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Starving our Microbial Self: The Deleterious Consequences of a Diet Deficient in Microbiota-Accessible Carbohydrates

2014; Cell Press; Volume: 20; Issue: 5 Linguagem: Inglês

10.1016/j.cmet.2014.07.003

1932-7420

Erica D. Sonnenburg, Justin L. Sonnenburg,

Gastrointestinal motility and disorders

The gut microbiota of a healthy person may not be equivalent to a healthy microbiota. It is possible that the Western microbiota is actually dysbiotic and predisposes individuals to a variety of diseases. The asymmetric plasticity between the relatively stable human genome and the more malleable gut microbiome suggests that incompatibilities between the two could rapidly arise. The Western lifestyle, which includes a diet low in microbiota-accessible carbohydrates (MACs), has selected for a microbiota with altered membership and functionality compared to those of groups living traditional lifestyles. Interactions between resident microbes and host leading to immune dysregulation may explain several diseases that share inflammation as a common basis. The low-MAC Western diet results in poor production of gut microbiota-generated short-chain fatty acids (SCFAs), which attenuate inflammation through a variety of mechanisms in mouse models. Studies focused on modern and traditional societies, combined with animal models, are needed to characterize the connection between diet, microbiota composition, and function. Differentiating between an optimal microbiota, one that increases disease risk, and one that is causative or potentiates disease will be required to further understand both the etiology and possible treatments for health problems related to microbiota dysbiosis. The gut microbiota of a healthy person may not be equivalent to a healthy microbiota. It is possible that the Western microbiota is actually dysbiotic and predisposes individuals to a variety of diseases. The asymmetric plasticity between the relatively stable human genome and the more malleable gut microbiome suggests that incompatibilities between the two could rapidly arise. The Western lifestyle, which includes a diet low in microbiota-accessible carbohydrates (MACs), has selected for a microbiota with altered membership and functionality compared to those of groups living traditional lifestyles. Interactions between resident microbes and host leading to immune dysregulation may explain several diseases that share inflammation as a common basis. The low-MAC Western diet results in poor production of gut microbiota-generated short-chain fatty acids (SCFAs), which attenuate inflammation through a variety of mechanisms in mouse models. Studies focused on modern and traditional societies, combined with animal models, are needed to characterize the connection between diet, microbiota composition, and function. Differentiating between an optimal microbiota, one that increases disease risk, and one that is causative or potentiates disease will be required to further understand both the etiology and possible treatments for health problems related to microbiota dysbiosis. The human gut harbors a diverse ecosystem of trillions of microbial cells (Costello et al., 2012Costello E.K. Stagaman K. Dethlefsen L. Bohannan B.J. Relman D.A. The application of ecological theory toward an understanding of the human microbiome.Science. 2012; 336: 1255-1262Crossref PubMed Scopus (932) Google Scholar, Qin et al., 2010Qin J. Li R. Raes J. Arumugam M. Burgdorf K.S. Manichanh C. Nielsen T. Pons N. Levenez F. Yamada T. et al.MetaHIT ConsortiumA human gut microbial gene catalogue established by metagenomic sequencing.Nature. 2010; 464: 59-65Crossref PubMed Scopus (7347) Google Scholar). The traditional view that gut microbiota effects are limited to the host’s digestive tract, or more recently extended to metabolism and immune status, has given way to the realization that these microbes can have widespread impact on diverse aspects of a host’s physiology (Sommer and Backhed, 2013Sommer F. Backhed F. The gut microbiota—masters of host development and physiology.Nat. Rev. 2013; 11: 227-238Google Scholar). Externally applied forces, such as diet or antibiotics, result in rapid alterations of the microbiota, thereby affecting the status of host-microbiota relations (David et al., 2014David L.A. Maurice C.F. Carmody R.N. Gootenberg D.B. Button J.E. Wolfe B.E. Ling A.V. Devlin A.S. Varma Y. Fischbach M.A. et al.Diet rapidly and reproducibly alters the human gut microbiome.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5616) Google Scholar, Dethlefsen et al., 2008Dethlefsen L. Huse S. Sogin M.L. Relman D.A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing.PLoS Biol. 2008; 6: e280Crossref PubMed Scopus (1728) Google Scholar, Dethlefsen and Relman, 2010Dethlefsen L. Relman D.A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.Proc. Natl. Acad. Sci. USA. 2010; 108: 4554-4561PubMed Google Scholar, Walker et al., 2011Walker A.W. Ince J. Duncan S.H. Webster L.M. Holtrop G. Ze X. Brown D. Stares M.D. Scott P. Bergerat A. et al.Dominant and diet-responsive groups of bacteria within the human colonic microbiota.ISME J. 2011; 5: 220-230Crossref PubMed Scopus (1120) Google Scholar). The malleability of our gut residents is further reframing this community’s role as a platform for rational manipulation of host biology: the microbiota provides a manipulatable lever to improve human health and to treat or prevent disease (Sonnenburg and Fischbach, 2011Sonnenburg J.L. Fischbach M.A. Community health care: therapeutic opportunities in the human microbiome.Sci. Transl. Med. 2011; 3: 78ps12Crossref PubMed Scopus (66) Google Scholar, van Nood et al., 2013van Nood E. Vrieze A. Nieuwdorp M. Fuentes S. Zoetendal E.G. de Vos W.M. Visser C.E. Kuijper E.J. Bartelsman J.F. Tijssen J.G. et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N. Engl. J. Med. 2013; 368: 407-415Crossref PubMed Scopus (2564) Google Scholar, Vrieze et al., 2012Vrieze A. Van Nood E. Holleman F. Salojarvi J. Kootte R.S. Bartelsman J.F. Dallinga-Thie G.M. Ackermans M.T. Serlie M.J. Oozeer R. et al.Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.Gastroenterology. 2012; 143: 913-916Abstract Full Text Full Text PDF PubMed Scopus (1926) Google Scholar). At a more fundamental level, the very plasticity that makes the gut microbiota an attractive therapeutic avenue can result in unintentional and maladaptive changes, or dysbiosis. A plethora of microbiota enumeration studies in recent years have implicated microbiota dysbiosis in a growing list of Western diseases, such as metabolic syndrome, inflammatory bowel disease, and cancer. These studies rely on comparing the microbiota of individuals that are diseased to those that are healthy. The contribution of the dysbiotic microbiota to disease phenotype has been illustrated via microbiota transplant in several instances (Koren et al., 2012Koren O. Goodrich J.K. Cullender T.C. Spor A. Laitinen K. Bäckhed H.K. Gonzalez A. Werner J.J. Angenent L.T. Knight R. et al.Host remodeling of the gut microbiome and metabolic changes during pregnancy.Cell. 2012; 150: 470-480Abstract Full Text Full Text PDF PubMed Scopus (1216) Google Scholar, Liou et al., 2012Liou A.P. Paziuk M. Luevano Jr., J.M. Machineni S. Turnbaugh P.J. Kaplan L.M. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity.Sci. Trans. Med. 2012; 5: 178ra141Google Scholar, Ridaura et al., 2013Ridaura V.K. Faith J.J. Rey F.E. Cheng J. Duncan A.E. Kau A.L. Griffin N.W. Lombard V. Henrissat B. Bain J.R. et al.Gut microbiota from twins discordant for obesity modulate metabolism in mice.Science. 2013; 341: 1241214Crossref PubMed Scopus (2435) Google Scholar, Turnbaugh et al., 2006Turnbaugh P.J. Ley R.E. Mahowald M.A. Magrini V. Mardis E.R. Gordon J.I. An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (8235) Google Scholar, Vijay-Kumar et al., 2010Vijay-Kumar M. Aitken J.D. Carvalho F.A. Cullender T.C. Mwangi S. Srinivasan S. Sitaraman S.V. Knight R. Ley R.E. Gewirtz A.T. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.Science. 2010; 328: 228-231Crossref PubMed Scopus (1533) Google Scholar). However, use of the term “dysbiotic” must be accompanied by the recognition that the definition of a healthy microbiota that should serve as a frame of reference is still poorly defined. It is possible that the microbiota of a healthy Westerner is also dysbiotic, significantly increasing the risk of developing diseases characterized by excessive or inappropriate immune inflammatory responses. Much of the carbon and energy for members of the microbiota originate from plant- and animal-derived dietary carbohydrates (Koropatkin et al., 2012Koropatkin N.M. Cameron E.A. Martens E.C. How glycan metabolism shapes the human gut microbiota.Nat. Rev. 2012; 10: 323-335Google Scholar, Salyers et al., 1977Salyers A.A. West S.E. Vercellotti J.R. Wilkins T.D. Fermentation of mucins and plant polysaccharides by anaerobic bacteria from the human colon.Appl. Environ. Microbiol. 1977; 34: 529-533Crossref PubMed Google Scholar). These carbohydrates are composed of monosaccharides that are connected through numerous types of glycosidic linkages and, in some instances, further modified by chemical substituents like acetyl and sulfate groups. The variation in their chemical composition, solubility, and size differentiates these carbohydrates into a vast array of ecological niches. However, microbial competition within the gut is intense for metabolic access to the energy and carbon sequestered in these molecules. Residents of the microbiota are equipped with a specialized collection of enzymes such as glycoside hydrolases and polysaccharide lyases, which can break down complex carbohydrate linkages into consumable oligosaccharides or monosaccharides (Cantarel et al., 2009Cantarel B.L. Coutinho P.M. Rancurel C. Bernard T. Lombard V. Henrissat B. The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics.Nucleic Acids Res. 2009; 37: D233-D238Crossref PubMed Scopus (4129) Google Scholar, Martens et al., 2011Martens E.C. Lowe E.C. Chiang H. Pudlo N.A. Wu M. McNulty N.P. Abbott D.W. Henrissat B. Gilbert H.J. Bolam D.N. Gordon J.I. Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts.PLoS Biol. 2011; 9: e1001221Crossref PubMed Scopus (517) Google Scholar). A model microbiota containing ∼160 species has in excess of 9,000 glycoside hydrolases and 2,000 polysaccharide lyases, which serve as the gateway to a complex microbial food web within the gut (El Kaoutari et al., 2013El Kaoutari A. Armougom F. Gordon J.I. Raoult D. Henrissat B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota.Nat. Rev. 2013; 11: 497-504Google Scholar). When extrapolating to ∼1,000 species, a single human gut microbiota may contain upward of 60,000 carbohydrate-degrading enzymes. The human genome, on the other hand, has only a small number of glycoside hydrolases (∼17) and no polysaccharide lyases that are involved in carbohydrate digestion within the gut. Carbohydrates for gut microbe fermentation can come from a variety of sources including (1) dietary or host-derived animal glycans (2) synthesized by other microbes that are food-borne (e.g., the yeast cell wall) or a gut resident, and (3) dietary plant material, commonly referred to as dietary fiber, which is the most common fuel for the microbiota of many humans (Flint et al., 2012Flint H.J. Scott K.P. Duncan S.H. Louis P. Forano E. Microbial degradation of complex carbohydrates in the gut.Gut Microbes. 2012; 3: 289-306Crossref PubMed Scopus (1158) Google Scholar, Koropatkin et al., 2012Koropatkin N.M. Cameron E.A. Martens E.C. How glycan metabolism shapes the human gut microbiota.Nat. Rev. 2012; 10: 323-335Google Scholar). The role of dietary fiber on human health has been discussed for decades. In the 1960s and 1970s, Denis Burkitt and Hugh Trowell documented the significantly larger intake of dietary fiber by Africans relative to Westerners and their coincident lack of Western diseases such as diabetes, heart disease, and colorectal cancer. Many of these diseases, including asthma, allergies, and inflammatory bowel diseases, appear in young Westerners and are therefore not simply a product of our modern extension of lifespan, but share a dysregulated immune system as a common basis. Burkitt reported that rural Africans passed stool that was up to five times greater by mass, had intestinal transit times that were more than twice as fast, and ate three to seven times more dietary fiber (60–140 g versus 20 g) than their Western counterparts (Burkitt et al., 1972Burkitt D.P. Walker A.R. Painter N.S. Effect of dietary fibre on stools and the transit-times, and its role in the causation of disease.Lancet. 1972; 2: 1408-1412Abstract PubMed Scopus (804) Google Scholar). However, the mechanisms by which dietary fiber would exert positive health effects were unknown. Burkitt and others hypothesized that the increased transit time and stool size that accompanied a high-fiber diet may serve to dilute potentially hazardous microbial metabolic products and quickly remove them from the colonic lining (Burkitt and Trowell, 1977Burkitt D.P. Trowell H.C. Dietary fibre and western diseases.Ir. Med. J. 1977; 70: 272-277PubMed Google Scholar, Trowell and Burkitt, 1986Trowell H. Burkitt D. Physiological role of dietary fiber: a ten-year review.Bol. Asoc. Med. P. R. 1986; 78: 541-544PubMed Google Scholar). But recent studies are suggesting that the missing mechanistic explanation for the beneficial effects of dietary fiber may be largely attributed to fermentation by the microbiota. In discussing carbohydrate substrates that fuel the colonic microbial ecosystem, dietary fiber is a problematic term commonly employed for lack of a better option. The definition of dietary fiber has evolved over the past 60 years since the concept was first introduced (Hipsley, 1953Hipsley E.H. Dietary “fibre” and pregnancy toxaemia.BMJ. 1953; 2: 420-422Crossref PubMed Scopus (217) Google Scholar, Trowell, 1976Trowell H. Definition of dietary fiber and hypotheses that it is a protective factor in certain diseases.Am. J. Clin. Nutr. 1976; 29: 417-427Crossref PubMed Scopus (214) Google Scholar, Trowell et al., 1976Trowell H. Southgate D.A. Wolever T.M. Leeds A.R. Gassull M.A. Jenkins D.J. Letter: dietary fibre redefined.Lancet. 1976; 1: 967Abstract PubMed Scopus (308) Google Scholar, Trowell and Burkitt, 1987Trowell H.C. Burkitt D.P. The development of the concept of dietary fibre.Mol. Aspects Med. 1987; 9: 7-15Crossref PubMed Scopus (19) Google Scholar). Current use of this term is complicated by multiple definitions associated with different official organizations (Raninen et al., 2011Raninen K. Lappi J. Mykkänen H. Poutanen K. Dietary fiber type reflects physiological functionality: comparison of grain fiber, inulin, and polydextrose.Nutr. Rev. 2011; 69: 9-21Crossref PubMed Scopus (163) Google Scholar). In addition, multiple laboratory tests may be used to determine “dietary fiber” content specified on nutritional labels, none of which provides an accurate measure of what the definitions specify. The most standard method of quantifying dietary fiber content neglects many types of carbohydrates that are destined for microbiota fermentation in the colon, like inulin, but includes noncarbohydrate entities like lignin. In addition, the term dietary fiber encompasses the carbohydrates that are fermentable by an individual’s microbiota plus those that remain unfermented and serve a bulking role (Kashyap et al., 2013aKashyap P.C. Marcobal A. Ursell L.K. Larauche M. Duboc H. Earle K.A. Sonnenburg E.D. Ferreyra J.A. Higginbottom S.K. Million M. et al.Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice.Gastroenterology. 2013; 144: 967-977Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar). Attempts to use measurements of soluble verses insoluble fiber as approximations of fermentable versus nonfermentable, respectively, have proven inaccurate. Similar to “dietary fiber,” the term “plant polysaccharides” is a common euphemism for “microbiota food,” but this category excludes important nonplant carbohydrates and oligosaccharides. When referring to the carbohydrates that can be metabolically used by gut microbes, we propose the term “microbiota-accessible carbohydrate” (MAC; see Box 1 for expanded discussion of MACs). MACs serve as selective agents, altering the composition of the microbiota, but also dictate the functionality and metabolic output. Multiple studies have shown that diet can serve as a selective potent force in reshaping the microbiota (David et al., 2014David L.A. Maurice C.F. Carmody R.N. Gootenberg D.B. Button J.E. Wolfe B.E. Ling A.V. Devlin A.S. Varma Y. Fischbach M.A. et al.Diet rapidly and reproducibly alters the human gut microbiome.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5616) Google Scholar, Walker et al., 2011Walker A.W. Ince J. Duncan S.H. Webster L.M. Holtrop G. Ze X. Brown D. Stares M.D. Scott P. Bergerat A. et al.Dominant and diet-responsive groups of bacteria within the human colonic microbiota.ISME J. 2011; 5: 220-230Crossref PubMed Scopus (1120) Google Scholar, Wu et al., 2011Wu G.D. Chen J. Hoffmann C. Bittinger K. Chen Y.Y. Keilbaugh S.A. Bewtra M. Knights D. Walters W.A. Knight R. et al.Linking long-term dietary patterns with gut microbial enterotypes.Science. 2011; 334: 105-108Crossref PubMed Scopus (4127) Google Scholar). Highly controlled experiments in mice have shown that the quantity and type of carbohydrates that feed the microbiota alter simplified and complex microbial communities (Faith et al., 2011Faith J.J. McNulty N.P. Rey F.E. Gordon J.I. Predicting a human gut microbiota’s response to diet in gnotobiotic mice.Science. 2011; 333: 101-104Crossref PubMed Scopus (368) Google Scholar, Kashyap et al., 2013aKashyap P.C. Marcobal A. Ursell L.K. Larauche M. Duboc H. Earle K.A. Sonnenburg E.D. Ferreyra J.A. Higginbottom S.K. Million M. et al.Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice.Gastroenterology. 2013; 144: 967-977Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, Sonnenburg et al., 2010Sonnenburg E.D. Zheng H. Joglekar P. Higginbottom S.K. Firbank S.J. Bolam D.N. Sonnenburg J.L. Specificity of polysaccharide use in intestinal bacteroides species determines diet-induced microbiota alterations.Cell. 2010; 141: 1241-1252Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar, Turnbaugh et al., 2009bTurnbaugh P.J. Ridaura V.K. Faith J.J. Rey F.E. Knight R. Gordon J.I. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.Sci. Transl. Med. 2009; 1: 6ra14Crossref PubMed Scopus (2082) Google Scholar). Humans eating controlled diets supplemented with nonstarch polysaccharides or resistant starch, both with high levels of potential MACs, exhibit diet-induced alterations in microbiota composition (Walker et al., 2011Walker A.W. Ince J. Duncan S.H. Webster L.M. Holtrop G. Ze X. Brown D. Stares M.D. Scott P. Bergerat A. et al.Dominant and diet-responsive groups of bacteria within the human colonic microbiota.ISME J. 2011; 5: 220-230Crossref PubMed Scopus (1120) Google Scholar). Due to the “gateway” role of primary fermenters within the colonic ecosystem, MACs can promote certain microbes either directly (those that consume a substrate) or indirectly (via crossfeeding interactions) (Fischbach and Sonnenburg, 2011Fischbach M.A. Sonnenburg J.L. Eating for two: how metabolism establishes interspecies interactions in the gut.Cell Host Microbe. 2011; 10: 336-347Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). Despite a large gap in our understanding of how the diversity and quantity of dietary MACs influence host health, many studies are strengthening the links between MACs, microbiota diversity and metabolism, and host health.Box 1Microbiota-Accessible CarbohydratesMACs are carbohydrates that are metabolically available to gut microbes. MACs include carbohydrates that are dietary and resistant to degradation and absorption by the host, and they may be secreted by the host in the intestine (e.g., mucus) or produced by microbes within the intestine. Dietary MACs may come from a variety of sources including plants, animal tissue, or food-borne microbes, but must be metabolized by the microbiota. Much of the cellulose humans consume is not metabolized by gut microbes and does not qualify as a MAC (Chassard et al., 2010Chassard C. Delmas E. Robert C. Bernalier-Donadille A. The cellulose-degrading microbial community of the human gut varies according to the presence or absence of methanogens.FEMS Microbiol. Ecol. 2010; 74: 205-213Crossref PubMed Scopus (97) Google Scholar). The amount of dietary MACs present in a single food source differs for each individual, since which carbohydrates are metabolized depends upon the membership of each person’s microbiota. The individuality of which carbohydrates qualify as MACs is illustrated by the presence of genes for the consumption of the algal polysaccharide porphyran in the microbiomes of Japanese individuals, rarely found in North American and European individuals (Hehemann et al., 2010Hehemann J.H. Correc G. Barbeyron T. Helbert W. Czjzek M. Michel G. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota.Nature. 2010; 464: 908-912Crossref PubMed Scopus (729) Google Scholar, Hehemann et al., 2012Hehemann J.H. Kelly A.G. Pudlo N.A. Martens E.C. Boraston A.B. Bacteria of the human gut microbiome catabolize red seaweed glycans with carbohydrate-active enzyme updates from extrinsic microbes.Proc. Natl. Acad. Sci. USA. 2012; 109: 19786-19791Crossref PubMed Scopus (199) Google Scholar). For those harboring a porphyran-degrading strain, porphyran would be a MAC; but for those without a microbiota adaptation to seaweed, porphyran would not be a MAC. Similarly, germ-free mice that lack a microbiota might consume a diet high in potential MACs, but none of the carbohydrates would be considered bona fide MACs, since they would transit the digestive tract unmetabolized by microbes. Alternatively, lack of dietary MACs results in a microbial community reliant upon endogenous host-derived MACs in the form of mucin glycans (Sonnenburg et al., 2005Sonnenburg J.L. Xu J. Leip D.D. Chen C.H. Westover B.P. Weatherford J. Buhler J.D. Gordon J.I. Glycan foraging in vivo by an intestine-adapted bacterial symbiont.Science. 2005; 307: 1955-1959Crossref PubMed Scopus (831) Google Scholar). Different host genotypes can influence the identity of MACs available to the microbiota in multiple ways. For example, host genotype can dictate alteration of mucus structures, such as the absence of alpha-1-2 fucose residues in the mucus of nonsecretor individuals that lack alpha-1-2-fucosyltransferase activity in the intestine (Kashyap et al., 2013bKashyap P.C. Marcobal A. Ursell L.K. Smits S.A. Sonnenburg E.D. Costello E.K. Higginbottom S.K. Domino S.E. Holmes S.P. Relman D.A. et al.Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota.Proc. Natl. Acad. Sci. USA. 2013; 110: 17059-17064Crossref PubMed Scopus (189) Google Scholar). Similarly, host genotype can determine how efficiently carbohydrates are digested and absorbed in the small intestine. For example, lactose becomes a substrate for the microbiota in people who are lactose intolerant, and therefore should be considered a MAC for these individuals. For nursing infants, dietary MACs in breast milk are known as human milk oligosaccharides (Bode, 2012Bode L. Human milk oligosaccharides: every baby needs a sugar mama.Glycobiology. 2012; 22: 1147-1162Crossref PubMed Scopus (1066) Google Scholar, Marcobal et al., 2010Marcobal A. Barboza M. Froehlich J.W. Block D.E. German J.B. Lebrilla C.B. Mills D.A. Consumption of human milk oligosaccharides by gut-related microbes.J. Agric. Food Chem. 2010; 58: 5334-5340Crossref PubMed Scopus (362) Google Scholar, Marcobal et al., 2011Marcobal A. Barboza M. Sonnenburg E.D. Pudlo N. Martens E.C. Desai P. Lebrilla C.B. Weimer B.C. Mills D.A. German J.B. Sonnenburg J.L. Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways.Cell Host Microbe. 2011; 10: 507-514Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). Therefore, the term “microbiota-accessible carbohydrate” contributes to a conceptual framework for investigating and discussing the amount of metabolic activity that a specific food or carbohydrate can be expected to produce within a given microbiota (Figure 1). MACs are carbohydrates that are metabolically available to gut microbes. MACs include carbohydrates that are dietary and resistant to degradation and absorption by the host, and they may be secreted by the host in the intestine (e.g., mucus) or produced by microbes within the intestine. Dietary MACs may come from a variety of sources including plants, animal tissue, or food-borne microbes, but must be metabolized by the microbiota. Much of the cellulose humans consume is not metabolized by gut microbes and does not qualify as a MAC (Chassard et al., 2010Chassard C. Delmas E. Robert C. Bernalier-Donadille A. The cellulose-degrading microbial community of the human gut varies according to the presence or absence of methanogens.FEMS Microbiol. Ecol. 2010; 74: 205-213Crossref PubMed Scopus (97) Google Scholar). The amount of dietary MACs present in a single food source differs for each individual, since which carbohydrates are metabolized depends upon the membership of each person’s microbiota. The individuality of which carbohydrates qualify as MACs is illustrated by the presence of genes for the consumption of the algal polysaccharide porphyran in the microbiomes of Japanese individuals, rarely found in North American and European individuals (Hehemann et al., 2010Hehemann J.H. Correc G. Barbeyron T. Helbert W. Czjzek M. Michel G. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota.Nature. 2010; 464: 908-912Crossref PubMed Scopus (729) Google Scholar, Hehemann et al., 2012Hehemann J.H. Kelly A.G. Pudlo N.A. Martens E.C. Boraston A.B. Bacteria of the human gut microbiome catabolize red seaweed glycans with carbohydrate-active enzyme updates from extrinsic microbes.Proc. Natl. Acad. Sci. USA. 2012; 109: 19786-19791Crossref PubMed Scopus (199) Google Scholar). For those harboring a porphyran-degrading strain, porphyran would be a MAC; but for those without a microbiota adaptation to seaweed, porphyran would not be a MAC. Similarly, germ-free mice that lack a microbiota might consume a diet high in potential MACs, but none of the carbohydrates would be considered bona fide MACs, since they would transit the digestive tract unmetabolized by microbes. Alternatively, lack of dietary MACs results in a microbial community reliant upon endogenous host-derived MACs in the form of mucin glycans (Sonnenburg et al., 2005Sonnenburg J.L. Xu J. Leip D.D. Chen C.H. Westover B.P. Weatherford J. Buhler J.D. Gordon J.I. Glycan foraging in vivo by an intestine-adapted bacterial symbiont.Science. 2005; 307: 1955-1959Crossref PubMed Scopus (831) Google Scholar). Different host genotypes can influence the identity of MACs available to the microbiota in multiple ways. For example, host genotype can dictate alteration of mucus structures, such as the absence of alpha-1-2 fucose residues in the mucus of nonsecretor individuals that lack alpha-1-2-fucosyltransferase activity in the intestine (Kashyap et al., 2013bKashyap P.C. Marcobal A. Ursell L.K. Smits S.A. Sonnenburg E.D. Costello E.K. Higginbottom S.K. Domino S.E. Holmes S.P. Relman D.A. et al.Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota.Proc. Natl. Acad. Sci. USA. 2013; 110: 17059-17064Crossref PubMed Scopus (189) Google Scholar). Similarly, host genotype can determine how efficiently carbohydrates are digested and absorbed in the small intestine. For example, lactose becomes a substrate for the microbiota in people who are lactose intolerant, and therefore should be considered a MAC for these individuals. For nursing infants, dietary MACs in breast milk are known as human milk oligosaccharides (Bode, 2012Bode L. Human milk oligosaccharides: every baby needs a sugar mama.Glycobiology. 2012; 22: 1147-1162Crossref PubMed Scopus (1066) Google Scholar, Marcobal et al., 2010Marcobal A. Barboza M. Froehlich J.W. Block D.E. German J.B. Lebrilla C.B. Mills D.A. Consumption of human milk oligosaccharides by gut-related microbes.J. Agric. Food Chem. 2010; 58: 5334-5340Crossref PubMed Scopus (362) Google Scholar, Marcobal et al., 2011Marcobal A. Barboza M. Sonnenburg E.D. Pudlo N. Martens E.C. Desai P. Lebrilla C.B. Weimer B.C. Mills D.A. German J.B. Sonnenburg J.L. Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways.Cell Host Microbe. 2011; 10: 507-514Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). Therefore, the term “microbiota-accessible carbohydrate” contributes to a conceptual framework for investigating and discussing the amount of metabolic activity that a specific food or carbohydrate can be expected to produce within a given microbiota (Figure 1). Accumulating data suggest that host health is linked to dietary MAC-induced alterations in microbiota composition and diversity. A dietary intervention performed on 49 obese individuals showed an increase in microbiota gene richness when participants reduced energy intake and increased dietary fiber consumption for 6 weeks (Cotillard et al., 2013Cotillard A. Kennedy S.P