͺͳ
in aquaculture to enhance productivity has been published (Meena et al., 2013).
ʹͺʹ ʹͺ͵
3.2 Health benefits of beta-glucans
ʹͺͶ
Cumulative evidence obtained from animal models and human intervention studies
ʹͺͷ
strongly suggest the immunostimulatory effect of beta-glucans and the relevant
ʹͺ
knowledge has been summarized in several recent reviews (Volman et al, 2008; Ramberg
ʹͺ
et al., 2010; Di Bartolomeo et al., 2012; Licht et al., 2012; Daou & Zhang, 2012). Most
ʹͺͺ
recently, the effect of consumption of brewers’ yeast beta-(1, 3)-(1, 6)- D-glucan on the
ʹͺͻ
number of common cold episodes in healthy subjects was investigated using a placebo-
ʹͻͲ
controlled, double-blind, randomized, multicentric clinical trial which demonstrated that
ͳͶ
ʹͻͳ
yeast beta-glucan preparation increased the human potential to defend against invading
ʹͻʹ
pathogens (Auinger et al, 2013).
ʹͻ͵ ʹͻͶ
Structure-function relationships have been studied among different beta-glucans, which
ʹͻͷ
offer plausible explanations of their different potency in health promoting effects as they
ʹͻ
relate to molecular structure of the polysaccharides. A recent review has summarized the
ʹͻ
beneficial influence of beta-glucans with different structures and the related potency in
ʹͻͺ
different biological functions (Zhang et al., 2007; Ahmad et al., 2012b; Du et al., 2013).
ʹͻͻ
For example, glucans with beta-(1, 3) (1, 6) linkages are found to have stronger anti-
͵ͲͲ
tumor property (Chan et al, 2009) and both beta-glucans with beta-(1, 3) (1, 4) and beta-
͵Ͳͳ
(1, 3) (1, 6) linkages are found to have greater immune-modulating potency (Rieder &
͵Ͳʹ
Samuelsen, 2012) and blood cholesterol lowering capacity (Chen & Seviour, 2007). Both
͵Ͳ͵
barley and oat kernel derived beta-glucans were found in vitro to inhibit cytokine-induced
͵ͲͶ
protein expression of adhesion molecules in human aortic endothelial cells in a
͵Ͳͷ
concentration- and molecular structure-dependent manner (Lazaridou et al., 2011); i.e.
͵Ͳ
the experimental data suggested that soluble cereal beta-glucans could act beneficially in
͵Ͳ
inhibiting the early stages of atherosclerosis, with the barley polysaccharides showing
͵Ͳͺ
greater physiological potency than the respective oat beta-glucans of similar molecular
͵Ͳͻ
weight. Anti-tumor property is another light-spotting field of interests on beta-glucans
͵ͳͲ
research. Recent scientific research in Japan and China has been focused more on the
͵ͳͳ
anti-tumor potentials and showed the effects of these specific beta-glucans to be
͵ͳʹ
comparable to chemotherapy and radiation, but without the side effects of the latter
͵ͳ͵
treatments (Tzianabos, 2000; Chung et al., 2010). The characteristics of beta-glucans
ͳͷ
͵ͳͶ
from fungal mycelial walls as modulators of the immunity and their possible use as
͵ͳͷ
antitumor agents have been summarized most recently (Vannucci et al., 2013). The
͵ͳ
beneficial effects of beta-glucans are not only limited in immunomodulation and
͵ͳ
anticancer activities. The effects of pleuran (a type of beta-glucans from Pleurotus
͵ͳͺ
ostreatus) supplementation on cellular immune response and respiratory tract infections
͵ͳͻ
in athletes have been reported (Bergendiova et al., 2011), depicting the possible
͵ʹͲ
association between beta-glucan consumption and enhanced performance in sports.
͵ʹͳ ͵ʹʹ
Beta-glucans activity was studied mainly in human cell culture and animal models with
͵ʹ͵
comparatively fewer human studies (Wasser, 2011). It was revealed that stronger anti-
͵ʹͶ
tumor activity was observed with beta-glucans linked with proteins compared to pure
͵ʹͷ
beta-glucans in clinical trials (Jeurink et al., 2008). However, the molecular mechanism
͵ʹ
behind this is still not yet understood in spite of increasing evidence from phenotypic
͵ʹ
studies. Results from human studies are accumulating rapidly. The applications of beta-
͵ʹͺ
glucans in cancer therapy, based on clinical trials and epidemiological data assessing the
͵ʹͻ
efficacy and safety of mushroom-derived beta-glucans in cancer treatment and
͵͵Ͳ
prevention, have been recently reviewed (Aleem, 2013).
͵͵ͳ ͵͵ʹ
Apart from exerting the health-related benefits mentioned above, beta-glucans may also
͵͵͵
provide their health promoting effects by their action as potential prebiotics. Details of
͵͵Ͷ
the recent studies in this aspect will be discussed later. However, it is worth mentioning
͵͵ͷ
that since beta-glucans are fermented in the colon by the gut microbiome, it is certain that
͵͵
their consumption could cause flatulence, bloating, and abdominal cramps if their dietary
ͳ
͵͵
intake is suddenly increased. Based on some human intervention studies, it has been
͵͵ͺ
concluded that the consumption of a daily dose of up to 10 g of beta-glucans by humans
͵͵ͻ
is well tolerated and even a higher consumption level of beta-glucans might not be
͵ͶͲ
harmful for human health (Cloetens et al, 2012). It should be also emphasized that a dose
͵Ͷͳ
higher than 10 g/day is uncommon in a single meal (Cloetens et al, 2012). Due to its
͵Ͷʹ
health promoting effects, there is an increasing trend of consumption of beta-glucans as
͵Ͷ͵
dietary supplements in the functional food markets.
͵ͶͶ ͵Ͷͷ
3.3 Sources and preparations of beta-glucans
͵Ͷ
3.3.1 Sources
͵Ͷ
Sources for beta-glucans are quite diversified (Ahmad et al, 2012a). The major sources
͵Ͷͺ
for beta-glucans are from cereals, especially oat and barley, which have very high beta-
͵Ͷͻ
glucan content (Lazaridou & Biliaderis, 2007). Beta-glucans can also be extracted from
͵ͷͲ
rye and rice, with the latter being marketed in the name of ‘NutrimXe’ (Inglett et al.,
͵ͷͳ
2004). Among these sources, the content of beta-glucans differs from cultivar to cultivar
͵ͷʹ
(Zhang et al., 2002) and varies in different parts of the plant such as the kernels and bran
͵ͷ͵
in barley (Wirkijowska et al., 2012).
͵ͷͶ ͵ͷͷ
During the extraction of beta-glucans, the extraction yield varies and depends upon on the
͵ͷ
botanical sources, temperature, and pH (Zhang et al., 2002; Temelli, 1997). Extraction
͵ͷ
yield of beta-glucans from oat can be 50 to 80%, while that of barley ranges from 70 to
͵ͷͺ
80% (Freimund et al., 2003). Extraction of beta-glucans from Saccharomyces cerevisiae
͵ͷͻ
could give up to 87% -glucans (Freimund et al., 2003).
ͳ
͵Ͳ ͵ͳ
Recently, beta-glucans obtained from edible mushrooms (or edible fungi) have attracted
͵ʹ
much research interest because mushrooms are a good source of beta-glucans. The most
͵͵
renowned edible mushroom sources include Agaricus brasiliensis (Kodama et al, 2003),
͵Ͷ
Pleurotus tuberregium (Zhang et al, 2004), Grifola frondosa (Kodama et al., 2003),
͵ͷ
Lentinus edodes (Chihara, 1993), Pleurotus eryngii (Synytsya et al., 2009) and Pleurotus
͵
ostreatus (Carbonero et al., 2006; Yoshioka et al., 1985; Synytsya et al., 2009; Tong et
͵
al., 2009). A review on the beta-glucans content of these mushrooms has been published
͵ͺ
recently (Aida et al., 2009). The pharmacological effects of beta-glucans including
͵ͻ
antimicrobial, antiviral, antitumor, antiallergic, immunomodulating, anti-inflammatory,
͵Ͳ
antiatherogenic, hypoglycemic, and hepatoprotective have also been reported (Lindequist
͵ͳ
et al., 2005). A few fungal sources that are not used for edible purpose can also be used
͵ʹ
for extraction of beta-glucans including Termitomyces eurhizus (Chakraborty et al.,
͵͵
2006), Penicillium chrysongenum (Wang et al, 2002). Table 1 summarizes the source and
͵Ͷ
chemical structure of some native and modified beta-glucans available in the current
͵ͷ
market.
͵ ͵
3.3.2 Preparations
͵ͺ
The most direct method to obtain beta-glucans is to extract them from natural sources.
͵ͻ
However, isolation and purification of beta-glucans are complicated involving different
͵ͺͲ
extraction procedures using acids, alkalis and enzymes. Generally, extraction of beta-
͵ͺͳ
glucans relies on the solubility of beta-glucans in hot water or in alkaline solutions and
͵ͺʹ
the removal of non-targeted contaminants such as proteins. For example, dissolved
ͳͺ
͵ͺ͵
proteins can be removed by isoelectric precipitation, and then beta-glucans can be
͵ͺͶ
precipitated by ammonium sulphate, 2-propanol, or ethanol (Wood et al., 1978).
͵ͺͷ
Repeated precipitations and enzymatic hydrolysis of residual starch and proteins have
͵ͺ
been demonstrated to yield beta-glucans isolates with purity greater than 90% (Wood et
͵ͺ
al., 1991; Westerlund et al., 1993; Lazaridou & Biliaderis, 2007).
͵ͺͺ ͵ͺͻ
Alkaline extraction of beta-glucans has also been widely employed. Extraction with
͵ͻͲ
distilled water, by adjusting the pH to 10 with 20% sodium carbonate, was used to extract
͵ͻͳ
beta-glucans from oat bran, with a yield of 61% of crude beta-glucans. A beta-glucan
͵ͻʹ
isolate with a 84% purity was obtained by centrifugation, termamyl addition and alcohol
͵ͻ͵
precipitation after acidification using 2M hydrochloric acid to pH 4.5 (Bhatty, 1993).
͵ͻͶ
Similar methodologies have been further developed to improve the yield of beta-glucans
͵ͻͷ
extraction by alcohol precipitation (Beer et al., 1996). Another method to extract beta-
͵ͻ
glucans from the fruiting bodies of Pleurotus sajorcaju using cell wall-degrading
͵ͻ
enzymes (xylanase and cellulose) was developed to produce beta-glucans with a purity of
͵ͻͺ
up to 90.2% with enhanced immunostimulatory activity in a macrophage cell culture
͵ͻͻ
model (Satitmanwiwat et al., 2012). When comparing extraction methods using acids,
ͶͲͲ
alkalis, or enzymes, it was reported that enzymatic extraction was the best because it did
ͶͲͳ
not only give the highest yield but also removed most residual starch, fat, and pentosans
ͶͲʹ
during the extraction process (Ahmad et al., 2010). In a recent review, a comprehensive
ͶͲ͵
list of all recent extraction and purification processes of beta-glucans with their sources,
ͶͲͶ
salient features of the extraction process has been given (Ahmad et al., 2012b). This
ͳͻ
ͶͲͷ
review also summarizes the differences in the molecular weight of beta-glucans obtained
ͶͲ
by the different methods and from different sources (Ahmad et al., 2012b).
ͶͲ ͶͲͺ
In addition to the conventional production of beta-glucans by extraction from natural
ͶͲͻ
sources, beta-glucans can also be synthesized from microorganisms. The synthesis of
ͶͳͲ
beta-(1, 3)-D-glucans by lactic acid bacteria using a recombinant probiotic strain
Ͷͳͳ
Lactobacillus paracasei NFBC 338, which contains the Pediococcus parvulus
Ͷͳʹ
glycosyltransferase gene responsible for beta-glucans production was reported recently
Ͷͳ͵
(Kearney et al., 2011). Such synthesized beta-glucan could increase the viability of
ͶͳͶ
probiotic bacteria and did not alter the functional properties of the food products
Ͷͳͷ
(Kearney et al., 2011).
Ͷͳ Ͷͳ
3.4 Recent studies on the beta-glucans as prebiotics
Ͷͳͺ
Beta-glucans can show prebiotic characteristics when incorporated into food products.
Ͷͳͻ
There is growing market for food products having probiotics and prebiotics in their
ͶʹͲ
formulations. Such products are available in large food stores across the world in the
Ͷʹͳ
form of fresh and fermented milk products (e.g., yoghurts, kefir), fruit juices and so on
Ͷʹʹ
(Tomasik & Tomasik, 2003).
Ͷʹ͵ ͶʹͶ
In the 1990s, many studies have pointed out the phenotypic response of beta-glucans as
Ͷʹͷ
fermentation substrate. Lichenase hydrolysates of oat beta-glucans and xylans were also
Ͷʹ
studied as selective substrates for Bifidobacterium sp. and Lactobacillus sp. strains
Ͷʹ
(Jaskari et al, 1998). In this study, low molecular weight oat beta-glucooligomers and
ʹͲ
Ͷʹͺ
xylooligomers both enhanced the growth of probiotic strains, but not to a significant level
Ͷʹͻ
compared to raffinose and fructooligomers (Jaskari et al, 1998). In another study, glucans
Ͷ͵Ͳ
with beta-(1, 4) linkages were shown to be cleaved more slowly by beta-galactosidase of
Ͷ͵ͳ
B. bifidum compared to beta-(1, 3) and beta-(1, 6) linkages (Dumortier et al, 1994). The
Ͷ͵ʹ
beta-(1, 3) and beta-(1, 6) linkages have also been described as being more selectively
Ͷ͵͵
hydrolyzed by the enzymic systems of Bifidobacterium sp. (Rowland & Tanaka, 1993).
Ͷ͵Ͷ Ͷ͵ͷ
In the late 1990s and early 2000s, beta-glucans have been reported as a potential
Ͷ͵
prebiotic, selectively promoting the growth of beneficial intestinal microorganisms such
Ͷ͵
as lactobacilli and bifidobacteria according to some in vitro studies (Jaskari et al., 1998;
Ͷ͵ͺ
Kontula et al., 1998b) and animal experiments (Dongowski et al., 2002; Drzikova et al.,
Ͷ͵ͻ
2005; Snart et al., 2006). Beta-glucans (Su et al., 2007), and especially their oligomeric
ͶͶͲ
fragments (Grootaert et al., 2007; Kontula et al., 1998a; Lee et al., 2002; Manderson et
ͶͶͳ
al., 2005; Olano-Martin et al., 2002) have been also proposed as prebiotics. In 2009,
ͶͶʹ
Synytsya and others (2009) have used different extraction methods to obtain beta-glucans
ͶͶ͵
from Pleurotus sp. (pleuran) and demonstrated their prebiotic effects using nine probiotic
ͶͶͶ
strains of Lactobacillus, Bifidobacterium and Enterococcus, showing different substrate
ͶͶͷ
dependency of their growth and strain specificity.
ͶͶ ͶͶ
At present, active research on beta-glucans as potential source of prebiotics is still going
ͶͶͺ
on. The most updated research studies have been summarized in Table 2, involving both
ͶͶͻ
basic research and clinical studies. Currently, research on beta-glucans as a potential
ͶͷͲ
source of prebiotics is shifting from basic studies towards human clinical work. For basic
ʹͳ
Ͷͷͳ
research studies, there is also an increasing effort to unravel the molecular mechanism
Ͷͷʹ
behind the selective fermentation of beta-glucans by different probiotic bacterial strains.
Ͷͷ͵ ͶͷͶ
4. Structure–function relationships
Ͷͷͷ
4.1 Pathways for bacterial fermentation of beta-glucans
Ͷͷ
There is detailed structural information on beta-glucans from different sources obtained
Ͷͷ
by modern analytical techniques (Satitmanwiwat et al., 2012). For example, enzymic
Ͷͷͺ
digestion (lichenase) combined with high performance liquid chromatography (HPLC)
Ͷͷͻ
analysis of the oligosaccharides in the hydrolyzate as well as nuclear magnetic resonance
ͶͲ
(NMR) analysis of beta-glucans from oat and other cereal grains revealed that cello-
Ͷͳ
oligosaccharides are joined by beta-(1,3) linkages and that the main components of cereal
Ͷʹ
beta-glucans are cellotri- and cellotetrasaccharides (95% of the whole beta-glucan)
Ͷ͵
(Wood et al., 1991; Johansson et al., 2000; Lazaridous & Biliaderis, 2007). Although
ͶͶ
there has been some research interest in the structure-function relationships of prebiotics
Ͷͷ
such as FOS and GOS in terms of specific enzymes or transporters that are present in the
Ͷ
bacteria for their utilization (Rastall & Maitin, 2002; Van den Broek et al., 2008a; Van
Ͷ
Den Broek & Voragen, 2008b), it is clear that more work is needed to fully elucidate the
Ͷͺ
roles of cell-associated enzymes and prebiotic transport systems. Besides the differences
Ͷͻ
in fermentation selectivity among the various strains of probiotic microorganisms, there
ͶͲ
are some key studies on oligosaccharides, comparing the structural characteristics with
Ͷͳ
their fermentation selectivity, primarily in relation to the monosaccharide composition,
Ͷʹ
glycosidic linkage, and molecular mass of the prebiotics (Sarbini & Rastall, 2011).
Ͷ͵
ʹʹ
ͶͶ
Our current understanding of prebiotic substances is that low-molecular-mass
Ͷͷ
oligosaccharides are more rapidly and more selectively fermented by bifidobacteria and
Ͷ
lactobacilli than their high-molecular-weight counterparts. This property may be due to
Ͷ
the fact that the low molecular mass substrates have more non-reducing ends per unit
Ͷͺ
mass, which favors a more rapid attack by the exo-acting enzymes produced by probiotic
Ͷͻ
organisms (Gibson, 2004). However, the detailed mechanism on bacterial selective
ͶͺͲ
fermentation of beta-glucans remains unclear and there are many research challenges for
Ͷͺͳ
further study in this area.
Ͷͺʹ Ͷͺ͵
In our laboratory, beta-glucans obtained from barley, seaweed, bacteria, and mushroom
ͶͺͶ
sclerotia were incubated with pure cultures of Bifidobacterium infantis, Bifidobacterium
Ͷͺͷ
longum, and Bifidobacterium adolescentis for a 24-hour batch fermentation in order to
Ͷͺ
evaluate their bifidogenic effect with inulin as the positive control (Zhao & Cheung,
Ͷͺ
2011). The results showed that the utilization of all the beta-glucans isolated from
Ͷͺͺ
different sources regardless of their differences in glycosidic linkages and molecular
Ͷͺͻ
weight by all three bifidobacteria was comparable to that of inulin (Zhao & Cheung,
ͶͻͲ
2011). A plausible explanation for these observations might be the similarity of enzymic
Ͷͻͳ
and transporter systems of the different bifidobacterial species investigated.
Ͷͻʹ Ͷͻ͵
In the last decade, “omics approaches” have inuenced tremendously the way of studying
ͶͻͶ
the biology of microorganisms including probiotics. The “omics approach” is a powerful
Ͷͻͷ
tool to reveal the molecular mechanism behind (Mozzi et al, 2012). A recent review
Ͷͻ
summarized different “omics approaches” in the microbiological field and suggested the
ʹ͵
Ͷͻ
requirement of systematic omic measurements at different areas and at different time-
Ͷͻͺ
points can help resolved different omics profiles (genomics, transcriptomics, proteomics
Ͷͻͻ
and metabolomics) of samples, employing a discovery-driven approach instead of
ͷͲͲ
traditional targeted investigation (Muller et al., 2013). Recently, Van de Guchte and
ͷͲͳ
others reviewed different proteomics-based methods to gain understanding of the
ͷͲʹ
mechanisms underlying the characteristics of probiotic bacteria, such as gel
ͷͲ͵
electrophoresis, mass spectrometry based proteomics, stable isotope labeling with amino
ͷͲͶ
acids in cell culture, shaving (the use of bead-anchored trypsin to digest cell surface
ͷͲͷ
proteins, followed by mass spectrometry analysis and comparison with computer
ͷͲ
stimulated trypsin digestion of selected proteins in database), proteome fractionation and
ͷͲ
in silico proteomics (Van de Guchte et al, 2012). Siciliano & Mazzeo (2012) also
ͷͲͺ
summarized the different microbial proteomics strategies that can be possibly employed
ͷͲͻ
to investigate molecular mechanisms underlying the probiotic effects. These proteomic
ͷͳͲ
approaches allow us to better understand how probiotic bacteria can adapt to the harsh
ͷͳͳ
physical–chemical environment of the gastro-intestinal tract, adhere to host epithelial
ͷͳʹ
cells and intestinal mucosa and exert immunomodulatory properties (Siciliano & Mazzeo,
ͷͳ͵
2012).
ͷͳͶ ͷͳͷ
Most recently, our group elucidated the metabolic pathway of beta-glucan catabolism in
ͷͳ
the widely used probiotic B. longum subsp. infantis using a comparative proteomic
ͷͳ
analysis along with two-dimensional gel electrophoresis, real-time reverse transcription-
ͷͳͺ
polymerase chain reaction (real-time RT-PCR) for validation, and enzyme activity assay
ͷͳͻ
on samples obtained from cultures grown on beta-glucans derived from barley, seaweed,
ʹͶ
ͷʹͲ
and mushroom (Zhao & Cheung, 2013). On the basis of the above results, a model for
ͷʹͳ
catabolism of beta-glucans in B. infantis is proposed as follows (Figure 1): beta-glucan
ͷʹʹ
molecules in the medium are transported into the cell through the ABC (ATP-binding
ͷʹ͵
cassette) transport system and PTS (phosphotransferase system) proteins followed by
ͷʹͶ
hydrolysis through the action of intracellular glucanase to glucose, which is subsequently
ͷʹͷ
incorporated into the central fermentative pathway ‘bifid shunt’. This study for the first
ͷʹ
time reveals the possible degradation pathway of beta-glucans by B. infantis, which has
ͷʹ
implications for potential use of these beta-glucans as novel prebiotics in development of
ͷʹͺ
synbiotic formulations (Zhao & Cheung, 2013).
ͷʹͻ ͷ͵Ͳ
The proposal of biochemical pathways with relevant enzymes and transporters
ͷ͵ͳ
participating in beta-glucans catabolism can be regarded as the first step to elucidate the
ͷ͵ʹ
mechanism. However, validation of pathways by employing genetic manipulation of
ͷ͵͵
probiotic organisms must be performed. In addition, the use of novel meta-omics
ͷ͵Ͷ
approaches (Sánchez et al., 2013) including metagenomics, metaproteomics and
ͷ͵ͷ
metatranscriptomics, as well as focus on the analysis of the biological molecules in
ͷ͵
complex microbial communities, are worth mentioning (Del Chierico et al., 2012;
ͷ͵
McNulty et al., 2011; Wu, et al., 2011) Although these approaches are still nascent
ͷ͵ͺ
disciplines, they are expected to gain a deeper insight into the role of probiotics and their
ͷ͵ͻ
relationships with our bacterial community and human physiology.
ͷͶͲ ͷͶͳ
4.2 New approaches for pathways validations
ʹͷ
ͷͶʹ
The carbohydrates uptake, transport, and substrate utilization capability of a probiotic
ͷͶ͵
bacterium is considered as a competitive edge in the host gut for microbial adaptation.
ͷͶͶ
For example, more than 10% of bifidobacterial genome encodes related enzymes and
ͷͶͷ
transporters (Schell et al. 2002). Different probiotic bacteria show capabilities of
ͷͶ
utilization of different sources of carbohydrates. For instance, Lactobacillus plantarum
ͷͶ
adapts to many different environments and thus it encodes a large number of enzymes for
ͷͶͺ
utilization of many different carbohydrates (Kleerebezem et al. 2003). Furthermore, most
ͷͶͻ
carbohydrate-digesting genes are present as gene clusters or as operons. The L.
ͷͷͲ
acidophilus msm operon is an example for FOS metabolism (Barrangou et al. 2003).
ͷͷͳ
Similar response might take place for probiotic organisms fermenting beta-glucans.
ͷͷʹ ͷͷ͵
The “omics approach” is a powerful tool to construct possible pathways from the
ͷͷͶ
knowledge of relative expression of particular biomolecules of interests. Omics
ͷͷͷ
methodologies comprise high-throughput techniques directed to understand the cell
ͷͷ
metabolism as one integrated system, rather than merely a collection of independent
ͷͷ
parts, by using information about the relationships between different molecules (Zhang et
ͷͷͺ
al., 2010). However, validation of any proposed metabolic pathways for prebiotic
ͷͷͻ
fermentation is the direct evidence and it is essential to confirm the function of all the
ͷͲ
participating biomolecules involved in the proposed pathways.
ͷͳ ͷʹ
In molecular biology, the golden standard method to determine the function of predicted
ͷ͵
genes and establish which genes are essential under specific environmental conditions is
ͷͶ
to disrupt the candidate genes and determine the phenotypic changes. However, in order
ʹ
ͷͷ
to perform such functional genomic investigations, it will be necessary to develop
ͷ
effective genetic tools such as highly efficient transformation protocols and to implement
ͷ
effective gene knockout methodologies for probiotics (Law et al., 1995; Serafini et al.,
ͷͺ
2012). Such reverse genetic approach can be exemplified by a recent review on lactic
ͷͻ
acid bacteria engineering (Bron & Kleerebezem, 2011).
ͷͲ ͷͳ
Recently, there is an increasing number of studies on the forward genetics investigation
ͷʹ
of probiotic bacteria, especially bifidobacteria by bacterial conjugation (Dominguez &
ͷ͵
O’Sullivan, 2013) with the machinery composed of an oriT sequence and tra genes
ͷͶ
(Smillie et al., 2010). There is also an earlier review on bacterial conjugation for Gram-
ͷͷ
positive bacteria (Schröder & Lanka, 2005). Other approaches including transformation,
ͷ
reporter systems, heterologous gene expression and mutagenesis, using bifidobacteria as
ͷ
an example, have been reviewed (Cronin et al., 2011). Most recently, a group of scientists
ͷͺ
described the generation of transposon insertion mutants in two bifidobacterial strains, B.
ͷͻ
breve UCC2003 and B. breve NCFB2258 and reported the creation of the first transposon
ͷͺͲ
mutant library in a bifidobacterial strain, using the B. breve UCC2003 and a Tn5- based
ͷͺͳ
transposome strategy (Ruiz et al., 2013). The usefulness of this library to perform
ͷͺʹ
phenotypic screenings was confirmed through identification and analysis of mutants
ͷͺ͵
defective in D-galactose, D-lactose or pullulan utilization abilities (Ruiz et al., 2013). The
ͷͺͶ
same group of scientists have also developed an efficient and reproducible conjugation-
ͷͺͷ
based gene transfer system for bifidobacteria based on the RP4 conjugative machinery in
ͷͺ
the Escherichia coli strain WM3064 (pBB109) and this novel conjugative gene transfer
ͷͺ
protocol can be used for the introduction of genetic material into Bifidobacterium species
ʹ
ͷͺͺ
and is particularly useful for strains that are recalcitrant to electroporation (Dominguez &
ͷͺͻ
O’Sullivan, 2013). With so many genetic tools being developed by different scientists,
ͷͻͲ
the function of particular genes or proteins can be elucidated with ease.
ͷͻͳ ͷͻʹ
In addition, massively parallel sequencing has been combined with traditional transposon
ͷͻ͵
mutagenesis (Van Opijnen & Camilli, 2013). These techniques can be referred to as
ͷͻͶ
transposon sequencing (Tnಣseq), highಣthroughput insertion tracking by deep sequencing
ͷͻͷ
(HITS), insertion sequencing (INSeq) and transposonಣdirected insertion site sequencing
ͷͻ
(TraDIS), making it possible to identify putative gene functions in a highಣthroughput
ͷͻ
manner (Van Opijnen & Camilli, 2013).
ͷͻͺ ͷͻͻ
4.3 Molecular mechanism of beta-glucan fermentation at protein level
ͲͲ
Carbohydrates are biomolecules involved in many life processes such as metabolism,
Ͳͳ
structural support, energy storage, antibiosis, immunological recognition, targeting,
Ͳʹ
attachment, etc. To exert these multiple cellular functions, several carbohydrate-active
Ͳ͵
proteins have acquired non-catalytic modules that interact very specifically with mono-,
ͲͶ
oligo-, and polysaccharides. In general, these carbohydrate-binding modules (CBM) are
Ͳͷ
auxiliary domains with autonomous folding and skilled recognition of the heterogeneous
Ͳ
and complex carbohydrate arrangement (Boraston et al. 2004).
Ͳ Ͳͺ
In carbohydrate-active enzymes (CAZymes) like glycoside hydrolases or glycosyl
Ͳͻ
transferases, CBMs can be localized at the N- or C-terminal end of these proteins (Abe et
ʹͺ
ͳͲ
al. 2004; Juge et al. 2002). Certainly, the main function of CBMs is to recognize and bind
ͳͳ
specifically to carbohydrates. The biological consequences of this event result in different
ͳʹ
functions, such as increased hydrolysis of insoluble substrates, bringing the catalytic
ͳ͵
domain in close proximity to the substrate, substrate structure disruption, and so on
ͳͶ
(Guillén et al., 2010). Relevant information on CBM, focusing on the biological
ͳͷ
importance of CBMs–ligand interactions, including the basis of modern classification and
ͳ
the function of these versatile proteins, can be found in a comprehensive review (Guillén
ͳ
et al., 2010). Enzymes that are believed to function against beta-glucans include
ͳͺ
endoglucanases and exoglucanases (Boraston et al. 2002; Cosgrove 2005; Barral et al.
ͳͻ
2005). CBMs have been classified based on amino acid similarity. In the latest update of
ʹͲ
the CAZY database (July 3rd, 2013), a total of 30,581 CBMs were grouped into 67
ʹͳ
families (http://www.cazy.org). The information in this database is continuously updated
ʹʹ
so that new families are frequently added (Cantarel et al. 2009). Among all the different
ʹ͵
types of CBMs, Type B CBMs is responsible for the recognition of substrates like beta-
ʹͶ
(1, 3)- glucans, mixed beta-(1,3)(1,4)-glucans, beta-1,4-mannan, glucomannan, and
ʹͷ
galactomannan (Boraston et al, 2002; Guillén et al., 2010).
ʹ ʹ
A very good example of beta-glucan catabolic enzymes is the Family 3 of glycosyl
ʹͺ
hydrolases (GH3), which consists of nearly 44 beta-glucosidases and hexosaminidases
ʹͻ
from bacteria, molds, and yeasts. Most of the fungal beta-glucosidases studied belong to
͵Ͳ
GH3. Structural data on representatives of GH3 are still scarce, since only three of their
͵ͳ
structures are known and only one of them has been thoroughly characterized, which is
͵ʹ
the beta-D-glucan-(exo1-3, 1-4)-glucanase (Exo 1) from Hordeum vulgare, which
ʹͻ
͵͵
catalyzes the hydrolysis of cell-wall polysaccharides (Bhatia et al., 2002). The enzyme
͵Ͷ
consists of N-terminal (alpha/beta) 8 trans-membrane barrel domain and a C-terminal
͵ͷ
domain of six stranded beta sandwich. The non-homologous region, a helix-like strand of
͵
16 amino acid residues, connects the two domains (Bhatia et al., 2002). The catalytic
͵
center is located in the pocket at the interface of the two domains with Asp285 in the N-
͵ͺ
terminal domain acting as a catalytic nucleophile, while Glu491 in the C-terminal domain
͵ͻ
acting as a proton donor (Varghese et al., 1999). A more detailed discussion on glycosyl
ͶͲ
hydrolases (GH) such as classification, different structure isoforms and cloning
Ͷͳ
approaches, can be found in a recent review by Singhania and others (Singhania et al,
Ͷʹ
2013). Moreover, an earlier review on the carbohydrate-binding module (CBM) for
Ͷ͵
alpha-glucans might shed light on the future studies on beta-glucans CBM using similar
ͶͶ
approaches such as in silico prediction (such as the prediction of the CBMs from the
Ͷͷ
amino acid sequence of proteins, based on homology of conserved sequences),
Ͷ
evolutionary analysis, three-dimensional structure analysis, docking, determination of the
Ͷ
binding constants, stoichiometry, and thermodynamics (Christiansen et al, 2009).
Ͷͺ Ͷͻ
Further studies on the roles played by particular enzymes or transporters in probiotics
ͷͲ
especially at a protein level during fermentation of beta-glucans are required.
ͷͳ ͷʹ
5. Conclusion and future perspectives
ͷ͵
The introduction of functional compounds like prebiotics in the diet seems to be an
ͷͶ
attractive alternative to ameliorate the quality of life ridden with obesity, cancer,
ͷͷ
hypersensitivity, vascular diseases and degenerative ailments. For example, beta-glucans
͵Ͳ
ͷ
have demonstrated beneficial effects to human health especially due to their immune-
ͷ
stimulatory effects. There is also an accumulating evidence suggesting beta-glucans as
ͷͺ
potential source of prebiotics. However, the molecular mechanism behind how the beta-
ͷͻ
glucans are being utilized by specific probiotics is still not fully understood. The
Ͳ
employment of the “omics approach”, forward or reverse genetic approach and deeper
ͳ
understanding of the mechanism at a protein level may shed light to the detailed function
ʹ
of the beta-glucans as prebiotics.
͵ Ͷ
Also, modification of the chemical structure of prebiotics might alter their bioactivities.
ͷ
Modification of beta-glucans has not yet received much attention in the field of prebiotic
research. Physical (reduction in molecular mass, branching), chemical (addition of
functional groups), and biochemical (enzymatic treatment) modifications might enhance
ͺ
the probiogenic property of beta-glucans. It is anticipated that the potential use of beta-
ͻ
glucans as prebiotics will continue to draw much attention in the near future.
Ͳ
͵ͳ
ͳ
Figure captions
ʹ
Figure 1: Schematic representation of the proposed catabolic pathway of beta-glucans
͵
by B. infantis. Enzymes involved in the carbohydrate catabolism are denoted by numbers:
Ͷ
1, glucokinase; 2, glucose-6-phosphate isomerase; 3, fructose-6-phosphate
ͷ
phosphoketolase; 4, transaldolase; 5, transketolase; 6, ribose 5-phosphate isomerase; 7,
ribulose 5-phosphate epimerase; 8, xylulose-5-phosphate phosphoketolase; 9, acetate
kinase; 10, glyceraldehyde-3-phosphate dehydrogenase; 11, phosphoglycerate kinase; 12,
ͺ
phosphoglycerate mutase; 13, enolase; 14, pyruvate kinase; 15, lactate dehydrogenase,
ͻ
16, pyruvate formate lyase. Numbers circled in red denote the proteins identified in this
ͺͲ
study with different abundances among treatments (adapted from Zhao & Cheung, 2013).
ͺͳ
EPS: exo-polysaccharides; E I: enzyme E I; EIIA: enzyme E II A; EIIBC: enzyme E II B
ͺʹ
& C; HPr: histidine protein/heat-stable protein; P: a phosphate group; PEP:
ͺ͵
phosphoenolpyruvate.
͵ʹ
ͺͶ
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ͳ͵͵
ͷ
ͳ͵Ͷ
Figures and Tables
ͳ͵ͷ ͳ͵
Figure 1
ͳ͵ Source
Genetically engineered,
beta-(1, 3)-D-glucan with beta-(1, 6) branching, at
Yeast, Saccharomyces cerevisiae
Seaweed: Laminaria species
PGG (betafectin),
pharmaceutical grade
Laminarin
Betafectin is a soluble
20-25 glucose units
zymocel
little beta-(1, 6) branching
cerevisiae
zymosan
Crude beta-glucan extract
high beta-(1, 6) branching
beta-(1, 3)-D-glucan with
Yeast, Saccharomyces
Zymocel, purified
& Fiore, 1958;
non-uniform branches
Read et al., 1996;
Kuda et al., 1992 ;
al., 1998
1998; Michalek et
Kernodle et al.,
2008;
Volman et. al
Suzuki et al, 1996;
Miura et al., 1999
1941; Di Carlo
Pillemer & Ecker,
Reference
beta-glucan and mannan
hydrolysis product from
little beta-(1, 6) branching
cerevisiae
Crude extract with
Remarks
beta-(1, 3)-D-glucan with
beta-(1, 3)-D-glucan with
Zymosan
Yeast, Saccharomyces
Structure
Source and chemical structure of some native and modified beta-glucans
Beta-glucans from plant and yeast/fungi
Beta-glucans
Table 1
cerevisiae
zymosan, OX-ZYM
Yeast, Saccharomyces
(1, 6-)-linked glucan
beta-(1, 3)-linked and beta-
glucan
Gram negative bacteria, Alcaligenes faecalis
Unbranched beta-(1, 3)-D-
beta-(1, 3)-D-glucan
Exopolysaccharide of
(a Basidiomycetes sp.)
sclerotia of Poria cocos
Hypochlorite oxidized
Modified beta-glucans
Curdlan
Pachyman
the 3:1 ratio
moiety about 10–50,
DP of beta-(1, 6)-glucan
ͺ
Ohno et al., 2001
Miura et al., 1996;
Zhan et al., 2012
& Cheung, 2011;
et. al 2008; Zhao
al., 2001; Volman
1968; Shimizu et
Harada et al.,
Bian et al., 2010
Wong et al., 2005;
Ding et al., 1998;
Cheung, 2011
1974; Zhao &
Nelson & Lewis,
DS about 0.28-0.54 using
Sclerotia of Pleurotus tuber-regium
Same as pachyman
Sulphated beta-glucans
(pleuran)
Carboxymethylated
curdlan
Carboxymethylated
pachyman
Same as curdlan
(1, 3)-D-glucan
cerevisiae
al., 1995; Volman
(C6H10O5)7·PO3H2
1979; Sasaki et al., 1978; Na et
chloroacetic acid for carboxymethylation
Sasaki et al.,
Stone, 1969
carboxymethylation DS about 0.4 to 0.65 using
1962; Barras &
ͻ
Clarke & Stone,
Zhao et al., 2006
et. al 2008
1991; Müller et
William et al.,
formula is
Repeating-unit empirical
chloroacetic acid for
DS about 0.2 to 0.4 using
pyridine complex
with chlorosulfonic acid –
Synthetic modified, beta-
Yeast, Saccharomyces
Glucan phosphate, GluP
oxidation
solubility increased after
residues, every 4th being substituted with single Dglucopyranosyl groups
P. tuberregium, and P. pulmonarius
600,000 and 700,000 Da
ostreatus or genus Pleurotus, linked D-glucopyranosyl
name: Imunoglukan) P. eryngii, P. ostreatoroseus,
Molecular mass between
Backbone of beta-(1, 3)-
Oyster mushroom Pleurotus
Pleuran (commercial
combination of these
al., 2010;
2006; Baggio et
ͺͲ
Carbonero et al.,
Zhang et al., 2003;
Kuniak, 1994;
Karácsonyi &
& Miller, 1994
glycerol, succinic acid, methylmalonic acid, or a
1996; Breedveld
with sn-1-phospho-
Gonzalez et al.,
Roset et al., 2006;
Brucella sp.
and cyclic beta-(1, 2)-
Cogez et al., 2002;
backbones substituted
cyclic beta-(1, 2)-glucan
Rhizobium,
17–25 glucose residues;
Sinorhizobium, and
Heterogeneously sized
Agrobacterium,
Beta-glucans from macrofungi/mushrooms
Cyclic beta-(1, 2)-glucans
al., 2000
frondosa
name: GRN)
Maitake mushroom Grifola
stranded helix form bears
beta-(1, 3) linkages, triple
Mao et al., 2007;
ͺͳ
approximately 450,000 Da Tada et al., 2009
Molecular mass of
2013
structure
Grifolan, (common
2007; Zhang et al.,
Van & Teramoto,
residue, triple helical
450,000 Da
Van et al., 1984;
1982; Kony et al.,
beta-(1, 6) branching at
commune
sizofiran, SPG
Molecular mass of about
approximately every third
Beta-(1, 3)-D-glucan with
Fungus, Schizophyllum
linkages
linked by beta-(1, 6)
al., 2011
2000; Brauer et
to 2 molecules of glucose
molecular mass
Ooi and Liu,
al., 2010; Zhang et
backbone linked by beta-
Lentinula edodes
Have great divergence in
(1, 3) linkages connected
5 molecules of glucose in
Shiitake mushroom
Schizophyllan,
Lentinan, LNT
2011
Bergendiov et al.,
20K, PSG, Gl-1)
Ganoderan, (MW
beta-(1, 3)-glucan
al., 2008; Rop et al., 2009
immunomodulatory proteins) and GPP
ͺʹ
2007; Volman et
(fungal
(Ganoderma
2000; Zhou et al.,
Ooi and Liu,
al., 2007
2000; Moradali et
Ooi and Liu,
proteins, known as FIMs
Consists of 4% of
Da
molecular mass is 100,000
Ganoderma lucidum
Proteoglucan that contains
K)
beta-(1, 3)-D-glucan
2008
beta-(1, 6) branches
25–38% of proteins,
Coriolus versicolor
Crestin, (common
Volman et. al
beta-(1, 3)-D-glucan with
name: polysaccharide
Glomerella cingulata
Glomerellan
curdlan
(1, 3)-glucans such as
resemblance to other beta-
ͳ͵ͻ
ͳ͵ͺ
Chaga extract beta-(1, 6) branches
polysaccharide of Inonotu obliquus
beta-(1, 3)-D-glucans with
Mycelial endoWater soluble
polysaccharides peptide)
ͺ͵
Rhee et al., 2008
Chen et al., 2007;
Zjawiony, 2004;
ͳͶͳ
ͳͶͲ
Recent studies of beta-glucans as prebiotics in the last 4 years.
elucidated, including ABC transporter for sugars, enolase, and phosphotransferase
different beta-glucans with pure culture of Bifidobacterium infantis (JCM 1222) for a 24 h followed by 2 dimensional gel electrophoresis and MALDI-TOF analysis, validated by real-time RT-PCR & enzyme activity assay
(Laminarin), barley
beta-glucan,
mushroom beta-
glucan prepared from
the sclerotia of
Pleurotus tuber-
native liquid form of the extract, not the
liquid/spray-dried fucoidan and laminarin extract, studied the effects on
Laminaria digitata
were higher in the ileum of pigs fed the
Supplementing animal feed with a
Counts of lactobacilli and bifidobacteria
beta-glucans in B. infantis is proposed
Laminarin from
regium
Enzymes and transporters participated are
in vitro batch fermentation of the 3
Seaweed beta-glucan
system protein; a model for catabolism of
Major findings
Method
Source
Basic research studies
Table 2
2013
Murphya et al,
2013
Zhao & Cheung,
Reference
ͺͶ
Low concentration (0.1% to 0.5%) of polysaccharides enhance the survival rate of
Mushroom polysaccharides with different concentration incubated with probiotics bacteria and check vability after cold storage of 28 days
Mixture of
polysaccharides from
Lentinula edodes,
Pleurotus eryngii, and
significant decrease of number of Enterobacteriaceae decreased, both in a dose-dependent manner
groups of 40 rats each, control group fed with saline, and 4 groups fed with oat & barley derived beta-glucans intragastric gavaged at a dose of 0.35 g/
commercial oat bran
or naked barley
based animal feed with endogenous
based diets vs. oats
Supplementing barley based & oat-
Formulated barley-
for 6 weeks
kg of body weight and 0.70 g/kg daily
Significant increase of population of
200 male rats were divided into 5
Oat & barley from
populations of lactobacilli, higher counts of
Oat based diet gave most diverse
Lactobacillus and Bifidobacterium &
longum during cold storage
Flammulina velutipes
casei, and Bifidobacterium longum subsp.
Lactobacillus acidophilus, Lactobacillus
spray-dried one
the porcine gastrointestinal microbiota
ͺͷ
Murphy et al., 2012
Shen et al., 2012
Chou et al., 2013
diets
beta-glucanase and endo-1, 4-beta-
Bifidobacterium genus with 0.3- 0.7 log10 cells/ml increase & Lactobacillus 0.7 to 1 log10 cells/ml increase
carbon sources in the 1L batch fermentation with Bifidobacterium pseudocatenulatum G4, B. longum BB536 and B. breve ATCC 15700 for 24h in 37oC with glucose used as
Ganoderma lucidum
(including beta-D-
glucans,
heteropolysaccharides
and glycoproteins)
glucans of bacterial origin & all the
WCFS1, L. acidophilus strain NCFM,
(EPS), mainly beta-
Demonstrated prebiotic action of a beta-
Growth kinetics of L. plantarum strain
Exo-polysaccharides
control
growth of probiotics with population of
Crude polysaccharides were used as
Polysaccharides from
explored Polysaccharide mixtures supported the
caecum and colon than the barley-based
enzyme supplementation (endo-1, 3-
xylanase) in both diets was also
Bifidobacterium counts in the ileum,
gastrointestinal microbiota, effect of
intrinsic beta-glucans
Lactobacillus in the caecum and colon and
beta-glucans on the 28 porcine
based diets with
ͺ
Russo et al., 2012
Yamin et al., 2012
Bifidobacterium longum, and
a relatively larger increase in populations
Bifidobacterium infantis,
mushroom sclerotia
2011
three bifidobacteria with B. infantis, having
were incubated with pure cultures of
bacteria, and
storage.
Bulgaricus)
All beta-glucans supported the growth of the Zhao & Cheung,
high viability (>108 cfu/mL) during 28 days
and Lactobacillus delbrueckii ssp.
strain
Beta-glucans from different sources
recombinant probiotic strain maintaining
cultures (Streptococcus thermophilus
paracasei NFBC 338
ͺ
Kearney et al., 2011
Barley, seaweed,
yoghurt cultures were found, with the
synergistic effect
glucose, EPS or both
Lactobacillus strain and 2 other yoghurt
into stationary phase, suggesting a
supplementing the same medium with
Lactobacillus
EPS as carbon sources delayed the entry
absence of carbon source or
No effect on growth and viability of the
simultaneous availability of D-glucose and
WCFS1-gal) were evaluated either in
Yoghurt with beta-glucan producing
consume beta-glucans for growth;
the -galactosidase gene (L. plantarum
Pediococcus parvulus
Recombinant
investigated bacterial strains were able to
recombinant strain that overexpresses
glucan, produced by
but later fermented rapidly with little remaining in the final half of the fermentation period
dietary fibers, including long-chain inulin, psyllium, the alkali-soluble fraction of corn bran arabinoxylan and
Barley & oat
Oat fiber
gas and short chain fatty acid production,
various purported slowly fermentable
beta-glucan type & exogenous enzyme
Endogenous beta-glucans had higher
of probiotic bacteria
starch and probiotics (B. breve & B. longum)
Addition beta-glucan improve the survival
Yogurt with beta-glucan, modified corn
long-chain beta-glucan
slower fermenting with comparatively low
of starch-entrapped microspheres, with
flour
Long-chain beta-glucan initially appeared
Comparison of fermentation properties
Corn bran and barley
positive control
bifidogenic effect with inulin as the
batch fermentation to evaluate their
Bifidobacterium adolescentis for a 24 h
Reilly et al, 2010
ͺͺ
Rosburg et al, 2010
Kaur et al., 2011
intervention but no significant increase in Bifidobacteria and Lactobacilli
(placebo group), for 3 months to determine the effect of barley-derived beta-glucans in the gut microbiota of
Barley
concentration on the 90th day of the
beta-glucans (3 g/d), or without
Zurich, Switzerland
Daily intake of food containing barley betaglucan is well-tolerated and barley beta-
in vivo prebiotic efficacy of barley betaglucans in human fecal microbiota
polypectomized patients
decrease of Clostridium perfringens
consume 125 g of bread per day with
Switzerland Ltd.,
on the 30th day of the trial & significant
20 subjects were randomly assigned to
and mineral metabolism in pigs
Significant decrease in total coliform counts
commercial purified beta-glucans
concentrations, nutrient digestibility,
Barley, DKSH
Clinical studies
pigs offered diets supplemented with
populations, volatile fatty acid
indole and skatole levels in the digesta
populations of Bifidobacterium compared to
supplementation on microbial
ͺͻ
Mitsou et al., 2010
Turunen et al., 2011
ͳͶ͵
ͳͶʹ
volunteers
clinical trial in 52 human healthy
double-blinded, placebo-controlled
specimen by conducting a randomized,
glucan induced a strong bifidogenic effect
ͻͲ