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Murine Gut Microbiota—Diet Trumps Genes

2015; Cell Press; Volume: 17; Issue: 1 Linguagem: Inglês

10.1016/j.chom.2014.12.004

1934-6069

Jens Walter,

Agriculture Sustainability and Environmental Impact

Both environmental factors and host genetics shape the composition of gut microbiota in mammals, but what matters more is insufficiently understood. In this issue of Cell Host & Microbe, Carmody et al., 2015Carmody R.N. Gerber G.K. Luevano J.M. Gatti D.M. Somes L. Svenson K.L. Turnbaugh P.J. Cell Host Microbe. 2015; 17 (this issue): 72-84Google Scholar show that diet can overrule genotype-related differences in gut microbiota composition in different mouse populations. Both environmental factors and host genetics shape the composition of gut microbiota in mammals, but what matters more is insufficiently understood. In this issue of Cell Host & Microbe, Carmody et al., 2015Carmody R.N. Gerber G.K. Luevano J.M. Gatti D.M. Somes L. Svenson K.L. Turnbaugh P.J. Cell Host Microbe. 2015; 17 (this issue): 72-84Google Scholar show that diet can overrule genotype-related differences in gut microbiota composition in different mouse populations. The gut microbiome is considered an important determinant of human health, and therefore identifying the mechanisms by which communities are assembled and structured is of significant interest. When considering a human population as a whole, the gut microbiota constitutes a metacommunity dominated by around 70 bacterial species (Schloissnig et al., 2013Schloissnig S. Arumugam M. Sunagawa S. Mitreva M. Tap J. Zhu A. Waller A. Mende D.R. Kultima J.R. Martin J. et al.Nature. 2013; 493: 45-50Crossref PubMed Scopus (556) Google Scholar). Within individuals, species and strains are for the most part stably maintained over years, but community membership and relative abundance of members differs markedly among individuals (referred to as β-diversity). What causes this substantial degree of inter-individual variation remains a key question in the field. In a paper published this issue of Cell Host & Microbe, a research team led by Peter Turnbaugh investigated whether host genotype or diet are the dominant drivers of gut microbiota structure (Carmody et al., 2015Carmody R.N. Gerber G.K. Luevano J.M. Gatti D.M. Somes L. Svenson K.L. Turnbaugh P.J. Cell Host Microbe. 2015; 17 (this issue): 72-84Google Scholar). Host genotype has a measurable impact on gut microbiota composition in both mice (Benson et al., 2010Benson A.K. Kelly S.A. Legge R. Ma F. Low S.J. Kim J. Zhang M. Oh P.L. Nehrenberg D. Hua K. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 18933-18938Crossref PubMed Scopus (884) Google Scholar) and humans (Goodrich et al., 2014Goodrich J.K. Waters J.L. Poole A.C. Sutter J.L. Koren O. Blekhman R. Beaumont M. Van Treuren W. Knight R. Bell J.T. et al.Cell. 2014; 159: 789-799Abstract Full Text Full Text PDF PubMed Scopus (1827) Google Scholar), but does not explain most inter-individual variation as monozygotic twins, although slightly more similar than dizygotic twins, still exhibit a substantial degree of individuality (Goodrich et al., 2014Goodrich J.K. Waters J.L. Poole A.C. Sutter J.L. Koren O. Blekhman R. Beaumont M. Van Treuren W. Knight R. Bell J.T. et al.Cell. 2014; 159: 789-799Abstract Full Text Full Text PDF PubMed Scopus (1827) Google Scholar). To determine what matters more, host genotype or diet, Turnbaugh's team fed two distinct diets, a low-fat, high-plant polysaccharide diet; LFPP, and a high-fat, high-sugar diet; HFHS, to five inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, NOD/LtJ, and NZO/HlLtJ), mice deficient for genes with an established role in shaping the gut microbiota (MyD88−/−, NOD2−/−, ob/ob, and Rag1−/−), and a population of outbred mice (the Diversity Outbred population). In all cases, the HFHS diet led to reproducible shifts in the fecal microbiota, causing the bacterial communities to cluster primarily by diet. Sub-clustering by genotype was observed for both the inbred and knockout mouse lines, confirming the importance of host genes in shaping the microbiome (Benson et al., 2010Benson A.K. Kelly S.A. Legge R. Ma F. Low S.J. Kim J. Zhang M. Oh P.L. Nehrenberg D. Hua K. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 18933-18938Crossref PubMed Scopus (884) Google Scholar, Goodrich et al., 2014Goodrich J.K. Waters J.L. Poole A.C. Sutter J.L. Koren O. Blekhman R. Beaumont M. Van Treuren W. Knight R. Bell J.T. et al.Cell. 2014; 159: 789-799Abstract Full Text Full Text PDF PubMed Scopus (1827) Google Scholar). However, the genetic influence was clearly secondary to that of diet. The research team then shifted its focus to the temporal dynamics of diet-induced microbiome shifts and the consequence of repeated dietary disturbances on community composition, using the outbred mice. These experiments revealed some intriguing insight into the specifics of diet-induced perturbations. Shifts in response to the HFHS diet occurred fast, with altered communities reaching a new steady state within 3 days in mice that were previously fed the LFPP diet, confirming previous work in humans that diet-induced changes occur within days (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.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5602) 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.Science. 2011; 334: 105-108Crossref PubMed Scopus (4119) Google Scholar). Interestingly, the microbiome of mice previously exposed to the HFHS diet needed 1–2 weeks to respond to a second HFHS disturbance. Next, the authors analyzed two groups of mice on oscillating diets staggered by 3 days. This experiment revealed that the gut microbiota was rapidly and consistently changed by the alternating diets, with most changes being reversible. Closer analysis revealed that 125 species-level operational taxonomic units (OTUs) showed consistent responses, while 32 OTUs showed hysteresis in response to the dietary shifts, meaning that their abundance was dependent on both current and past dietary exposure. Overall, the experiments revealed that most changes to the fecal microbiota are reversible, while also uncovering bacterial taxa whose abundance depended on prior consumption and who showed cumulative changes in response to alternating diets. Whereas resilience of the gut microbiota to dietary shifts has also been observed in humans (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.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5602) Google Scholar, Martínez et al., 2010Martínez I. Kim J. Duffy P.R. Schlegel V.L. Walter J. PLoS ONE. 2010; 5: e15046Crossref PubMed Scopus (439) Google Scholar), cumulative effects have not yet been reported. This study provided conclusive evidence that diet can play a more important role in driving gut microbiota community structure than host genotype. However, the authors' conclusion that the data provides evidence for a dominant role of diet in shaping inter-individual variations of the gut microbiota needs further substantiation. The experiments did not specifically address the role of diet in creating β-diversity, and although the HFHS diet altered community structure so that previous differences between mice could no longer be predicted, β-diversity was not reduced. In this respect it is important to point out that mice, even if fed the same diet, show highly individualized microbiome configurations with significant cage and facility effects. More importantly, human studies have established that standardized diets, although having a rapid and measurable impact on gut microbiota composition, do not reduce inter-subject variation (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.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5602) 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.Science. 2011; 334: 105-108Crossref PubMed Scopus (4119) Google Scholar). In fact, the inclusion of non-digestible carbohydrates to the human diet does generally result in gut microbiota shifts that are highly individualized (Martínez et al., 2010Martínez I. Kim J. Duffy P.R. Schlegel V.L. Walter J. PLoS ONE. 2010; 5: e15046Crossref PubMed Scopus (439) Google Scholar). When applying conceptual knowledge from the field of community ecology, which seeks to understand the mechanisms of community assembly and how they produce patterns in both space and time (Nemergut et al., 2013Nemergut D.R. Schmidt S.K. Fukami T. O'Neill S.P. Bilinski T.M. Stanish L.F. Knelman J.E. Darcy J.L. Lynch R.C. Wickey P. Ferrenberg S. Microbiol. Mol. Biol. Rev. 2013; 77: 342-356Crossref PubMed Scopus (899) Google Scholar), one has to consider that the high inter-individual variation of the mammalian gut microbiome is unlikely to be primarily driven by diet and genotype. According to ecological theory (Vellend, 2010Vellend M. Q. Rev. Biol. 2010; 85: 183-206Crossref PubMed Scopus (1346) Google Scholar), diversity at local scales is not only shaped by deterministic, niche-related factors (selection) under which both diet and genotype fall, but also diversification, dispersal, and drift, which can only be described in probabilistic terms. In addition, colonization history, which is inherently stochastic and influenced by dispersal, is predicted to impact both selection and diversification during community assembly, and interactions between these two processes (Walter and Ley, 2011Walter J. Ley R. Annu. Rev. Microbiol. 2011; 65: 411-429Crossref PubMed Scopus (451) Google Scholar). Ecological theory provides an ideal framework (Figure 1) by which to explain characteristics of gut ecosystems and the findings from the study by Carmody and co-workers. Stochastic events (e.g., chance colonization, colonization order, in situ evolution, niche construction, etc.) during gut microbiome assembly, especially during infancy, are likely to constitute a significant contributor to microbiome individuality. This can be inferred from the differences in monozygotic twins who grew up and live in the same environment, and cage and facility effects in inbred laboratory animals for which environment and diet are strictly controlled. Although a homogenization of diet does little to reduce β-diversity in both mice (Carmody et al., 2015Carmody R.N. Gerber G.K. Luevano J.M. Gatti D.M. Somes L. Svenson K.L. Turnbaugh P.J. Cell Host Microbe. 2015; 17 (this issue): 72-84Google Scholar) and humans (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.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5602) 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.Science. 2011; 334: 105-108Crossref PubMed Scopus (4119) Google Scholar), the shift in nutrient content changes the niche environment in the gut. This leads to reproducible changes in gut microbiota structure by enriching bacteria taxa that can increase their fitness through utilization of the nutrients that became available (which falls under selection in Figure 1). Diet-induced fluctuations of the niche environment are a likely contributor to the temporal dynamics observed in the human gut 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.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5602) Google Scholar), and if the dietary shifts are sufficiently extreme, as in mice moved from a LFPP to a HFHS diet, the impact of diet can dominate that of host genotype (Figure 1). If the mice are moved back to the original diet, the niche environment reverts to its original state, causing most microbiome changes to be reversible. However, longer-term, recurrent dietary treatments provide opportunity for evolutionary processes and the adaptation toward dietary substrates by specific microbial taxa, which falls under diversification in Figure 1. Thus, in situ evolution provides a potential mechanism for the hysteresis observed in the fecal gut microbiota of the mice on repeated dietary shifts (Carmody et al., 2015Carmody R.N. Gerber G.K. Luevano J.M. Gatti D.M. Somes L. Svenson K.L. Turnbaugh P.J. Cell Host Microbe. 2015; 17 (this issue): 72-84Google Scholar). The study by Carmody et al. provides some novel insight regarding the relative importance of diet and host genotype in shaping the gut microbiota and the effects of dietary patterns on its temporal dynamics and composition. The findings that diet can overrule allelic effects on gut microbiota composition, especially in mice with deletions in genes with roles in various pathologies linked to the microbiome, are significant as they suggest that dietary interventions could overcome heritable components that contribute to host disease predisposition by adversely affecting microbiome structure. The differences in the two diets used in the mouse studies were undoubtedly extreme, and similar strategies might be difficult to implement in humans. However, dietary supplements can have substantial, albeit individualized, effects on specific bacterial taxa within the gut microbiota in humans (Martínez et al., 2010Martínez I. Kim J. Duffy P.R. Schlegel V.L. Walter J. PLoS ONE. 2010; 5: e15046Crossref PubMed Scopus (439) Google Scholar). The findings that repeated dietary disturbances can cause microbiome changes that depend on previous exposure provide direct evidence for the importance of dietary history in shaping gut microbiome structure. The mechanisms by which microbial species change their abundance due to repeated dietary exposure have not been evaluated in the study, but the findings are relevant as similar historic processes might underlie associations between long-term dietary patterns and gut microbiota composition in humans (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.Science. 2011; 334: 105-108Crossref PubMed Scopus (4119) Google Scholar). Clearly, the experimental approaches developed by Turnbaugh's team provide appropriate models by which to test specific hypotheses and study the underlying mechanisms. Future research on the relative importance of factors that shape and maintain gut ecosystems should be informed by ecological theory, which predicts that a combination of deterministic (diet and genotype) and stochastic processes (dispersal, diversification, colonization history) converge and interact during gut microbiota assembly to structure patterns of biodiversity. Ultimately, the use of theory will provide the conceptual understanding that will allow us to more successfully modulate gut microbiomes. Diet Dominates Host Genotype in Shaping the Murine Gut MicrobiotaCarmody et al.Cell Host & MicrobeDecember 18, 2014In BriefDiet-induced manipulation of gut microbes holds therapeutic potential, but the reproducibility of effects across individuals remains unknown. Carmody et al. show that diet reproducibly alters the gut microbiota despite differences in host genotype. Although most bacteria respond rapidly and consistently to repeated dietary shifts, some exhibit dependence on past diet. Full-Text PDF Open Archive