Microbiome: Focus on Causation and Mechanism
2018; Cell Press; Volume: 174; Issue: 4 Linguagem: Inglês
10.1016/j.cell.2018.07.038
ISSN1097-4172
Autores Tópico(s)Tryptophan and brain disorders
ResumoThere is tremendous enthusiasm for the microbiome in academia and industry. This Perspective argues that in order to realize its potential, the field needs to focus on establishing causation and molecular mechanism with an emphasis on phenotypes that are large in magnitude, easy to measure, and unambiguously driven by the microbiota. There is tremendous enthusiasm for the microbiome in academia and industry. This Perspective argues that in order to realize its potential, the field needs to focus on establishing causation and molecular mechanism with an emphasis on phenotypes that are large in magnitude, easy to measure, and unambiguously driven by the microbiota. The microbiome research community is producing exciting results at a rapid clip. Many of these early findings are correlative and associative, but phenomenology often precedes mechanism in a new area; by uncovering important phenotypes impacted by the microbiome, these studies illustrate why we should delve deeper. Indeed, there is broad agreement that the microbiome is ready to mature into a mechanism-based discipline, and a small but growing number of studies have pioneered the quest for molecular understanding in this space. In industry, a raft of early entrants is seeking to develop therapies based on tantalizing observations in the areas of infectious disease, cancer immunotherapy, and immune modulation (Atarashi et al., 2013Atarashi K. Tanoue T. Oshima K. Suda W. Nagano Y. Nishikawa H. Fukuda S. Saito T. Narushima S. Hase K. et al.Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.Nature. 2013; 500: 232-236Crossref PubMed Scopus (1878) Google Scholar, Gopalakrishnan et al., 2018Gopalakrishnan V. Spencer C.N. Nezi L. Reuben A. Andrews M.C. Karpinets T.V. Prieto P.A. Vicente D. Hoffman K. Wei S.C. et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (2221) Google Scholar, Matson et al., 2018Matson V. Fessler J. Bao R. Chongsuwat T. Zha Y. Alegre M.L. Luke J.J. Gajewski T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018; 359: 104-108Crossref PubMed Scopus (1429) Google Scholar, Routy et al., 2018Routy B. Le Chatelier E. Derosa L. Duong C.P.M. Alou M.T. Daillère R. Fluckiger A. Messaoudene M. Rauber C. Roberti M.P. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (2588) 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 (2542) Google Scholar). However, high-profile failures (Ratner, 2016Ratner M. Seres's pioneering microbiome drug fails mid-stage trial.Nat. Biotechnol. 2016; 34: 1004-1005Crossref PubMed Google Scholar) have led to hand wringing about the feasibility of drug discovery and development in a murky space with few hard landmarks. Although there is an abundance of enthusiasm for the microbiome, the approaches most likely to yield impactful molecular mechanisms are still topics of intense debate. The central argument of this Perspective is that academic and industrial efforts should focus on causality and mechanism with an eye toward phenotypes that are large in magnitude, easy to measure, and unambiguously driven by the microbiota. I examine two areas ripe for mechanistic inquiry, small-molecule production and immune modulation by the microbiome, and then consider two topics critical to studying and exploiting these phenotypes: the role of individual bacterial species and molecules in complex mixtures and synthetic ecology as a tool for studying and developing therapeutics from the microbiome. Many microbiota-host interaction studies share a common format: they start with a phenotype (often linked to disease) and seek to understand the microbial taxa or genes responsible for it. This is akin to forward genetics, with three important distinctions (Figure 1): the phenotype and genotype are in different organisms (host and microbe, respectively), the primary technique is differential sequence analysis rather than genetics, and the outcome is usually a bacterial taxon associated with a phenotype rather than a gene responsible for the phenotype. The forward genetic approach has had notable successes, which can be grouped into three categories (referenced examples throughout are meant to be illustrative, not exhaustive): (1) comparative sequence analyses of disease cohorts that result in taxonomic associations (Gevers et al., 2014Gevers D. Kugathasan S. Denson L.A. Vázquez-Baeza Y. Van Treuren W. Ren B. Schwager E. Knights D. Song S.J. Yassour M. et al.The treatment-naive microbiome in new-onset Crohn's disease.Cell Host Microbe. 2014; 15: 382-392Abstract Full Text Full Text PDF PubMed Scopus (1897) Google Scholar, Qin et al., 2012Qin J. Li Y. Cai Z. Li S. Zhu J. Zhang F. Liang S. Zhang W. Guan Y. Shen D. et al.A metagenome-wide association study of gut microbiota in type 2 diabetes.Nature. 2012; 490: 55-60Crossref PubMed Scopus (3988) Google Scholar), (2) studies that show a phenotype can be transferred by microbiome transplant in germ-free mice (Gopalakrishnan et al., 2018Gopalakrishnan V. Spencer C.N. Nezi L. Reuben A. Andrews M.C. Karpinets T.V. Prieto P.A. Vicente D. Hoffman K. Wei S.C. et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (2221) Google Scholar, Matson et al., 2018Matson V. Fessler J. Bao R. Chongsuwat T. Zha Y. Alegre M.L. Luke J.J. Gajewski T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018; 359: 104-108Crossref PubMed Scopus (1429) Google 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 (2423) Google Scholar, Routy et al., 2018Routy B. Le Chatelier E. Derosa L. Duong C.P.M. Alou M.T. Daillère R. Fluckiger A. Messaoudene M. Rauber C. Roberti M.P. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (2588) Google Scholar, Thaiss et al., 2016Thaiss C.A. Itav S. Rothschild D. Meijer M. Levy M. Moresi C. Dohnalová L. Braverman S. Rozin S. Malitsky S. et al.Persistent microbiome alterations modulate the rate of post-dieting weight regain.Nature. 2016; 540: 544-551Crossref PubMed Scopus (287) Google Scholar), and (3) efforts that narrow down to one or a few species that modulate a host phenotype (Atarashi et al., 2013Atarashi K. Tanoue T. Oshima K. Suda W. Nagano Y. Nishikawa H. Fukuda S. Saito T. Narushima S. Hase K. et al.Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.Nature. 2013; 500: 232-236Crossref PubMed Scopus (1878) Google Scholar, Buffie et al., 2015Buffie C.G. Bucci V. Stein R.R. McKenney P.T. Ling L. Gobourne A. No D. Liu H. Kinnebrew M. Viale A. et al.Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile.Nature. 2015; 517: 205-208Crossref PubMed Scopus (1094) Google Scholar, Buffington et al., 2016Buffington S.A. Di Prisco G.V. Auchtung T.A. Ajami N.J. Petrosino J.F. Costa-Mattioli M. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring.Cell. 2016; 165: 1762-1775Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, Surana and Kasper, 2017Surana N.K. Kasper D.L. Moving beyond microbiome-wide associations to causal microbe identification.Nature. 2017; 552: 244-247Crossref PubMed Scopus (140) Google Scholar). Two challenges stand out: first, given the large number of strains in a comparative sequence analysis, the process of narrowing down species that are causally linked to a phenotype can suffer from the statistical problems of cherry picking. Given the practical challenges of testing every possible strain, strains that are merely correlated are often assumed to be causative. Second, even when a causative strain is identified, it remains difficult to establish the mechanistic link to phenotype. In contrast, an approach analogous to reverse genetics has been used less often in microbiome studies. Two related experimental formats are most common: (1) colonizing mice with communities that differ only in the presence of a single strain and comparing the outcome (Buffie et al., 2015Buffie C.G. Bucci V. Stein R.R. McKenney P.T. Ling L. Gobourne A. No D. Liu H. Kinnebrew M. Viale A. et al.Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile.Nature. 2015; 517: 205-208Crossref PubMed Scopus (1094) Google Scholar, Faith et al., 2015Faith J.J. Colombel J.-F. Gordon J.I. Identifying strains that contribute to complex diseases through the study of microbial inheritance.Proc. Natl. Acad. 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A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites.Nature. 2017; 551: 648-652Crossref PubMed Scopus (512) Google Scholar, Round et al., 2011Round J.L. Lee S.M. Li J. Tran G. Jabri B. Chatila T.A. Mazmanian S.K. The Toll-LIKE receptor 2 pathway establishes colonization by a commensal of the human microbiota.Science. 2011; 332: 974-977Crossref PubMed Scopus (1128) Google Scholar). Although it can suffer from the problem of cherry picking, reverse genetics has the advantage that it is a simpler entry point to establish causality and enable studies of mechanism. More complex model microbiomes, improvements in genetic tools for prominent gut bacterial strains, methods to cultivate previously uncultured bacterial strains (Browne et al., 2016Browne H.P. Forster S.C. Anonye B.O. Kumar N. Neville B.A. Stares M.D. Goulding D. Lawley T.D. Culturing of 'unculturable' human microbiota reveals novel taxa and extensive sporulation.Nature. 2016; 533: 543-546Crossref PubMed Scopus (652) Google Scholar, Lagier et al., 2016Lagier J.C. Khelaifia S. Alou M.T. Ndongo S. Dione N. Hugon P. Caputo A. Cadoret F. Traore S.I. Seck E.H. et al.Culture of previously uncultured members of the human gut microbiota by culturomics.Nat. Microbiol. 2016; 1: 16203Crossref PubMed Scopus (584) Google Scholar), new technologies that facilitate colonization in the background of a complex community (Shepherd et al., 2018Shepherd E.S. DeLoache W.C. Pruss K.M. Whitaker W.R. Sonnenburg J.L. An exclusive metabolic niche enables strain engraftment in the gut microbiota.Nature. 2018; 557: 434-438Crossref PubMed Scopus (172) Google Scholar), and better animal models of microbiome-related disease will strengthen both forward and reverse approaches in addressing causality and mechanism more directly. Future technologies—e.g., the microbiome equivalents of whole-genome knockout and CRISPR screens—will blur the distinction between forward and reverse genetics. The important thing is not the difference between these approaches but, for a given situation, whether they can reveal causation and molecular mechanism. In the remainder of this section, we consider two areas in which inroads into causality and mechanism seem likely: (1) production of small molecules and (2) modulation of the host immune response. Readers are referred to recent literature in a third area ripe for mechanistic investigation: colonization resistance against pathogens (Pamer, 2016Pamer E.G. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens.Science. 2016; 352: 535-538Crossref PubMed Scopus (247) Google Scholar, Panigrahi et al., 2017Panigrahi P. Parida S. Nanda N.C. Satpathy R. Pradhan L. Chandel D.S. Baccaglini L. Mohapatra A. Mohapatra S.S. Misra P.R. et al.A randomized synbiotic trial to prevent sepsis among infants in rural India.Nature. 2017; 548: 407-412Crossref PubMed Scopus (301) Google Scholar). We then raise the speculative possibility of outlier phenotypes with large effect sizes that, like rare human genetic variants, could hold great therapeutic promise. Given the prominent role of small molecules in mediating signaling interactions, the fact that the gut microbiota produce a pool of molecules tens of millimolar in concentration is of particular interest. One familiar example is the short-chain fatty acids (SCFAs) that accumulate at 150–600 mM/day (Wilson, 2005Wilson M. Microbial inhabitants of humans: their ecology and role in health and disease. Cambridge University Press, New York2005Google Scholar) and signal through G protein-coupled receptors 41 and 43 (GPR41 and GPR43) to modulate the host immune and metabolic systems (Ulven, 2012Ulven T. Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets.Front. Endocrinol. (Lausanne). 2012; 3: 111Crossref PubMed Google Scholar). Another is trimethylamine N-oxide (TMAO), which derives from gut microbial metabolism of choline and carnitine and is present at 2–6 μM in plasma (Tang et al., 2013Tang W.H. Wang Z. Levison B.S. Koeth R.A. Britt E.B. Fu X. Wu Y. Hazen S.L. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.N. Engl. J. Med. 2013; 368: 1575-1584Crossref PubMed Scopus (2042) Google Scholar). It is proposed to be not just a marker of cardiovascular disease but itself proatherogenic (Brown and Hazen, 2014Brown J.M. Hazen S.L. Metaorganismal nutrient metabolism as a basis of cardiovascular disease.Curr. Opin. Lipidol. 2014; 25: 48-53Crossref PubMed Scopus (63) Google Scholar) and prothrombotic (Zhu et al., 2016Zhu W. Gregory J.C. Org E. Buffa J.A. Gupta N. Wang Z. Li L. Fu X. Wu Y. Mehrabian M. et al.Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.Cell. 2016; 165: 111-124Abstract Full Text Full Text PDF PubMed Scopus (1009) Google Scholar) in mouse models of disease. Although SCFAs and TMAO are heavily studied, the microbiota produce many other small molecules at concentrations comparable to those achieved by drugs used in the clinic. Aromatic amino acid metabolites are common and include the tryptophan metabolite indole, which is converted in the liver to indoxyl sulfate (IS) (10–130 mg/day) (Patel et al., 2012Patel K.P. Luo F.J. Plummer N.S. Hostetter T.H. Meyer T.W. The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores.Clin. J. Am. Soc. Nephrol. 2012; 7: 982-988Crossref PubMed Scopus (160) Google Scholar); the tyrosine metabolite p-cresol, which the host transforms into p-cresol sulfate (PCS) (20–230 mg/day) (Patel et al., 2012Patel K.P. Luo F.J. Plummer N.S. Hostetter T.H. Meyer T.W. The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores.Clin. J. Am. Soc. Nephrol. 2012; 7: 982-988Crossref PubMed Scopus (160) Google Scholar); and the phenylalanine metabolite phenylacetic acid, which the host conjugates to glutamine to form phenylacetylglutamine (PAG) (4.5–70 μm/mM creatinine) (Bouatra et al., 2013Bouatra S. Aziat F. Mandal R. Guo A.C. Wilson M.R. Knox C. Bjorndahl T.C. Krishnamurthy R. Saleem F. Liu P. et al.The human urine metabolome.PLoS ONE. 2013; 8: e73076Crossref PubMed Scopus (928) Google Scholar). TMAO, IS, and PCS accumulate in patients with renal failure (Sirich et al., 2013Sirich T.L. Funk B.A. Plummer N.S. Hostetter T.H. Meyer T.W. Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular secretion.J. Am. Soc. Nephrol. 2013; 25: 614-622Google Scholar, Tang et al., 2015Tang W.H.W. Wang Z. Kennedy D.J. Wu Y. Buffa J.A. Agatisa-Boyle B. Li X.S. Levison B.S. Hazen S.L. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.Circ. Res. 2015; 116: 448-455Crossref PubMed Scopus (722) Google Scholar), suggesting that a microbiota-targeted therapy to eliminate their production could be a new therapeutic opportunity in renal disease. An important source of small molecules is common dietary input, which can be converted by gut bacterial species into a variety of metabolic end products with different biological activities. For example, tryptophan can be converted to IS, indolepropionic acid, indoleacetic acid, and tryptamine. The levels of these metabolites vary widely among individuals, presumably reflecting differences in metabolic gene content among their gut communities. Thus, given a common diet, divergent microbiota can generate a metabolic output that can vary widely among individuals. This paradigm raises questions that are relevant to basic research and industry alike: which molecules are beneficial, and which others deleterious? What is the optimal gut metabolic output, and how will it vary based on disease susceptibility? Can robust, resilient gut communities be designed to produce (and not produce) specific sets of molecules? Several studies have demonstrated that the microbiota directly modulates the host immune response. Two key observations suggest that immune modulation by the microbiota might be far more specific than had previously been recognized. First, Littman and coworkers showed that the TH17 cells induced in response to segmented filamentous bacterium (SFB), a well-studied mouse symbiont, express a T cell receptor (TCR) specific for an SFB antigen (Yang et al., 2014Yang Y. Torchinsky M.B. Gobert M. Xiong H. Xu M. Linehan J.L. Alonzo F. Ng C. Chen A. Lin X. et al.Focused specificity of intestinal TH17 cells towards commensal bacterial antigens.Nature. 2014; 510: 152-156Crossref PubMed Scopus (354) Google Scholar). Although it was previously known that SFB induces TH17 cells, it is striking that a gut colonist—without breaching the intestinal epithelium—can "program" a population of immune cells that are specific to it. This paradigm has been extended by recent work on Helicobacter hepaticus (Hh), which induces Hh-specific regulatory T cells (Xu et al., 2018Xu M. Pokrovskii M. Ding Y. Yi R. Au C. Harrison O.J. Galan C. Belkaid Y. Bonneau R. Littman D.R. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont.Nature. 2018; 554: 373-377Crossref PubMed Scopus (258) Google Scholar). Belkaid and coworkers have further demonstrated the generality of this result by showing that the CD8+ T cell response to strains of the skin commensal Staphylococcus epidermidis not only is specific, but also lasts for months, indicating that the "programming" effect is potent and persistent (Naik et al., 2015Naik S. Bouladoux N. Linehan J.L. Han S.J. Harrison O.J. Wilhelm C. Conlan S. Himmelfarb S. Byrd A.L. Deming C. et al.Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature. 2015; 520: 104-108Crossref PubMed Scopus (471) Google Scholar). This unanticipated degree of specificity in the mucosal immune response to the commensal microbiota has far-reaching implications and raises several key questions. (1) How many gut commensals induce their own corresponding immune cell population? Can a designed or engineered gut consortium serve as a tool for programming the host T cell response? (2) Does this phenomenon explain the profound influence of the microbiome on the efficacy of anti-PD1 therapy in melanoma and other cancers? (Gopalakrishnan et al., 2018Gopalakrishnan V. Spencer C.N. Nezi L. Reuben A. Andrews M.C. Karpinets T.V. Prieto P.A. Vicente D. Hoffman K. Wei S.C. et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (2221) Google Scholar, Matson et al., 2018Matson V. Fessler J. Bao R. Chongsuwat T. Zha Y. Alegre M.L. Luke J.J. Gajewski T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018; 359: 104-108Crossref PubMed Scopus (1429) Google Scholar, Routy et al., 2018Routy B. Le Chatelier E. Derosa L. Duong C.P.M. Alou M.T. Daillère R. Fluckiger A. Messaoudene M. Rauber C. Roberti M.P. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (2588) Google Scholar) (3) What are the presumptive microbiota-derived or -induced molecules that determine T cell fate—and the cell types and signaling pathways through which they act? (4) If commensal-induced T cells express a TCR specific for a bacterial antigen, how do they—by cross-reactivity, proximity, or otherwise—modulate the immune response against host tissues? And can this antigen-specific response be re-directed by expressing host antigens in bacterial strains? One goal, perhaps realizable in the near term, would be to use commensals or commensal-derived molecules as the basis of a new class of immunotherapies. One great advantage of this approach would be its selectivity, which could lead to a cleaner side-effect profile than systemic immunotherapies. For example, fine control over the local T cell response could enable an enhanced CD8+ T cell response to potentiate checkpoint blockade for melanoma or colorectal adenocarcinoma without the risks of systemic immune stimulation. Likewise, local Treg stimulation could suppress immune activity in the small and large intestines (for inflammatory bowel disease) or skin (for psoriasis) without the downsides of general immune suppression. One could even imagine engineering a Treg-inducing bacterial strain to express a host autoantigen to reverse autoimmune disease. One of the most direct benefits of DNA sequencing to human medicine has been to identify genetic outliers who harbor a rare mutation that confers protection against disease. For example, nonsense mutations in the proprotein convertase PCSK9 lower LDL-C and are protective against cardiovascular disease (Cohen et al., 2005Cohen J. Pertsemlidis A. Kotowski I.K. Graham R. Garcia C.K. Hobbs H.H. 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Microbiome-wide association studies link dynamic microbial consortia to disease.Nature. 2016; 535: 94-103Crossref PubMed Scopus (424) Google Scholar), which often reveal common variants with a small effect size, the goal would be to look for rare communities (harboring unusual bacterial species or common species in unusual ratios) with large, protective effects against a disease of interest. For example, do there exist rare individuals whose gut bacteria are exceptionally efficient at harvesting calories and therefore protect against metabolic disease? Might there be people with risk alleles for Crohn's disease who are protected against disease by a gut community that suppresses inflammation or prevents a bad actor from blooming? How about hospital workers who, despite constant exposure to Staphylococcus aureus, are not colonized due to a rare, protective skin community? Phenotypes like these would be a great setting in which to explore mechanism, and the transplantability of the microbiome could make it possible to endow millions of people with a rare disease-preventive gut or skin community. The sheer complexity of a host-associated community—hundreds of microbial species, thousands of molecules—raises the question of how much difference a single organism or molecule can make. Are most microbiota-related phenomena the result of dozens of microbes or molecules acting in concert, irreducible to the effects of individual actors? Early evidence suggests otherwise. The specific T cell responses to SFB and S. epidermidis are examples of how a single bacterial species can exert a clear effect on the host, but several others are worth noting. Faecalibacterium prausnitzii (Miquel et al., 2013Miquel S. Martín R. Rossi O. Bermúdez-Humarán L.G. Chatel J.M. Sokol H. Thomas M. Wells J.M. Langella P. Faecalibacterium prausnitzii and human intestinal health.Curr. 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Though not an individual organism, a mixture of 17 anaerobic Firmicutes potently induces regulatory T cells (Atarashi et al., 2013Atarashi K. Tanoue T. Oshima K. Suda W. Nagano Y. Nishikawa H. Fukuda S. Saito T. Narushima S. Hase K. et al.Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.Nature. 2013; 500: 232-236Crossref PubMed Scopus (1878) Google Scholar). Although these interactions are not yet understood at the level of molecular mechanism, individual molecules from the microbiota are known to have a signal that rises well above background. In addition to the well-documented examples of SCFAs and TMAO (see above), polysaccharide A (Mazmanian et al., 2008Mazmanian S.K. Round J.L. Kasper D.L. A microbial symbiosis factor prevents intestinal inflammatory disease.Nature. 2008; 453: 620-625Crossref PubMed Scopus (1696) Google Scholar) and α-galactosylceramide from B. fragilis (An et al., 2014An D. Oh S.F. Olszak T. Neves J.F. Avci F.Y. 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