Nutrition, the gut microbiome and the metabolic syndrome

Best Practice & Research Clinical Gastroenterology 27 (2013) 59–72

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Best Practice & Research Clinical Gastroenterology

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Nutrition, the gut microbiome and the metabolic syndrome Petia Kovatcheva-Datchary, PhD, Postdoctoral Fellow *, Tulika Arora, PhD, Postdoctoral Fellow 1 Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Bruna Straket 16, 413 45 Gothenburg, Sweden

a b s t r a c t Keywords: Gut microbiota Metabolic syndrome Obesity Prebiotic Probiotic

Metabolic syndrome is a lifestyle disease, determined by the interplay of genetic and environmental factors. Obesity is a significant risk factor for development of the metabolic syndrome, and the prevalence of obesity is increasing due to changes in lifestyle and diet. Recently, the gut microbiota has emerged as an important contributor to the development of obesity and metabolic disorders, through its interactions with environmental (e.g. diet) and genetic factors. Human and animal studies have shown that alterations in intestinal microbiota composition and shifts in the gut microbiome towards increased energy harvest are associated with an obese phenotype. However, the underlying mechanisms by which gut microbiota affects host metabolism still need to be defined. In this review we discuss the complexity surrounding the interactions between diet and the gut microbiota, and their connection to obesity. Furthermore, we review the literature on the effects of probiotics and prebiotics on the gut microbiota and host metabolism, focussing primarily on their anti-obesity potential. Ó 2013 Elsevier Ltd. All rights reserved.

Introduction Diet and lifestyle are crucial factors that influence the susceptibility of humans to metabolic diseases. Metabolic syndrome is a modern concept and is defined as a combination of metabolic and medical disorders such as obesity, elevated fasting glucose, high blood pressure and dyslipidemia [1,2]. * Corresponding author. Tel.: þ46 31 3428672; fax: þ46 31 82 3762. E-mail addresses: [email protected] (P. Kovatcheva-Datchary), [email protected] (T. Arora). 1 Tel.: þ46 31 3428672; fax: þ46 31 82 3762. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.03.017

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The rates of occurrence of these conditions and interactions with each other differ between sex, age and ethnicities. However, diagnosis with any component of the metabolic syndrome increases the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [3]. The recent rise in obesity is regarded as the triggering factor for expansion of the metabolic syndrome. Although genetics play a role in the development of obesity, environmental factors are thought to be responsible for the recent dramatic increase in the prevalence of obesity. Obesity results from an imbalance between energy intake and expenditure. Growing evidence reveals the importance of the gut microbiota in the development of obesity (obesity pathogenesis). Thus dietary strategies to manipulate the gut microbiota, particularly the use of probiotics and prebiotics as therapeutics, are proposed for obesity and metabolic syndrome management (Fig. 1) [4]. The human gut harbours an immense assemblage of microorganisms, the gut microbiota, which comprise a population of 1014 cells. Their collective genome, termed the metagenome or microbiome, outnumbers the human genome by 150-fold [5]. Interestingly, this metabolic repertoire delicately affects our physiology with functions that we have not to evolve on our own. Gut microbiota possess an array of activities associated with utilization of non-digestible dietary carbohydrates and host-derived glycoconjugates (e.g. mucin), deconjugation and dehydroxylation of bile acids, biosynthesis of vitamins (K and B group) and isoprenoids, and metabolism of amino acids and xenobiotics. Based on this collective metabolic potential, the gut microbiota can be viewed as a separate ‘microbial organ’ [6]. In this review, recent advances in understanding the role of the gut microbiota in the development of obesity and potential therapeutic applications will be explored. Nutrition and gut microbiota maturation The interactions between diet and the gut microbiota in mammals are extremely complex, and any major change in lifestyle or diet is likely to affect microbial stability. Diet is a primary determinant in the development of the microbiota colonization pattern from the first stages of life. Exclusive breastfeeding results in an infant gut microbiota composition that is enriched in bifidobacteria and lactic acid bacteria, while formula feeding results in a more diverse community that is dominated by

Fig. 1. Interaction between diet and gut microbiota affects host metabolism. Dietary manipulation with probiotics and prebiotics alters the composition and metabolic capacity of gut microbiota. Dietary manipulation in obesity with prebiotics and probiotics changes gut microbiota by favouring bacteria beneficial to the host and enhances the production of short chain fatty acids (SCFAs) – acetate, propionate and butyrate. These result in decreased lipogenesis, reduced inflammation and oxidative stress in liver; decreased adipogenesis, and reduced adipocyte size and number in adipose tissue; increased production of gut hormones and intestinal transit in the large intestine; reduced appetite in the brain. GLP-1: Glucagon like peptide-1, PYY: Peptide YY.

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bifidobacteria, Bacteroides spp., Clostridium spp., and facultative anaerobes [7,8]. Breast milk is rich in oligosaccharides, which are known to act as substrates for fermentation in the distal gut and promote the growth of beneficial microbes as bifidobacteria [7]. The introduction of solid food leads to a large compositional shift into the intestinal microbiota composition [8,9]. Recently, the impact of diet on the gut microbiota composition at the stage of infant weaning has been studied. Comparison of the fecal microbiota by 16S rDNA sequencing of children from Burkina Faso (BF) consuming a rural African diet with children from Italy consuming a modern Western diet showed no significant differences in the microbiota composition between the two cohorts during the breastfeeding period [10]. However, weaning resulted in significant changes in the gut microbiota in both groups. In the BF children, enrichment in Bacteroidetes, with a significant abundance of bacteria from the genera Prevotella and Xylanibacter, was observed. These functional groups encode enzymes for hydrolysis of cellulose and xylan, thus enabling degradation of polysaccharides. In addition, fecal levels of short chain fatty acids (SCFAs), the main products of polysaccharide fermentation, were higher in BF children. A relative depletion of Firmicutes was also observed in the BF children. In the Italian children, these features were completely absent. Parallel ontogenetic changes of the microbiome among Malawian, Venezuelan and American populations from infants to adults, associated with differences in diet, culture and lifestyle, have been reported by Gordon’s group [11]. Greatest interpersonal variation, both in species and genes level, has been recorded in the infant microbiome, but still bifidobacteria was the dominant microbial group. The functional repertoire of the infant microbiome of the three populations was shaped with genes necessary for folate biosynthesis with a later shift to folate metabolism. Genes necessary for synthesis of vitamins, like B1, B7 and especially B12, were more enriched in the adult microbiome, together with genes involved in fermentation, methanogenesis, and metabolism of certain amino acids. Interestingly, the authors observed that the gut microbiomes of the Malawian and Venezuelan populations, which consume a ‘rural’ diet, were enriched in Prevotella spp., similar to the observation of De Filipo et al [10] in the Burkina Faso cohort. In the American population, since the diet is higher in protein, the microbiome is enriched with genes necessary for breaking down amino acids. Moreover, the microbiome of the American tends to shift to a more Bacteroides-enriched gut community [11]. These results support previous findings that carnivore microbiomes are enriched in protein degradation genes, while herbivore microbiomes are enriched in genes necessary to break down starch [12]. Together, these data confirm that nutrition is a driving factor in shaping gut microbiota composition and its functional maturation, from birth to adulthood. Nevertheless, more studies are needed to determine what factors or events during gut microbiota maturation might contribute to the development of metabolic disorders. Gut microbiome and obesity The development of obesity is a multifactorial process involving genetic susceptibility and environmental factors, such as lifestyle and inappropriate diet. Still the root of obesity aetiology is an imbalance between food intake and energy expenditure. Recently, the gut microbiota has been suggested as a driving force in the pathogenesis of metabolic disease and particularly obesity. Bäckhed and co-workers showed that mice raised in absence of microorganisms, termed germ-free (GF), had less total body fat than mice that were colonized with a normal microbiota at birth, termed conventionally raised (CONV-R), despite the fact that GF animals had higher caloric intake [13]. Colonization of GF mice with cecal content from CONV-R donors (resulting in ‘conventionalized’ (CONV-D) mice) resulted in increased total body fat without any increase in food consumption or energy expenditure. The CONV-D animals also displayed impaired glucose metabolism, increased levels of circulating leptin and glucose, and adipocyte hypertrophy after the two-week colonization period [13]. In a following study, Bäckhed and co-workers demonstrated that GF mice fed a high-fat, high-carbohydrate Western diet for eight weeks gained significantly less weight than CONV-R mice and were protected against diet-induced glucose intolerance and insulin resistance [14]. These findings suggest a relationship between nutrition, gut microbiota and energy homeostasis. Furthermore, several studies have suggested that the obese microbiome has an altered composition and functional repertoire. The development of obesity in genetically obese leptin deficient ob/ob mice

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has been associated with a reduction in the abundance of Bacteroidetes and a proportional increase in Firmicutes, two of the major bacterial phyla in the gut microbiota [15]. Similar changes in microbiota composition have been observed in wild-type mice fed a high-fat/high-sugar Western diet [16]. However, comparisons of the abundance of the two major bacterial phyla in obese vs. lean microbiome in animals and humans, have produced conflicting results. While several studies have reported similar increases in the ratio between Firmicutes and Bacteroidetes in obese individuals [17–19], other studies have not observed a change in the Firmicutes/Bacteroidetes ratio [20–22]. For example, one study reported reductions in Bifidobacterium spp. and Bacteroidetes and increases in specific members of Firmicutes (e.g. Staphylococcus) and Proteobacteria (e.g. Enterobacteriaceae) in overweight pregnant women [19], while another study found enrichment in Prevotellaceae, a group within the Bacteroidetes phylum, in obese individuals [20]. These disparities highlight the importance of considering factors such as diet, age, degree of obesity, demographic geography and population size, as well as technique and methodology used to profile the gut microbiota, when comparing studies. Nevertheless, an altered functional repertoire has been associated with the obese microbiome. Turnbaugh and co-workers identified a ‘core microbiome’ of microbial genes shared among individuals and found that variations from that core are associated with obesity [23]. Further metagenomic and systems biology-based approaches reached a similar conclusion, indicating that obese microbiomes have reduced taxonomic richness and a less modular metabolic network in comparison with lean microbiomes [5,24,25]. Comparable observations have been reported in a study comparing the microbiomes of pregnant women in the first and third trimester. The microbiomes from women in the third trimester were characterized by reduced microbial diversity and enrichment in Proteobacteria and Actinobacteria. Moreover, the transfer of fecal microbiota from women in the third trimester to germ-free mice induced symptoms of metabolic syndrome in the mice [26]. We might need more studies focused on identifying important microbial genes instead of on characterizing gut microbiota composition in order to describe the obese microbiome and further predict its response after therapeutics treatment. More mechanistic studies in animals are needed in order to elucidate functions of specific gut microbes on the host and to better understand their interactions with environmental factors (e.g. diet). Dietary manipulation in obesity As discussed earlier, it is possible to manipulate the gut microbiota composition with diet. The major dietary ingredients studied in recent years include prebiotics, probiotics and synbiotics. The interaction of these dietary ingredients with the microbiota is accompanied by physiological changes in the host. We will focus on the metabolic interaction of probiotics and prebiotics with the host and their anti-obesity potential (Fig. 1). Probiotics Metabolic interactions of probiotics with gut microbiota Probiotics are dietary supplements consumed in the form of fermented milk products, fermented foods or as drugs. Probiotics are defined as the live microorganisms that, when administered in adequate amounts, confer health benefits to the host [27]. Probiotic supplementation results in enrichment of the probiotic species in intestinal contents. It also results in alterations in the composition of gut microbiota and microbial metabolites, like SCFAs, in both murine models [28] and humans [29]. Recent applications of metagenomic and associated techniques have provided insight into the interaction of probiotics with the host gut microbiome. To reduce the complexity of studying crosstalk between probiotic species and millions of resident bacteria, GF mice were colonized with a simplified microbiota or mono- or bi-associated with representative bacterial species. Their interaction with probiotic bacteria was determined in this simplified setting by either global transcriptomics or global metabolite analysis as discussed in the following section. With regard to energy homeostasis, probiotics have been reported to expand the carbohydrate utilization properties of host microbiota members. In GF mice monocolonized with Bacteroides

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thetaiotamicron, co-colonization with Bifidobacterium longum resulted in upregulation of a gene locus in B. thetaiotamicron involved in the hydrolysis of xylose containing glycans. In contrast, cocolonization with Lactococcus casei upregulated a different set of genes encoding hexosaminidases and arabinosidases [30]. Enhanced carbohydrate utilization from non-digestible plant polysaccharides is known to result in higher production of SCFAs that contribute to total energy in the host. In GF mice monoassociated with the probiotic strains Lactobacillus plantarum WCFS1 [31] and Lacobacillus johnsonii NCC533 [32], an upregulation of genes involved in carbohydrate transport and metabolism was observed. While increased efficiency to hydrolyse different complex sugars in L. plantarum WCFS1 resulted in higher production of fumarate and alcohol [31], it led to a longer colonization period of L. johnsonii NCC533 in the mouse gut [32]. Consumption of fermented milk containing multiple probiotic strains led to enrichment of enzymes catalysing carbohydrates into propionate in both monozygotic twins and gnotobiotic mice containing a model human microbiota community [33]. Global metabolite profiling has also demonstrated that probiotics may affect the gut microbiome. L. paracasei altered levels of lipid species, creatine and glutathione implicating changes in lipid synthesis, nutrient absorption and oxidative stress in gnotobiotic mice [34]. L. paracasei and L. rhamnosus administration decreased the acetate:propionate ratio and increased catabolism of amino acids in humanized gnotobiotic mice. Changes in bile acid metabolism were observed with L. paracasei exclusively [35]. Thus, probiotics can alter both gene expression and function of the gut microbiota, thereby altering energy homeostasis and physiological functions in the host. Anti-obesity potential of probiotics With advancing knowledge of how probiotics interact with the gut microbiome, there is an increasing interest in exploring the anti-obesity potential of probiotics. Our main focus is to include the studies that have reported effects of probiotic supplementation on weight loss, energy intake or epididymal fat reduction (Table 1). Conjugated linoleic acid (CLA) is a naturally occurring derivative of linoleic acid found in foods and dairy products and has been shown to increase metabolic rate in mice [36]. The CLA-producing probiotic strain L. rhamnosus PL60 has been reported to reduce body weight gain and white adipose tissue mass with no effect on food intake in high-fat diet fed mice. The effect was coupled to higher expression of uncoupling protein-2 (UCP2), while expression of fatty acid synthase (fas) and serum leptin and glucose levels were reduced [37]. Another probiotic strain that produces CLA, L. plantarum PL62, also resulted in reduced body weight gain and glucose levels in diet-induced obese mice [38]. Probiotics have been shown to reduce adipocyte size in different adipose depots [39,40], which is considered an important parameter in assessing their anti-obesity potential. The putative mechanisms put forth are increased fecal excretion of neutral sterols and bile acids, decreased lymphatic absorption of triglycerides, phospholipids and cholesterol [41], or increased lipolysis [42]. In the 3T3-L1 cell line, incubation with L. plantarum KY1032 cell free extract resulted in reduced adipogenesis [43], and incubation with the insoluble fraction from fermented kefir resulted in reduced adipocyte differentiation [44]. Administration of L. paracasei NCC2461 to rats increased sympathetic nerve activity in white and brown adipose tissue, resulting in higher thermogenesis in brown adipose tissue and increased lipolysis in white adipose tissue [45]. Supplementation with L. paracasei F19 resulted in reduced total body fat and decreased triglyceride levels in different lipoprotein fractions in mice fed high-fat diet [46]. In addition, both GF and CONV-R mice supplemented with L. paracasei F19 had increased serum levels of Angiopoietin-like 4 (ANGPTL4), a microbially regulated lipoprotein lipase inhibitor that regulates lipid deposition into adipocytes [14,46]. Administration of L. paracasei F19 and L. acidophilus NCFB1748 to GF mice resulted in enrichment of probiotic strains in the ileum compared to the colon and upregulation of insulin-sensitizing hormones, adipsin and adiponectin. Decreased expression of resistin-like b, known to induce insulin resistance, was also reported [47]. Apoe/ mice that were supplemented with L. reuteri ATCC exhibited reduced body weight gain, reduced adipose and liver weights, and increased expression of carnitine palmitoyl transferase1a (cpt1a), suggesting higher hepatic b-oxidation [48]. There are relatively few studies that couple changes in microbiota composition upon probiotic supplementation with anti-obesity functions. Supplementation of L. rhamnosus GG and L. sakei NR28

Table 1 Anti-obesity effects of probiotic supplementation in animal and human studies. Animal strain or human

Diet

Probiotic strain

Dose

C57/BL6J mice C57/BL6J mice Sprague– Dawley rats

HFD

L. rhamnosus PL60

HFD

L. plantarum PL62

HFD

L. gasseri SBT2055

1 1 1 1 6

4.

Zucker obese and lean rats

HFD

L. gasseri SBT2055

6  107 cfu/g diet

5.

C57/BL6 mice

HFD

L. plantarum 14

1  108 cfu/mouse

Fermented milk powder added to diet in 20% concentration Fermented milk powder added to diet in 20% concentration PBS

6.

Sprague– Dawley rats db/db mice Sprague– Dawley rats

HCD

L. gasseri BNR 17

2  109/ml

PBS

1. 2. 3.

7. 9.

Regular diet HFD

    

7

107or 109 cfu/day 107or 109 cfu/day 107 cfu/g diet

10

Mode of delivery

Effects

PBS

YBWG, YAT mass, [37] No change in FI YBWG, YAT, [38] No change in FI YAdipocyte size, [39] No change in BWG, AT mass

PBS

[40]

[104]

1.5  109 cfu/mouse

Water

YAT, No change in BWG, FI

[66]

5  108/ml

Water

[45]

108–109 cfu

PBS

YBWG, YAT, No change in FI YBWG, YAT, No change in FI

2  109/ml

Saline

Water

PBS

HFD

14. Sprague– Dawley rats 15. C57/BL6J mice

HFD

L. plantarum DSM 15313

109 cfu/day

HFD

L. acidophilus NCDC13

5  107–9  107/ml Yoghurt

16. C57/BL6J mice

Normal Chow

L. sakei NR28 or L. rhamnosus GG

108 cfu/10 ml

Oral gavage

17. Balb/c mice

Normal Chow

L. ingluviei

4  1010

Gastric lavage

18. Apoe/ mice

High-fat western diet – 0.2% cholesterol Regular diet

L. reuteri ATCC PTA 4659, DSM 17938 (DSM), L6798

109 cfu/mouse per day

Drinking water

L. gasseri SBT2055

5  1010 cfu/100 g

Fermented product

L. rhamnosus GG

107 cfu/g

L. rhamnosus GG

1  1010

21. Pregnant women

YAdipocyte size, YAT, No effect on BWG YBWG, YAT, No effect on FI YBWG, YFI

VSL#3 (Lactobacilli, Bifidobacterium spp. & S. salivarius ssp. thermophilus) L. paracasei ST11 (NCC2461) B. pseudocatenulatum SPM 1204, B. longum SPM 1205, and B. longum SPM 1207 B. longum

cfu/day

12. Wistar rats

Formula diet Regular diet

[41]

10 –10

HFD

19. Healthy, overweight subjects 20. Infants

YAT, YAdipocyte size in lean rats, No effect on BWG, FI

L. gasseri BNR 17

10. Wistar rats 11. Sprague– Dawley rats

HFD

Reference

YBWG, YAT, Yblood glucose YBWG, YAT, Yleptin [Bifidobacterium spp., No change in FI, BWG, AT YFirmicutes – particularly Clostridium cluster XIVa, YBWG, YAT [Firmicutes, Lactobacillus spp., [BWG YBWG, YAT, Yliver weight

[105]

[106]

[107]

[108]

[50]

[49]

[51]

[48]

[52]

Formula diet

YVisceral, subcutaneous fat, YBWG, YBMI [Length, [weight

Capsules

YBWG in children

[54]

[53]

AT: Adipose tissue, BWG: Body weight gain, FI: Food intake, HCD: High-carbohydrate diet, HFD: High-fat diet, PBS: Phosphate buffered saline.

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reduced the relative abundance of both Firmicutes and Clostridium cluster XIVa in the small intestine of mice and was accompanied by reduced body weight gain, epididymal fat mass and expression of hepatic stearoyl-CoA desaturase-1 (scd-1), fas and acetyl-CoA carboxylase (acc) enzymes involved in lipogenesis [49]. However, supplementation with L. acidophilus NCDC13 in diet-induced obese mice increased total bifidobacteria in caecal contents as well as feces but did not decrease adiposity [50]. In yet another study, inoculation with L. ingluviei enriched total fecal Lactobacillus spp. and Firmicutes in mice and, in contrast to other studies, resulted in increased body weight gain, liver weight, and metabolism [51]. In healthy overweight subjects, administration of L. gasseri SBT2055 resulted in reduction of abdominal visceral and subcutaneous fat [52]. Supplementation of L. rhamnosus GG in the infant formula for six months resulted in better growth with higher weight gain [53]. However, in a follow up study, pre- and postnatal administration of L. rhamnosus GG inhibited excessive weight gain in children [54]. Thus, the physiological effects of probiotics are highly strain-dependant. The variations in outcomes between different studies appear to be due to choice of probiotic strain, route of administration and length of study. Probiotic effect on liver function Hepatic steatosis is closely linked to metabolic syndrome. It is characterized by aberrant lipid storage in liver and subsequent hepatic inflammation. Ischemia/reperfusion is a model of acute liver injury which leads to disruption of gut microbiota composition with increases in Enterococci and Enterobacteria and concomitant decreases in Lactobacillus spp. and Bifidobacterium spp., eventually resulting in higher plasma endotoxin levels. In addition, bacterial translocation to the kidney has been reported [55]. Colonization of GF mice with microbiota from hyperglycaemic mice has been shown to contribute to the development of fatty liver disease independent of obesity [56]. Probiotics have also been implicated in the improvement of liver functions. These effects are mediated by the role of probiotic bacteria in normalization of intestinal microbiota composition, immunomodulation and maintenance of gut barrier function [57]. L. paracasei F19 supplementation protected rats from ischemia/reperfusion-induced liver injury by restoring ileal lactobacilli and bifidobacteria numbers and intestinal barrier [58]. Supplementation with different lactobacilli strains (L. acidophilus NM1; L. rhamnosus ATCC 53103, and L. rhamnosus DSM 6594 þ L. plantarum DSM 9843) [59] or with the combination of L. fermentum and B. catenulatum [60] prevented bacterial translocation and decreased Enterobacteriaceae in a rat model of acute liver injury. However, B. animalis increased the bacterial translocation to mesenteric lymph nodes with no effect on liver damage [59]. L. rhamnosus GG ameliorated alcohol-induced liver disease by reducing inflammation and oxidative stress in both liver and colon [61]. It also reduced alcohol-induced gut leakiness, increased expression of ileal tight junction proteins maintaining the epithelial integrity [62], and decreased endotoxemia preserving the gut barrier function [62]. The effects exerted by the probiotic were found to be dependant on hypoxia-inducible factor [63]. Supplementation with VSL#3, another multistrain probiotic, mediated a natural killer T cell-dependant improvement in diet-induced steatosis and hepatic insulin signalling, resulting in improved insulin sensitivity [64]. VSL#3 supplementation also reduced c-jun kinase activity and hepatic lipogenesis in leptin deficient ob/ob mice [65]. The antioxidative effects of VSL#3, coupled with reductions in inflammatory enzymes like inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, have also been shown to protect against liver damage in mice [66]. Prebiotics Metabolic interactions of prebiotics with gut microbiota Prebiotics are defined as dietary ingredients that promote ‘the selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host’ [67]. Dietary fibres are known to exhibit prebiotic effects as they are utilized by specific bacteria, resulting in their proliferation, which are considered beneficial to the host.

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The most studied prebiotic supplements are inulin and related variants such as fructooligosaccharides, which have different degrees of polymerization. Inulin is generally bifidogenic in nature, i.e. it enhances the growth of Bifidobacterium spp. and some Lactobacillus spp. in different murine models. This effect is coupled with a reduction in body weight gain and improvements in glucose homeostasis [68–70] and obesity-related inflammation called metabolic endotoxemia [71,72]. However, pyrosequencing revealed that oligofructose feeding resulted in changes in more than 100 taxa, of which 16 taxa displayed more than ten fold change [73]. One of the identified species was Akkermansia muciniphila, which was negatively correlated with body weight [19]. Other studies have also shown that prebiotic fibre decreased the Firmicutes to Bacteroidetes ratio in obese rats [74]. Supplementation of fungal chitin glucan increased the number of bacteria closely related to Clostridium cluster XIVa including Roseburia spp., which was accompanied by reduced weight gain and fat mass development [75]. Wheat derived arabinoxylans also restored the levels of Bacteroides–Prevotella spp. and Roseburia spp. and markedly increased caecal bifidobacteria content, in particular B. animalis lactis, in high-fat diet fed mice [76]. In healthy humans, the consumption of polydextrose and soluble corn fibre led to greater fecal Clostridiaceae and Veillonellaceae and lower Eubacteriaceae. The abundance of Faecalibacterium, Phascolarctobacterium, and Dialister was greater following prebiotic intake [77]. Addition of inulin to the diet increased Bifidobacterium spp. and Faecalibacterium prausnitzi and decreased Bacteroides intestinalis, Bacteroides vulgatus and Propionibacterium in obese women [78]. Consumption of galactooligosaccharides for 12 weeks induced increases in several lineages of Bifidobacterium spp. at the expense of Bacteroides in healthy human subjects [79]. Anti-obesity potential of prebiotics Prebiotics exhibit anti-obesity potential owing to their fermentation in distal gut and impact on gut microbiota composition, which have different physiological prospects. The underlying mechanisms driving the response are not clear. However, there are some links associated with production of SCFAs, decrease in bacterial derived lipopolysaccharides and alteration in gut hormones production. The major studies reflecting anti-obesity effects of prebiotics in both humans and animal models are presented in Table 2. The major effect of inulin supplementation appears to be its influence on production of gastrointestinal hormones like glucagon like peptide-1 (GLP-1), peptide YY (PYY), ghrelin and other related peptide hormones both in rodents [70,74,80] and in humans [81–83]. These hormones modulate several physiologic functions such as insulin secretion (incretin effect), gastrointestinal motility and appetite regulation by modulating secretion of neuropeptides in major hypothalamic appetite centers. These factors may all contribute to the anti-obesity potential of prebiotics. Microbial production of SCFAs has been proposed to play a role in increasing secretion of gut hormones like GLP-1 [84,85]. Inulin supplementation has also been reported to reduce fat mass accumulation in different adipose tissue depots and to affect adipose tissue metabolism. It reduces lipolysis in subcutaneous adipose tissue and blunts the expression of GPR43, a G-protein coupled receptor that regulates adipogenesis in diet-induced obese mice [86]. A link between the endocannabinoid system (eCB), changes in gut microbiota composition and adipogenesis has also been suggested. The eCB system is overexpressed in obesity [87]. Inulin supplementation in ob/ob mice decreased adiposity and was coupled with reduced anadamide content and cannabinoid receptor-1 expression in adipose tissue [88]. Prebiotic supplementation has been shown to influence not only fat mass but also host energy homeostasis. When gnotobiotic mice were colonized with microbiota from human infants and supplemented with L. paracasei and galactooligosaccharides, global metabolites analysis revealed increased levels of glutamate, glutamine, branched-chain amino acids and alanine in the liver as well as accumulation of hepatic glycogen, suggesting increased gluconeogenesis and glycogenesis [89]. It also increased SCFAs production and excretion of protein breakdown metabolites [90]. The increased excretion of energyrich metabolites upon supplementation of inulin and beta-glucan was also shown in high-fat fed mice [91]. A role for prebiotic fibres in appetite regulation has also been demonstrated. The central hypothalamic brain centers like arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus and brainstem regions involved in appetite regulation were shown to be differentially activated upon prebiotic feeding. A satiating effect of resistant starch, supported by reduced neuronal activity in

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Table 2 Anti-obesity effects of prebiotic supplementation in animal and human studies. Animal strain or human

Diet/period

Prebiotic

Dose

Effects

Reference

1.

Wistar rats, male

Raftilose P95 (OFS based)

100 g/kg diet

Improve glycaemia and plasma insulin, [plasma portal GLP-1, YFI

[70]

2.

Wistar rats, male C57/BL6J mice, male C57/BL6J mice, male ob/ob C57/BL6J mice

Regular diet/six weeks HFD/five weeks HFD/four weeks HFD/14 weeks HFD/eight weeks

OFS

100 g/kg diet

[80]

OFS

100 g/kg diet

[plasma portal GLP-1, [serum GIP, YBWG Yfasted and fed blood glucose, YBWG

OFS

Not described

[71]

OFS

0.3 g/mouse per day

6.

C57/BL6J mice, male

HFD/four weeks

AX

100 g/kg diet

7.

C57/BL6J mice, male

HFD/ weeks

Chitin-glucan fibre

100 g/kg diet

8.

C57/BL6J mice, male

HFD/eight weeks

AXOS

75 g/kg diet

9.

Lean and obese JCR:LA-cp rats, male

Regular diet/six weeks

Inulin-OFS

0%, 10% and 20% Inulin–OFS mix

10.

Men and women

OFS

2  8.0 g/day

11.

Men and women

Orafti Synergy1

2  8.0 g/day

Yhunger, [satiety, [breath H2, [GLP-1, [PYY

[81]

12.

Men and women

AXOS

2  5.0 g/day

[Bifidobacterium spp., Yp-cresol urine excretion

[111]

13.

Men and women

GOS

0.0 g, 2.5 g, 5.0 g, 10.0 g/day

GOS dose dependant [Bifidobacterium spp.

[79]

14.

Men and women

Chitin-glucan fibre

1.5 g/day or 4.5 g/day

YLDL oxidation, YLDL cholesterol

[112]

15.

Obese women

Regular diet/two weeks Regular diet/two weeks Regular diet/three weeks Regular diet/12 weeks Regular diet/six weeks Regular diet/12 weeks

Restored Bifidobacterium spp. levels, improved blood glucose YFirmicutes, [Bacteroidetes, YProteobacteria, [Verrucomicrobia, [L-cell number, improved glucose tolerance and lipid metabolism, YLPS [Bifidobacterium spp. (e.g. B. animalis lactis), restored Roseburia spp. and Bacteroides–Prevotella spp. levels, YBWG, Yfat mass development, YAT [Firmicutes (Clostridium cluster XIVa – Roseburia spp.), YBWG, Yfat mass development, Yfasting glucose, improved glucose tolerance, Y hepatic triglycerides, Y cholesterol [Bifidobacterium spp., YLactobacillus spp., YBWG, Ycaloric intake, Yfat mass, [PYY, [GLP-1, YLPS [Firmicutes, YBacteroidetes, dose dependant [Bifidobacterium spp. and Lactobacillus spp., dose dependant [satiety hormones [satiety after breakfast and dinner, Yhunger and YFI following dinner

Inulin type fructan

16 g/day

[78]

16.

Men and women

AXOS

0.0 g, 2.2 g, 4.8 g/day

17.

Men and women

Regular diet/three weeks Regular diet/three weeks

[Actinobacteria (Bifidobacterium spp.), [Firmicutes (Clostridium leptum group – Faecalibacterium prausnitzii), YBacteroidetes (B. intestinalis and B. vulgatus), YPropionibacterium, YLPS Dose dependant [Bifidobacterium spp., Dose dependant [ferulic acid

GOS

2  4.0 g/day

[Bifidobacterium spp.

[114]

3. 4. 5.

[68]

[73]

[76]

[75]

[109]

[74]

[110]

[113]

AT: Adipose tissue, AX: Arabinoxylan, AXOS: Arabinoxylan-oligosaccharide, BWG: Body weight gain, FI: Food intake, GIP: Gastric inhibitory peptide, GLP-1: Glucagon like peptide-1, GOS: Galactooligosaccharide, HFD: High-fat diet, LDL: Low density lipoprotein, LPS: lipopolysaccharide, OFS: Oligofructose, PYY: Peptide YY.

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ventromedial and paraventricular hypothalamic nuclei, was shown [92]. Supplementation with betaglucan also resulted in reduced activity in the arcuate nucleus and related appetite centers, which could explain the reduced weight gain in animals [91]. On the contrary, inulin supplementation was shown to increase neuronal activity in the arcuate nucleus; however, a reduction in body weight gain was consistently observed [93]. Prebiotics effect on liver function Prebiotics may also ameliorate liver diseases by decreasing hepatic de novo lipogenesis [94]. A number of studies have shown reductions in enzymes like acc, malic enzyme, ATP citrate lipase and fas upon prebiotic supplementation [95–98]. However, other studies have not found any effect on fatty acid synthase, but rather on enzymes expression involved in b-oxidation of lipids [99,100]. Reduction in free fatty acid esterification to triglycerides in hepatocytes has also been reported [101]. Prebiotics may also contribute in this regard by altering the acetate:propionate ratio [102,103]. As acetate is lipogenic in nature, production of more propionate compared to acetate may decrease the hepatic lipogenic potential. Conclusion The prevalence of obesity and allied disorders such as metabolic syndrome are becoming a great challenge for health care throughout the world. Diet and lifestyle are crucial factors influencing the development and progression of obesity. Recent insights have examined obesity aetiology with a new perspective and found that our own microbiota might be involved in the development of these disorders. The plexus surrounding diet and the microbiome in mammals remains to be unravelled. More controlled human and animal studies are necessary to clarify these complex interactions. One possibility is the combination of metagenomic and metabolomic approaches in order to further elucidate the metabolic interactions between diet, the microbiota and the host and to understand how the microbiome is altered in obesity. Those approaches, combined with more mechanistic studies in animal models, will help to further describe in situ functions of distinct microbial groups or individual species of the gut microbiota and to understand their roles in human physiology including metabolic diseases.

Practice points  Nutrition is a driving factor in shaping gut microbiota composition and its functional maturation from the early stages of life.  The gut microbiota has been recognized as an important contributor to pathological conditions such as obesity and metabolic disorders.  Alterations of the composition and functional properties of the gut microbiota have been associated with obesity.  Increasing Bifidobacterium spp. by dietary means may have anti-obesity effects.

Research agenda  The mechanisms by which the gut microbiota contributes to the development or maintenance of obesity are not well understood.  The underlying mechanisms by which probiotics and prebiotics exert their anti-obesity effects need to be deduced.  There is a need for well-controlled studies with regard to gut microbiota modulation, changes in microbial metabolites and corresponding anti-obesity effects following probiotic supplementation.

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