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Impact of diet on the human intestinal microbiota
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ScienceDirect Impact of diet on the human intestinal microbiota Huizi Tan1,2 and Paul W O’Toole2,3 It is well established that habitual diet influences the establishment and composition of the human intestinal microbiota during the lifespan. Bacterial communities colonize the human gut, producing a complex array of metabolites and signalling molecules that impact on host intestinal and extraintestinal health. These functions are implicated in gastrointestinal diseases such as irritable bowel syndrome, inflammatory bowel disease and metabolic syndrome, and potentially even in enteric or even central nervous system related disorders. Bacterially encoded metabolic activities are involved in various metabolic processes in the host. In this review, we summarize and evaluate the impact of diet on the composition and function of the human gut microbiota. Addresses 1 School of Food Science and Technology, Jiangnan University, Wuxi 214122, China 2 School of Microbiology, University College Cork, Cork, Ireland 3 Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Corresponding author: O’Toole, Paul W ([email protected])
Current Opinion in Food Science 2015, 2:71–77 This review comes from a themed issue on Food Microbiology Edited by Marco Gobbetti
doi:10.1016/j.cofs.2015.01.005 S2214-7993/# 2015 Elsevier Ltd. All rights reserved.
Introduction There are an estimated 10–100 trillion microbes in the human intestine, which possess 100-fold more bacterial genes than human genes [1]. It is widely cognized that these gut microbiota is 10-fold more than human cells, but was challenged by J. Rosner (2014) who emphasized the variability of individual cell numbers due to body size, age and nutritional intake [2]. The individual gut microbiota has a broad range of variability. The traditional culture method estimates that there are around 100 bacterial species in the human gut [3], while culture-independent deep shotgun DNA sequencing indicates around 160 species. By abundance, Firmicutes and Bacteroidetes are the two predominant phyla within the gut microbiota, followed by Proteobacteria, Actinobacteria, Fusobacteria and Verrucomicrobia. The diversity changes throughout the lifespan of the individual, from infants whose intestinal microbiota composition is simple consisting mainly of www.sciencedirect.com
high levels of Bifidobacterium spp. and opportunistic aerobes like Staphylococcus, Streptococcus and Enterobacteriaceae, followed by clostridia and Bacteroidetes, through to the typical ten-phylum dominance of the healthy adult intestinal tract, and to the low diversity microbiota that is a feature in some elderly subjects [4]. Quantitative PCR (qPCR) was recently used to study human microbiota changes during ageing with faecal samples comprising 21 infants, 21 adults and 20 elderly. This study suggested that the Firmicutes/Bacteroidetes ratio of the sample groups differs from each other, with values of 0.4, 10.9 and 0.6 respectively [5]. However, gut microbiota composition varies not only as a function of age but also by dietary habitat, health status, geographical factors, and environmental factors such as hygiene and socioeconomic status. Intestinal bacteria interact with each other and the host through metabolite production and substrate fermentation, which explains why diet has such an important role in modifying human intestinal microbiota.
Diet influences the composition of gut microbiota Zhao et al. (2010) reported that 57% of variation in the composition of gut microbiota was related to dietary change, while only 12% was related to genetic differences [6]. Another study indicated that the general alteration in the structure of the gut microbiota in wild-type and RELM b knock-out mice was similar after a high-fat diet [7]. These results strongly suggest that diet is the dominant factor in shaping gut microbiota. Gordon et al. (2009) showed that the gut microbiota can be modified within one day of changing the diet and can maintain this change for 7 days in a humanized germ-free mouse model [8]. Though results from animal experiments cannot be extrapolated directly to humans, they provided proof of concept and paved the way for human dietary interventions described below. Many scientists focused their research on different geographical regions where people have vastly different diet types. For example, greater abundance of phylum Bacteroidetes, mainly Prevotella and Xylanibacter, was found in rural African children who generally have a diet with low content of fat and animal protein and high in fibre, starch and plant polysaccharides; whereas a significant over-abundance of Firmicutes like Acetitomaculum and Feacalibacterium, as well as Enterobacteriaceae (Shigella and Escherichia), was detected in European children who are fed a typical western diet with almost twice the number of calories as the diet of African children [9]. Another similar study compared the gut microbiota of Japanese-Hawaiians and North American Caucasians who Current Opinion in Food Science 2015, 2:71–77
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have a western diet with a lot of red meat and high fat, with rural native Japanese and rural native Africans who retain a ‘native’ diet which is completely different from the western diet [10]. They found that some Lactobacillus species as well as Collinsella aerofaciens were enriched in the ‘native’ diet population but species within the genera Bacteroides and Bifidobacterium were more abundant in the western diet subjects, which is suspected to be related with high risk of colon cancer. The relationship between habitual diet and gut microbiota composition has been investigated using different techniques. Ramakrishna et al. (2011) examined the differences in gut microbiota of vegetarians and omnivores in Southern India using real-time PCR, which showed that the Roseburia-Eubacterium rectale group within Clostridium cluster XIV was significantly abundant in omnivores [11]. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) fingerprinting analysis was used by Haslberger et al. (2008) to reveal that a higher level of Bacteroides and lower abundance of Clostridium cluster IV, especially Faecalibacterium sp. and Ruminococcus sp. was present in vegetarians compared with omnivores [12]. However, Enck et al. (2012) published a contradictory study where a reduction in the abundances of Escherichia coli, Bacteroides spp. and Bifidobacterium spp. and the Enterobacteriaceae family in vegans or vegetarians was detected using culture-dependent methods [13]. A recent study investigated the response of gut microbiota to short-term diet change. When the subject consumed an exclusively animal-based diet, Firmicutes, such as Roseburia, E. rectale and Ruminococcus bromii that are involved in utilizing fermentable carbohydrates showed decreased abundance while proportions of Alistipes, Bilophila and Bacteroides increased [14,15]. The gut microbiota of infants is also intensively researched. It is widely believed that the gut microbiota of breast-fed (BF) babies is less diverse than that of formula-fed (FF) babies. Breast milk has been suggested by one study to provide 109 microbes per litre [16], consisting of Bifidobacteria, Lactobacillus and Staphylococcus which help shape the infant microbiota. Regarding FF babies, their higher diversity gut microbiota contains bacterial taxa like Clostridium, Bacteroides, enterobacteria and Enterococcus, significantly distinguishing them from BF babies [17]. However, some reports maintain that there would be no significant differences when the formula milk is supplemented with prebiotics like galactooligosaccharides and fructooligosaccharides [18] which can promote the colonization of Bifidobacterium and Lactobacillus thus making the gut microbiota similar to that of BF babies. Dietary fibre is widely found in food derived from plants, such as resistant starch (RS), pectin, oligosaccharides and insulin, most of which can be broken down by intestinal Current Opinion in Food Science 2015, 2:71–77
bacteria [19]. Two species, R. bromii and E. rectale, showed significant response to RS type 2 compared to RS type 4 (RS4) [20]. RS 4 raised the proportions of Actinobacteria and Bacteroidetes and reduced Firmicutes; more especially, Bifidobacterium abundance was increased ten-fold to 18–30% in gut microbiota. A study from Walker et al. (2011) showed partial agreement with the above results and indicated that RS diet could also increase the abundance of the Oscillibacter group [15]. Pectin from apple intake was said to be associated with an increase in the abundances of Bifidobacterium, lactobacilli and streptococci and a corresponding reduction in the abundances of Enterobacteriaceae, Pseudomonas and some lectithinase-positive clostridia [21].
Effects of dietary changes on the gut microbiome Although the composition of gut microbiota is altered by dietary changes, the gut microbiome, that is, the total coding capacity of the gut bacterial community and its expression level, is also regulated by diet. For instance, polysaccharide-utilization loci in gut microbiota such as Bacteroides thetaiotaomicron are up-regulated in response to host-derived polysaccharides [22]. A mouse model study showed that when administered a high-fat diet, genes involved in signal transduction, cell motility, membrane transport, replication and repair within Proteobacteria, Bacteroidetes and Firmicutes phyla were up-regulated, whereas genes involved in carbohydrates metabolism, amino acid metabolism, energy metabolism were down-regulated [7]. However, in the humanized gnotobiotic mice, carbohydrate metabolism related genes were up-regulated on a western-diet, along with two phosphotransferase system (PTS) genes encoding glucose and fructose import and carbohydrates linked with host gut mucosa, whereas genes from Bacteroides sp. were up-regulated on low-fat/plant polysaccharides diet [8]. Genes associated with vitamin biosynthesis, b-lactamase and degeneration of polycyclic aromatic hydrocarbons were up-regulated when consuming an animal based diet [14]. Another study which focused on vegetarians concluded that there are more bacterial butyryl-CoA CoAtransferase genes in omnivore faeces than vegetarians, which relate to more butyrate produced [11]. This differs from previous studies that suggested that fewer saccharolytic elements in the gut microbiota resulted in less Short chain fatty acid (SCFA) production. Regarding feeding mode of infants, the gut microbiota of FF babies harboured a lower bacterial gene count compared to breast fed babies [23]. Furthermore, the genes NDST1, IL1A and ALOXS which are associated with immune response and mucosal defence were expressed at lower levels in breast fed babies, whereas genes associated with www.sciencedirect.com
Impact of diet on the human intestinal microbiota Tan and O’Toole 73
angiogenesis, peroxidase generation, intestine proliferation and gut motility were less expressed in FF babies. Apart from the regulatory function of diet on bacterial genes, diet can also ‘create’ or select functional genes in the gut microbiota. Porphyranases and agarases were frequently observed in the gut microbiota of Japanese subjects but were absent in Northern Americans [24]. This phenomenon is due to the large proportion of marine algae contained in the Japanese diet, and sulphated polysaccharides that are enriched only in marine products like seaweed [25]. This shows that genes encoding porphyranases and agarses were horizontally acquired by the gut microbiota, and highlights that the gut microbiota interacts with and may ultimately be genetically modified by environmental bacteria because of selection imposed by habitual diet.
Functional metabolites produced by the gut microbiota The gut microbiota produces a complex array of metabolites and signalling molecules that mediate the interactions between gut microbes and host intestinal and extraintestinal. As a result of modification in gut microbiota that maybe caused by dietary alteration, different metabolites will be produced and may perform anti-inflammatory or pro-inflammatory activities. Short chain fatty acid (SCFA) are a group of simple 2-carbon to 5-carbon fatty acids produced by the intestinal microbiota during fermentation of undigested resistant starch or oligosaccharides, mainly acetate, propionate, butyrate. Most of these metabolites can be absorbed through the colonic wall and exert various beneficial characteristics on the host other than providing basic energy [26,27]. SCFAs can induce neutrophil chemotaxis by activating G protein-coupled receptors GPR41 and GPR43 [28,29]. Butyrate is considered to be an anti-carcinogenic compound [30]. Nuclear factor kB (NF-kB) formation can be suppressed by butyrate and consequently relieve inflammation in IBD patients [31]. Butyrate can inhibit the migration of macrophages caused by LPS [32], and also reduce the production of inflammation promoting cytokines like TNF-a and IL-6 while increase anti-inflammation cytokines IL-10 from macrophages [29,33]; it can also enhance gut barrier [34] and improve intestinal motility disorders [35]. The production of butyrate accelerates as intestinal pH decreases while other SCFAs are being produced. This low pH environment allows the growth of Firmicutes especially Faecalibacterium prausntizii, E. rectale and Roseburia spp., but is apparently a less favourable environment for some potentially pathogenic gram-negative species such as Bacteroides spp. and E. coli [36,37]. Acetate is one of the most abundant SCFA metabolites in the human intestine. A recent elegant study showed that acetate produced by Bifidobacterium can protect epithelial cells against E. coli O157:H7 Shiga toxin www.sciencedirect.com
[38]. Propionate participates in the succinate pathway and acrylate pathway [39]. And propionate as well as butyrate can induce apoptosis of human colon carcinoma cells which are infinite proliferous and finally lead to tumours [40]. This discovery may provide a clue to help clean those carcinoma cells in a ‘healthy’ way. Vitamins are a class of organic compounds that help maintain normal physiological function but can only be obtained from diet. In point of fact, however, intestinal commensal bacteria can also contribute to providing their host with essential vitamins like vitamin K and water-soluble B vitamins. One sub-class of Vitamin K, Vitamin K2, is mainly synthesized by gut microbiota elements such as Bacteroides spp. [41]. Vitamin K can help prevent and treat osteoporosis by improving bone mineral density [42], and its deficiency can induce cardiovascular disease [43]. Microbial synthesis is the only source of Vitamin B12 in nature, including metabolism of intestinal microbiota. Vitamin B12 is involved in the methionine synthesis pathway and metabolism of folic acid [44]. Folate is a vitamin that has an important role in DNA replication, repair and methylation as well as proliferation of cells. A recent study demonstrated that Bifidobacterium strains such as B. adolescentis and B. pseudocatenulatum can utilize different carbohydrates to synthesis folate [45]. Another study identified readily absorbed monoglutamylated folate in the infant colon [36,46], and this may be related to the oligosaccharides in infant food can promote the growth of Bifidobacterium spp. [45] rendering it a major component in infant gut microbiota as described early in this review. For all the preceding proposed syntheses of vitamins by gut bacteria, the balance and relative importance of dietary versus microbiota-derived vitamin remains to be determined, and this is an active strand of our current research. Nevertheless vitamin production by gut bacteria may be a legitimate target for promoting life-long increases in vitamin production. Protein metabolites are large molecules secreted by gut microbiota that are directly involved in host immune modulation, for example the increasing realization of such activity for the bacteriocins produced by lactic acid bacteria (LAB). Nisin is one of the lanthionine-containing antibiotics produced by Lactococcus lactis subsp. Lactis. It can suppress the growth of Helicobacter pylori and promote the growth of Bifidobacterium, stimulate the production of immunoglobulin A (IgA), and help maintain a healthy intestinal homeostasis [47]. Lactobacillus salivarius UCC118 can reduce H2O2-induced inflammation in transepithelial resistance, but paradoxically production of the salivaricin bacteriocin, which is viewed as a desirable trait in terms of suppressing intestinal pathogens [48], reduces the improvement of barrier function because of inflammatory activity of the bacteriocin [49]. In addition to proteinaceous macromolecules that can affect the host, other classes of metabolite benefit the Current Opinion in Food Science 2015, 2:71–77
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host through modulating inflammatory functions in different ways. Polysaccharide A (PSA) which is one component in the zwitterionic polysaccharides of Bacteroides fragilis and released in outer membrane vesicles (OMVs), can activate interleukin-10-producing CD4+ T cells via toll-like receptor 2 and abolish the expression of interleukin-17 (IL-17), so as to help the colonization of B. fragilis and alleviate colitis [50]. F. prausntizii helps to ameliorate TNBS colitis by accelerating IL-10 and suppress IL-12, particularly unknown factors in its supernatant which inhibit the activity of IL-1b-induced NF-kB [51]. The mechanism by which this occurs is unknown. g-Aminobutyric acid (GABA) is a natural non-protein amino acid, that is a neuroactive compound which plays a dominant role in inhibiting transmission in central nervous system (CNS) [52]; GABA is implicated in various physiological functions, such as hypotension, diuresis and sedation. GABA deficiency may cause anxiety, fatigue and depression [53]. GABA can be produced by the human intestinal microbiota, among which Lactobacillus brevis and Bifidobacterium dentium were identified to be two promising GABA producers [54]. L. brevis is being evaluated as a contributor to intestinal bacterial GABA production. Appetite-regulating peptides like leptin, ghrelin, peptide YY, and neuropeptide Y can be produced by various intestinal bacteria like Lactobacilli, Bacteroides, H. pylori, E. coli, and Candida sp. [55]. These peptides can trigger autoantibodies like IgA and IgG as well as affect the nerve signalling of human and other mammalian animals thus controlling hunger and satiety [56]. The biochemical activity of the intestinal microbiota may also lead to potentially toxic metabolites such as volatile phenols, mainly in the form of cresol, which can be produced by species of Clostridum and Bifidobacterium from tyrosine [57]. Increased levels of 4-cresol are associated with decreased abundance of Lactobacillus spp. [58] as well as the alteration of the Firmicutes to Bacteroidetes ratio [59], a phenomenon associated with weight loss and even inflammatory bowel diseases. Lipopolysaccharide (LPS) is a common part of the outer membrane of Gramnegative bacteria. A high-fat diet can increase the proportion of Gram-negative bacteria in the human gut microbiota and promote the release of LPS that may lead to chronic systemic inflammation [60].
Diet helps improve health status by microbiota-related mechanisms As diet strongly influences the composition of gut microbiota and consequently regulates functional gene expression and metabolism production as stated above, scientists are testing special functional diets that may help cure diseases by modifying the human gut microbiota. Current Opinion in Food Science 2015, 2:71–77
Gordon et al. (2006) tested the effects of a fat-restricted and a carbohydrate-restricted low calorie diet on body weight reduction. They found that both diets could give rise to an increase in Bacteroidetes abundance, which was considered to be in a direct ratio with the weight loss [59]. Research has shown that Mediterranean diet intake may aid treatment of obesity, type II diabetes and lower the risk of cardiovascular diseases [61,62]. The Mediterranean diet, including relatively large intake of vegetables, fruits, nuts, grains and olive oil, moderate or low amount of wine, fish, red meat, tea, coffee, and sweets, is a nutritionally recommended diet pattern that is consumed naturally in countries like Italy, Greece, Spain and Morocco. Polyphenols in wine, fruits, and vegetables may raise the proportions of Bifidobacterium, Enterococcus, Bacteroides, and Prevotella and decrease the abundance of pathogens like Clostridium perfringens, adjustments which in general improved inflammatory condition caused by obesity [63]. At the same time, low-fat content in this diet may link to increased proportions of Bifidobacterium and Bacteroidetes [6,59]. SalasSalvado et al. (2011) reported that more than 50% of the type II diabetes symptomology was relieved in 54 volunteers after having consumed a Mediterranean diet for 4 years [62]. A peanut-based, ready-to-use therapeutic food (RUTF), which contains peanut, vegetable oil, sugar, and milk fortified with vitamins and minerals, was found to be helpful for improving the nutritional and health status of children with severe acute malnutrition (SAM) or kwashiorkor [64]. Symptoms of SAM in Germ-free mice transplanted with kwashiorkor gut microbiota could be temporarily alleviated by RUTF. Thirty gut microbiota species experienced significant changes in abundance after RUTF intake, among which were bacteria with health-promoting function like Bifidobacterium, Lactobacillus, Feacalibacterium prausntizii that can produce bacteriocins, antagonize pathogens and potentially modulate inflammation. Other well-known dietary therapies like FODMAPs, which involves limiting consumption of fermentable Oligosaccharides, Disaccharides, Monosaccharide and Polyols that are poorly absorbed by the human body but can be quickly metabolized by gut microbiota [65], can reduce the discomfort of Irritable Bowel Syndrome and relieve symptoms of inflammatory bowel disease superior to other diet patterns. The mechanisms underlying changes in gut microbiota composition due to FODMAPs remains unknown for the moment, but may be due to their lowering metabolites driven by an over-abundance of members of the phylum Firmicutes in some subjects [66] which may be an interesting and worthwhile focus in the future.
Conclusions Herein, we discussed that how diet manipulate gut microbiota as well as their metabolites and finally influence the www.sciencedirect.com
Impact of diet on the human intestinal microbiota Tan and O’Toole 75
Figure 1
ARP
Diet
Western animalbased diet
SCFA, Folate, GABA, PSA
Bifidobacterium Faecalibacterium Roseburia Eubacterium
Highly diverse plant-based diet
Maintenance of epithelium & Immune modulation
Healthy status
pH
Gut microbiota
Bacteroides Clostridium Escherichia
Microbial Metabolites
Influence on host
Polyamines, cresol, LPS Metabolic disorder & Inflammation
Disease status Current Opinion in Food Science
Interactions between diet, gut microbiota, microbial metabolites and host. Different habitual diet may result in different health status by manipulating gut microbiota and their metabolites. ARP: appetite-regulating peptides; SCFA: short chain fatty acid; GABA: g-Aminobutyric acid; PSA: polysaccharide A; LPS: lipopolysaccharide.
host health status. Also, microbial metabolites have feedbacks on composition of gut microbiota through changing the intestinal pH and gut microbiota may slightly change the dietary habit of the host by secreting appetite-regulating hormones, as shown in Figure 1. It has been realized for several years that the gut microbiota acts like an organ and performs beneficial or inimical functions to the host, but it was only been paid great attention and made clear within recent years. Apart from traditional approaches like bacteria and tissue culture as well as animal studies, new techniques such as shot-gun sequencing are now well established and widely used in analysing the interactions of the human intestinal microbiota with diet, environment and disease. Processed food probably makes the gut microbiota of modern people different to that of our ancestors, and modern diseases such as obesity and functional gastrointestinal disorders result. Thus, functional diet such as FODMAPs and RUTF or an even more direct methods for example faecal bacteriotherapy [67], have been employed to improve symptoms of gastrointestinal diseases. However, there may be more new uncultured gut microbiota species www.sciencedirect.com
or unknown bacterial physiological functions yet to be identified, for example, the next generation probiotics [68]. Thus, more forms of food therapy can be discovered and modified to help not only gastrointestinal diseases, but others such as nervous system related disorders. Therefore, more research is necessary to investigate how diet can improve different health status through re-shaping gut microbiota more stably in the long term.
Acknowledgements This work is supported by the Government of Ireland National Development Plan by way of funding from the Department of Agriculture Food and Marine, as well as by a Science Foundation Ireland award to the Alimentary Pharmabiotic Centre. Huizi Tan is funded by a Chinese government Scholarship Council.
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54. Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C: gamma-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012, 113:411-417. Monosodium glutamate (MSG) can be converted to g-aminobutyric acid (GABA) by commensal gut microbiota, and this study proposed that MSG may also be useful in stimulating intestinal bacterial GABA production in vivo and enhancing nervous system function. 55. Fetissov SO, Sinno MH, Coeffier M, Bole-Feysot C, Ducrotte P, Hokfelt T, Dehelotte P: Autoantibodies against appetiteregulating peptide hormones and neuropeptides: putative modulation by gut microflora. Nutrition 2008, 24:348-359. 56. Vila G, Grimm G, Resl M, Heinisch B, Einwallner E, Esterbauer H, Dieplinger B, Mueller T, Luger A, Clodi M: B-Type natriuretic peptide modulates ghrelin, hunger, and satiety in healthy men. Diabetes 2012, 61:2592-2596. 57. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S: Host-gut microbiota metabolic interactions. Science 2012, 336:1262-1267. 58. Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, Folsch UR, Timmins KN, Schreiber S: Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 2004, 53:685-693. 59. Ley RE, Turnbaugh PJ, Klein S, Gordon JI: Microbial ecology: human gut microbes associated with obesity. Nature 2006, 444:1022-1023. 60. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C et al.: Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007, 56:1761-1772. 61. Rees K: Primary prevention of cardiovascular disease with a mediterranean diet. N Engl J Med 2014, 370 886–886.
47. Cotter PD, Hill C, Ross RP: Bacteriocins: developing innate immunity for food. Nat Rev Microbiol 2005, 3:777-788.
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48. Birri DJ, Brede DA, Nes IF: Salivaricin D, a novel intrinsically trypsin-resistant lantibiotic from Streptococcus salivarius 5M6c isolated from a healthy infant. Appl Environ Microbiol 2012, 78:402-410.
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64. Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng JY, Kau AL, Rich SS, Concannon P, Mychaleckyj JC et al.: Gut microbiomes of Malawian twin pairs discordant for Kwashiorkor. Science 2013, 339:548-554. This is a systematic investigation of gut microbiota of children suffering from kwashiorkor, as well as how a peanut-based, ready-to-use therapeutic food (RUTF) improved gut microbiota and relieved the malnutrition syndromes.
50. Shen Y, Torchia MLG, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK: Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 2012, 12:509-520. The authors found that Polysaccharide A (PSA) of Bacteroides fragilis which can activate interleukin-10-producing CD4 + T cells and alleviate colitis is associated with outer membrane vesicles (OMVs). OMVs also had an essential role in remitting weight loss in an IBD mouse model. This is the first study showing the mechanism of Bacteroides fragilis delivery of anti-inflammatory PSA to the host. 51. Sokol H, Pigneur B, Watterlot L, Lakhdari O, BermudezHumaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G et al.: Faecalibacterium prausnitzii is an antiinflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008, 105:16731-16736. 52. Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, Steinman L: Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A 2010, 107:2580-2585. 53. Komatsuzaki N, Nakamura T, Kimura T, Shima J: Characterization of glutamate decarboxylase from a high gamma-aminobutyric acid (GABA)-producer, Lactobacillus paracasei. Biosci Biotechnol Biochem 2008, 72:278-285.
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65. Gibson PR, Shepherd SJ: Evidence-based dietary management of functional gastrointestinal symptoms: the FODMAP approach. J Gastroenterol Hepatol 2010, 25:252-258. 66. Jeffery IB, O’Toole PW, Ohman L, Claesson MJ, Deane J, Quigley EMM, Simren M: An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 2012, 61:997-1006. The authors identified an increase of Firmicutes-related taxa and a reduction of Bacteroidetes-related taxa in irritable bowel syndrome (IBS) objects. This conclusion may help prognosis and more effective treatment of IBS. 67. Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D, Daigneault MC, Brown EM, Schroeter K, Allen-Vercoe E: Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013, 1:3. In a clinical trial, the authors proved that faecal bacteriotherapy or ‘RePOOPulating’ with thirty-three representative commensal isolates is an effective way of treating patients with Clostridium difficile infection. 68. Neef A, Sanz Y: Future for probiotic science in functional food and dietary supplement development. Curr Opin Clin Nutr Metab Care 2013, 16:679-687.
Current Opinion in Food Science 2015, 2:71–77
ScienceDirect Impact of diet on the human intestinal microbiota Huizi Tan1,2 and Paul W O’Toole2,3 It is well established that habitual diet influences the establishment and composition of the human intestinal microbiota during the lifespan. Bacterial communities colonize the human gut, producing a complex array of metabolites and signalling molecules that impact on host intestinal and extraintestinal health. These functions are implicated in gastrointestinal diseases such as irritable bowel syndrome, inflammatory bowel disease and metabolic syndrome, and potentially even in enteric or even central nervous system related disorders. Bacterially encoded metabolic activities are involved in various metabolic processes in the host. In this review, we summarize and evaluate the impact of diet on the composition and function of the human gut microbiota. Addresses 1 School of Food Science and Technology, Jiangnan University, Wuxi 214122, China 2 School of Microbiology, University College Cork, Cork, Ireland 3 Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Corresponding author: O’Toole, Paul W ([email protected])
Current Opinion in Food Science 2015, 2:71–77 This review comes from a themed issue on Food Microbiology Edited by Marco Gobbetti
doi:10.1016/j.cofs.2015.01.005 S2214-7993/# 2015 Elsevier Ltd. All rights reserved.
Introduction There are an estimated 10–100 trillion microbes in the human intestine, which possess 100-fold more bacterial genes than human genes [1]. It is widely cognized that these gut microbiota is 10-fold more than human cells, but was challenged by J. Rosner (2014) who emphasized the variability of individual cell numbers due to body size, age and nutritional intake [2]. The individual gut microbiota has a broad range of variability. The traditional culture method estimates that there are around 100 bacterial species in the human gut [3], while culture-independent deep shotgun DNA sequencing indicates around 160 species. By abundance, Firmicutes and Bacteroidetes are the two predominant phyla within the gut microbiota, followed by Proteobacteria, Actinobacteria, Fusobacteria and Verrucomicrobia. The diversity changes throughout the lifespan of the individual, from infants whose intestinal microbiota composition is simple consisting mainly of www.sciencedirect.com
high levels of Bifidobacterium spp. and opportunistic aerobes like Staphylococcus, Streptococcus and Enterobacteriaceae, followed by clostridia and Bacteroidetes, through to the typical ten-phylum dominance of the healthy adult intestinal tract, and to the low diversity microbiota that is a feature in some elderly subjects [4]. Quantitative PCR (qPCR) was recently used to study human microbiota changes during ageing with faecal samples comprising 21 infants, 21 adults and 20 elderly. This study suggested that the Firmicutes/Bacteroidetes ratio of the sample groups differs from each other, with values of 0.4, 10.9 and 0.6 respectively [5]. However, gut microbiota composition varies not only as a function of age but also by dietary habitat, health status, geographical factors, and environmental factors such as hygiene and socioeconomic status. Intestinal bacteria interact with each other and the host through metabolite production and substrate fermentation, which explains why diet has such an important role in modifying human intestinal microbiota.
Diet influences the composition of gut microbiota Zhao et al. (2010) reported that 57% of variation in the composition of gut microbiota was related to dietary change, while only 12% was related to genetic differences [6]. Another study indicated that the general alteration in the structure of the gut microbiota in wild-type and RELM b knock-out mice was similar after a high-fat diet [7]. These results strongly suggest that diet is the dominant factor in shaping gut microbiota. Gordon et al. (2009) showed that the gut microbiota can be modified within one day of changing the diet and can maintain this change for 7 days in a humanized germ-free mouse model [8]. Though results from animal experiments cannot be extrapolated directly to humans, they provided proof of concept and paved the way for human dietary interventions described below. Many scientists focused their research on different geographical regions where people have vastly different diet types. For example, greater abundance of phylum Bacteroidetes, mainly Prevotella and Xylanibacter, was found in rural African children who generally have a diet with low content of fat and animal protein and high in fibre, starch and plant polysaccharides; whereas a significant over-abundance of Firmicutes like Acetitomaculum and Feacalibacterium, as well as Enterobacteriaceae (Shigella and Escherichia), was detected in European children who are fed a typical western diet with almost twice the number of calories as the diet of African children [9]. Another similar study compared the gut microbiota of Japanese-Hawaiians and North American Caucasians who Current Opinion in Food Science 2015, 2:71–77
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have a western diet with a lot of red meat and high fat, with rural native Japanese and rural native Africans who retain a ‘native’ diet which is completely different from the western diet [10]. They found that some Lactobacillus species as well as Collinsella aerofaciens were enriched in the ‘native’ diet population but species within the genera Bacteroides and Bifidobacterium were more abundant in the western diet subjects, which is suspected to be related with high risk of colon cancer. The relationship between habitual diet and gut microbiota composition has been investigated using different techniques. Ramakrishna et al. (2011) examined the differences in gut microbiota of vegetarians and omnivores in Southern India using real-time PCR, which showed that the Roseburia-Eubacterium rectale group within Clostridium cluster XIV was significantly abundant in omnivores [11]. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) fingerprinting analysis was used by Haslberger et al. (2008) to reveal that a higher level of Bacteroides and lower abundance of Clostridium cluster IV, especially Faecalibacterium sp. and Ruminococcus sp. was present in vegetarians compared with omnivores [12]. However, Enck et al. (2012) published a contradictory study where a reduction in the abundances of Escherichia coli, Bacteroides spp. and Bifidobacterium spp. and the Enterobacteriaceae family in vegans or vegetarians was detected using culture-dependent methods [13]. A recent study investigated the response of gut microbiota to short-term diet change. When the subject consumed an exclusively animal-based diet, Firmicutes, such as Roseburia, E. rectale and Ruminococcus bromii that are involved in utilizing fermentable carbohydrates showed decreased abundance while proportions of Alistipes, Bilophila and Bacteroides increased [14,15]. The gut microbiota of infants is also intensively researched. It is widely believed that the gut microbiota of breast-fed (BF) babies is less diverse than that of formula-fed (FF) babies. Breast milk has been suggested by one study to provide 109 microbes per litre [16], consisting of Bifidobacteria, Lactobacillus and Staphylococcus which help shape the infant microbiota. Regarding FF babies, their higher diversity gut microbiota contains bacterial taxa like Clostridium, Bacteroides, enterobacteria and Enterococcus, significantly distinguishing them from BF babies [17]. However, some reports maintain that there would be no significant differences when the formula milk is supplemented with prebiotics like galactooligosaccharides and fructooligosaccharides [18] which can promote the colonization of Bifidobacterium and Lactobacillus thus making the gut microbiota similar to that of BF babies. Dietary fibre is widely found in food derived from plants, such as resistant starch (RS), pectin, oligosaccharides and insulin, most of which can be broken down by intestinal Current Opinion in Food Science 2015, 2:71–77
bacteria [19]. Two species, R. bromii and E. rectale, showed significant response to RS type 2 compared to RS type 4 (RS4) [20]. RS 4 raised the proportions of Actinobacteria and Bacteroidetes and reduced Firmicutes; more especially, Bifidobacterium abundance was increased ten-fold to 18–30% in gut microbiota. A study from Walker et al. (2011) showed partial agreement with the above results and indicated that RS diet could also increase the abundance of the Oscillibacter group [15]. Pectin from apple intake was said to be associated with an increase in the abundances of Bifidobacterium, lactobacilli and streptococci and a corresponding reduction in the abundances of Enterobacteriaceae, Pseudomonas and some lectithinase-positive clostridia [21].
Effects of dietary changes on the gut microbiome Although the composition of gut microbiota is altered by dietary changes, the gut microbiome, that is, the total coding capacity of the gut bacterial community and its expression level, is also regulated by diet. For instance, polysaccharide-utilization loci in gut microbiota such as Bacteroides thetaiotaomicron are up-regulated in response to host-derived polysaccharides [22]. A mouse model study showed that when administered a high-fat diet, genes involved in signal transduction, cell motility, membrane transport, replication and repair within Proteobacteria, Bacteroidetes and Firmicutes phyla were up-regulated, whereas genes involved in carbohydrates metabolism, amino acid metabolism, energy metabolism were down-regulated [7]. However, in the humanized gnotobiotic mice, carbohydrate metabolism related genes were up-regulated on a western-diet, along with two phosphotransferase system (PTS) genes encoding glucose and fructose import and carbohydrates linked with host gut mucosa, whereas genes from Bacteroides sp. were up-regulated on low-fat/plant polysaccharides diet [8]. Genes associated with vitamin biosynthesis, b-lactamase and degeneration of polycyclic aromatic hydrocarbons were up-regulated when consuming an animal based diet [14]. Another study which focused on vegetarians concluded that there are more bacterial butyryl-CoA CoAtransferase genes in omnivore faeces than vegetarians, which relate to more butyrate produced [11]. This differs from previous studies that suggested that fewer saccharolytic elements in the gut microbiota resulted in less Short chain fatty acid (SCFA) production. Regarding feeding mode of infants, the gut microbiota of FF babies harboured a lower bacterial gene count compared to breast fed babies [23]. Furthermore, the genes NDST1, IL1A and ALOXS which are associated with immune response and mucosal defence were expressed at lower levels in breast fed babies, whereas genes associated with www.sciencedirect.com
Impact of diet on the human intestinal microbiota Tan and O’Toole 73
angiogenesis, peroxidase generation, intestine proliferation and gut motility were less expressed in FF babies. Apart from the regulatory function of diet on bacterial genes, diet can also ‘create’ or select functional genes in the gut microbiota. Porphyranases and agarases were frequently observed in the gut microbiota of Japanese subjects but were absent in Northern Americans [24]. This phenomenon is due to the large proportion of marine algae contained in the Japanese diet, and sulphated polysaccharides that are enriched only in marine products like seaweed [25]. This shows that genes encoding porphyranases and agarses were horizontally acquired by the gut microbiota, and highlights that the gut microbiota interacts with and may ultimately be genetically modified by environmental bacteria because of selection imposed by habitual diet.
Functional metabolites produced by the gut microbiota The gut microbiota produces a complex array of metabolites and signalling molecules that mediate the interactions between gut microbes and host intestinal and extraintestinal. As a result of modification in gut microbiota that maybe caused by dietary alteration, different metabolites will be produced and may perform anti-inflammatory or pro-inflammatory activities. Short chain fatty acid (SCFA) are a group of simple 2-carbon to 5-carbon fatty acids produced by the intestinal microbiota during fermentation of undigested resistant starch or oligosaccharides, mainly acetate, propionate, butyrate. Most of these metabolites can be absorbed through the colonic wall and exert various beneficial characteristics on the host other than providing basic energy [26,27]. SCFAs can induce neutrophil chemotaxis by activating G protein-coupled receptors GPR41 and GPR43 [28,29]. Butyrate is considered to be an anti-carcinogenic compound [30]. Nuclear factor kB (NF-kB) formation can be suppressed by butyrate and consequently relieve inflammation in IBD patients [31]. Butyrate can inhibit the migration of macrophages caused by LPS [32], and also reduce the production of inflammation promoting cytokines like TNF-a and IL-6 while increase anti-inflammation cytokines IL-10 from macrophages [29,33]; it can also enhance gut barrier [34] and improve intestinal motility disorders [35]. The production of butyrate accelerates as intestinal pH decreases while other SCFAs are being produced. This low pH environment allows the growth of Firmicutes especially Faecalibacterium prausntizii, E. rectale and Roseburia spp., but is apparently a less favourable environment for some potentially pathogenic gram-negative species such as Bacteroides spp. and E. coli [36,37]. Acetate is one of the most abundant SCFA metabolites in the human intestine. A recent elegant study showed that acetate produced by Bifidobacterium can protect epithelial cells against E. coli O157:H7 Shiga toxin www.sciencedirect.com
[38]. Propionate participates in the succinate pathway and acrylate pathway [39]. And propionate as well as butyrate can induce apoptosis of human colon carcinoma cells which are infinite proliferous and finally lead to tumours [40]. This discovery may provide a clue to help clean those carcinoma cells in a ‘healthy’ way. Vitamins are a class of organic compounds that help maintain normal physiological function but can only be obtained from diet. In point of fact, however, intestinal commensal bacteria can also contribute to providing their host with essential vitamins like vitamin K and water-soluble B vitamins. One sub-class of Vitamin K, Vitamin K2, is mainly synthesized by gut microbiota elements such as Bacteroides spp. [41]. Vitamin K can help prevent and treat osteoporosis by improving bone mineral density [42], and its deficiency can induce cardiovascular disease [43]. Microbial synthesis is the only source of Vitamin B12 in nature, including metabolism of intestinal microbiota. Vitamin B12 is involved in the methionine synthesis pathway and metabolism of folic acid [44]. Folate is a vitamin that has an important role in DNA replication, repair and methylation as well as proliferation of cells. A recent study demonstrated that Bifidobacterium strains such as B. adolescentis and B. pseudocatenulatum can utilize different carbohydrates to synthesis folate [45]. Another study identified readily absorbed monoglutamylated folate in the infant colon [36,46], and this may be related to the oligosaccharides in infant food can promote the growth of Bifidobacterium spp. [45] rendering it a major component in infant gut microbiota as described early in this review. For all the preceding proposed syntheses of vitamins by gut bacteria, the balance and relative importance of dietary versus microbiota-derived vitamin remains to be determined, and this is an active strand of our current research. Nevertheless vitamin production by gut bacteria may be a legitimate target for promoting life-long increases in vitamin production. Protein metabolites are large molecules secreted by gut microbiota that are directly involved in host immune modulation, for example the increasing realization of such activity for the bacteriocins produced by lactic acid bacteria (LAB). Nisin is one of the lanthionine-containing antibiotics produced by Lactococcus lactis subsp. Lactis. It can suppress the growth of Helicobacter pylori and promote the growth of Bifidobacterium, stimulate the production of immunoglobulin A (IgA), and help maintain a healthy intestinal homeostasis [47]. Lactobacillus salivarius UCC118 can reduce H2O2-induced inflammation in transepithelial resistance, but paradoxically production of the salivaricin bacteriocin, which is viewed as a desirable trait in terms of suppressing intestinal pathogens [48], reduces the improvement of barrier function because of inflammatory activity of the bacteriocin [49]. In addition to proteinaceous macromolecules that can affect the host, other classes of metabolite benefit the Current Opinion in Food Science 2015, 2:71–77
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host through modulating inflammatory functions in different ways. Polysaccharide A (PSA) which is one component in the zwitterionic polysaccharides of Bacteroides fragilis and released in outer membrane vesicles (OMVs), can activate interleukin-10-producing CD4+ T cells via toll-like receptor 2 and abolish the expression of interleukin-17 (IL-17), so as to help the colonization of B. fragilis and alleviate colitis [50]. F. prausntizii helps to ameliorate TNBS colitis by accelerating IL-10 and suppress IL-12, particularly unknown factors in its supernatant which inhibit the activity of IL-1b-induced NF-kB [51]. The mechanism by which this occurs is unknown. g-Aminobutyric acid (GABA) is a natural non-protein amino acid, that is a neuroactive compound which plays a dominant role in inhibiting transmission in central nervous system (CNS) [52]; GABA is implicated in various physiological functions, such as hypotension, diuresis and sedation. GABA deficiency may cause anxiety, fatigue and depression [53]. GABA can be produced by the human intestinal microbiota, among which Lactobacillus brevis and Bifidobacterium dentium were identified to be two promising GABA producers [54]. L. brevis is being evaluated as a contributor to intestinal bacterial GABA production. Appetite-regulating peptides like leptin, ghrelin, peptide YY, and neuropeptide Y can be produced by various intestinal bacteria like Lactobacilli, Bacteroides, H. pylori, E. coli, and Candida sp. [55]. These peptides can trigger autoantibodies like IgA and IgG as well as affect the nerve signalling of human and other mammalian animals thus controlling hunger and satiety [56]. The biochemical activity of the intestinal microbiota may also lead to potentially toxic metabolites such as volatile phenols, mainly in the form of cresol, which can be produced by species of Clostridum and Bifidobacterium from tyrosine [57]. Increased levels of 4-cresol are associated with decreased abundance of Lactobacillus spp. [58] as well as the alteration of the Firmicutes to Bacteroidetes ratio [59], a phenomenon associated with weight loss and even inflammatory bowel diseases. Lipopolysaccharide (LPS) is a common part of the outer membrane of Gramnegative bacteria. A high-fat diet can increase the proportion of Gram-negative bacteria in the human gut microbiota and promote the release of LPS that may lead to chronic systemic inflammation [60].
Diet helps improve health status by microbiota-related mechanisms As diet strongly influences the composition of gut microbiota and consequently regulates functional gene expression and metabolism production as stated above, scientists are testing special functional diets that may help cure diseases by modifying the human gut microbiota. Current Opinion in Food Science 2015, 2:71–77
Gordon et al. (2006) tested the effects of a fat-restricted and a carbohydrate-restricted low calorie diet on body weight reduction. They found that both diets could give rise to an increase in Bacteroidetes abundance, which was considered to be in a direct ratio with the weight loss [59]. Research has shown that Mediterranean diet intake may aid treatment of obesity, type II diabetes and lower the risk of cardiovascular diseases [61,62]. The Mediterranean diet, including relatively large intake of vegetables, fruits, nuts, grains and olive oil, moderate or low amount of wine, fish, red meat, tea, coffee, and sweets, is a nutritionally recommended diet pattern that is consumed naturally in countries like Italy, Greece, Spain and Morocco. Polyphenols in wine, fruits, and vegetables may raise the proportions of Bifidobacterium, Enterococcus, Bacteroides, and Prevotella and decrease the abundance of pathogens like Clostridium perfringens, adjustments which in general improved inflammatory condition caused by obesity [63]. At the same time, low-fat content in this diet may link to increased proportions of Bifidobacterium and Bacteroidetes [6,59]. SalasSalvado et al. (2011) reported that more than 50% of the type II diabetes symptomology was relieved in 54 volunteers after having consumed a Mediterranean diet for 4 years [62]. A peanut-based, ready-to-use therapeutic food (RUTF), which contains peanut, vegetable oil, sugar, and milk fortified with vitamins and minerals, was found to be helpful for improving the nutritional and health status of children with severe acute malnutrition (SAM) or kwashiorkor [64]. Symptoms of SAM in Germ-free mice transplanted with kwashiorkor gut microbiota could be temporarily alleviated by RUTF. Thirty gut microbiota species experienced significant changes in abundance after RUTF intake, among which were bacteria with health-promoting function like Bifidobacterium, Lactobacillus, Feacalibacterium prausntizii that can produce bacteriocins, antagonize pathogens and potentially modulate inflammation. Other well-known dietary therapies like FODMAPs, which involves limiting consumption of fermentable Oligosaccharides, Disaccharides, Monosaccharide and Polyols that are poorly absorbed by the human body but can be quickly metabolized by gut microbiota [65], can reduce the discomfort of Irritable Bowel Syndrome and relieve symptoms of inflammatory bowel disease superior to other diet patterns. The mechanisms underlying changes in gut microbiota composition due to FODMAPs remains unknown for the moment, but may be due to their lowering metabolites driven by an over-abundance of members of the phylum Firmicutes in some subjects [66] which may be an interesting and worthwhile focus in the future.
Conclusions Herein, we discussed that how diet manipulate gut microbiota as well as their metabolites and finally influence the www.sciencedirect.com
Impact of diet on the human intestinal microbiota Tan and O’Toole 75
Figure 1
ARP
Diet
Western animalbased diet
SCFA, Folate, GABA, PSA
Bifidobacterium Faecalibacterium Roseburia Eubacterium
Highly diverse plant-based diet
Maintenance of epithelium & Immune modulation
Healthy status
pH
Gut microbiota
Bacteroides Clostridium Escherichia
Microbial Metabolites
Influence on host
Polyamines, cresol, LPS Metabolic disorder & Inflammation
Disease status Current Opinion in Food Science
Interactions between diet, gut microbiota, microbial metabolites and host. Different habitual diet may result in different health status by manipulating gut microbiota and their metabolites. ARP: appetite-regulating peptides; SCFA: short chain fatty acid; GABA: g-Aminobutyric acid; PSA: polysaccharide A; LPS: lipopolysaccharide.
host health status. Also, microbial metabolites have feedbacks on composition of gut microbiota through changing the intestinal pH and gut microbiota may slightly change the dietary habit of the host by secreting appetite-regulating hormones, as shown in Figure 1. It has been realized for several years that the gut microbiota acts like an organ and performs beneficial or inimical functions to the host, but it was only been paid great attention and made clear within recent years. Apart from traditional approaches like bacteria and tissue culture as well as animal studies, new techniques such as shot-gun sequencing are now well established and widely used in analysing the interactions of the human intestinal microbiota with diet, environment and disease. Processed food probably makes the gut microbiota of modern people different to that of our ancestors, and modern diseases such as obesity and functional gastrointestinal disorders result. Thus, functional diet such as FODMAPs and RUTF or an even more direct methods for example faecal bacteriotherapy [67], have been employed to improve symptoms of gastrointestinal diseases. However, there may be more new uncultured gut microbiota species www.sciencedirect.com
or unknown bacterial physiological functions yet to be identified, for example, the next generation probiotics [68]. Thus, more forms of food therapy can be discovered and modified to help not only gastrointestinal diseases, but others such as nervous system related disorders. Therefore, more research is necessary to investigate how diet can improve different health status through re-shaping gut microbiota more stably in the long term.
Acknowledgements This work is supported by the Government of Ireland National Development Plan by way of funding from the Department of Agriculture Food and Marine, as well as by a Science Foundation Ireland award to the Alimentary Pharmabiotic Centre. Huizi Tan is funded by a Chinese government Scholarship Council.
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