The Gut Microbial Bile Acid Modulation and Its Relevance to Digestive Health and Diseases

The human gut microbiome has been linked to numerous digestive disorders, but its metabolic products have been much less well characterized, in part due to the expense of untargeted metabolomics and lack of ability to process the data. In this review, we focused on the rapidly expanding information about the bile acid repertoire produced by the gut microbiome, including the impacts of bile acids on a wide range of host physiological processes and diseases, and discussed the role of short-chain fatty acids and other important gut microbiome–derived metabolites. Of particular note is the action of gut microbiome–derived metabolites throughout the body, which impact processes ranging from obesity to aging to disorders traditionally thought of as diseases of the nervous system, but that are now recognized as being strongly influenced by the gut microbiome and the metabolites it produces. We also highlighted the emerging role for modifying the gut microbiome to improve health or to treat disease, including the “engineered native bacteria'' approach that takes bacterial strains from a patient, modifies them to alter metabolism, and reintroduces them. Taken together, study of the metabolites derived from the gut microbiome provided insights into a wide range of physiological and pathophysiological processes, and has substantial potential for new approaches to diagnostics and therapeutics of disease of, or involving, the gastrointestinal tract. The human gut microbiome has been linked to numerous digestive disorders, but its metabolic products have been much less well characterized, in part due to the expense of untargeted metabolomics and lack of ability to process the data. In this review, we focused on the rapidly expanding information about the bile acid repertoire produced by the gut microbiome, including the impacts of bile acids on a wide range of host physiological processes and diseases, and discussed the role of short-chain fatty acids and other important gut microbiome–derived metabolites. Of particular note is the action of gut microbiome–derived metabolites throughout the body, which impact processes ranging from obesity to aging to disorders traditionally thought of as diseases of the nervous system, but that are now recognized as being strongly influenced by the gut microbiome and the metabolites it produces. We also highlighted the emerging role for modifying the gut microbiome to improve health or to treat disease, including the “engineered native bacteria'' approach that takes bacterial strains from a patient, modifies them to alter metabolism, and reintroduces them. Taken together, study of the metabolites derived from the gut microbiome provided insights into a wide range of physiological and pathophysiological processes, and has substantial potential for new approaches to diagnostics and therapeutics of disease of, or involving, the gastrointestinal tract. Reductions in data acquisition costs of DNA sequencing1National Human Genome Research Institute. DNA sequencing costs: data.https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Costs-DataDate accessed: December 21, 2021Google Scholar and mass spectrometry (MS), together with improved bioinformatics pipelines,2Bauermeister A. Mannochio-Russo H. Costa-Lotufo L.V. et al.Mass spectrometry-based metabolomics in microbiome investigations.Nat Rev Microbiol. 2022; 20: 143-160Crossref PubMed Scopus (0) Google Scholar, 3Aksenov A.A. da Silva R. Knight R. et al.Global chemical analysis of biology by mass spectrometry.Nat Rev Chem. 2017; 10054Crossref Scopus (112) Google Scholar, 4Knight R. 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Blaser M.J. Caporaso J.G. et al.Current understanding of the human microbiome.Nat Med. 2018; 24: 392-400Crossref PubMed Scopus (1050) Google Scholar However, it is unclear whether most therapies that target microbiome composition detectably impact the gut microbiome or are robust to the interpersonal diversity and plasticity of the microbiome in human hosts.7Kristensen N.B. Bryrup T. Allin K.H. et al.Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials.Genome Med. 2016; 8: 52Crossref PubMed Scopus (340) Google Scholar,8Mimee M. Citorik R.J. Lu T.K. Microbiome therapeutics - advances and challenges.Adv Drug Deliv Rev. 2016; 105: 44-54Crossref PubMed Scopus (0) Google Scholar Furthermore, many different gut microbiota configurations can lead to the same functional result,6Gilbert J.A. Blaser M.J. Caporaso J.G. et al.Current understanding of the human microbiome.Nat Med. 2018; 24: 392-400Crossref PubMed Scopus (1050) Google Scholar,9Turnbaugh P.J. Hamady M. Yatsunenko T. et al.A core gut microbiome in obese and lean twins.Nature. 2009; 457: 480-484Crossref PubMed Scopus (5694) Google Scholar suggesting that microbial functions may be more important than composition. To develop a better mechanistic understanding of the microbe–host relationship and more effective microbiome-mediated therapies, a different approach stressing the functional modulation of the gut microbiome is necessary.10Charbonneau M.R. Isabella V.M. Li N. et al.Developing a new class of engineered live bacterial therapeutics to treat human diseases.Nat Commun. 2020; 11: 1738Crossref PubMed Scopus (146) Google Scholar,11Landry B.P. Tabor J.J. Engineering diagnostic and therapeutic gut bacteria.Microbiol Spectr. 2017; 5Crossref PubMed Scopus (35) Google Scholar In contrast to functional characterization methods that elucidate the functional potential of the gut microbiome (ie, shotgun metagenomics and metatranscriptomics), there are 2 omics approaches that provide direct insight into the functional outputs and activity of the gut microbiome: metaproteomics and metabolomics. In this review, we focused on the latter. Research into the gut microbiome’s metabolome allowed us to understand mechanistically how the gut microbiome affects the etiology and pathogenesis of gastrointestinal (GI) disorders. Analyzing the response of the gut microbiome metabolome to defined interventions and using them to build predictive models that apply to individual patients, including re-engineering their microbiomes through the introduction of modified native bacteria,12Russell B.J. Brown S.D. 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M. et acid in PubMed Scopus Google Scholar to provide an of that the microbiome and metabolome in the gut and these metabolites to disease processes throughout the of bacterial metabolic functions as important many studies and physiological and short-chain fatty acid the is due to the through untargeted of many new the 2 Vrbanac A. et al.Global chemical of the microbiome include new 2020; PubMed Scopus Google Scholar, E. et affects microbiota and bile acid in 2020; 11: PubMed Scopus Google Scholar, et Chem. PubMed Scopus Google Scholar, et metabolomics approach for the of chemical from and of Scholar, M. et al.Mass spectrometry using 2020; PubMed Scopus Google Scholar, M. et of metabolites from 2022; PubMed Scopus Google Scholar and have in the Brown S.D. 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