Chemical transformation of xenobiotics by the human gut microbiota

BACKGROUND Humans ingest a multitude of small molecules that are foreign to the body (xenobiotics), including dietary components, environmental chemicals, and pharmaceuticals. The trillions of microorganisms that inhabit our gastrointestinal tract (the human gut microbiota) can directly alter the chemical structures of such compounds, thus modifying their lifetimes, bioavailabilities, and biological effects. Our knowledge of how gut microbial transformations of xenobiotics affect human health is in its infancy, which is surprising given the importance of the gut microbiota. We currently lack an understanding of the extent to which this metabolism varies between individuals, the mechanisms by which these microbial activities influence human biology, and how we might rationally manipulate these reactions. This deficiency stems largely from the difficulty of connecting this microbial chemistry to specific organisms, genes, and enzymes. ADVANCES Over the past several decades, studies of gut microbiota–mediated modification of xenobiotics have revealed that these organisms collectively have a larger metabolic repertoire than human cells. The chemical differences between human and microbial transformations of ingested compounds arise not only from the increased diversity of enzymes present in this complex and variable community but also from the distinct selection pressures that have shaped these activities. For example, whereas host metabolism evolved to facilitate excretion of many xenobiotics from the body, microbial modifications of these compounds and their human metabolites often support microbial growth through provision of nutrients or production of energy. Notably, the chemistry of microbial transformations often opposes or reverses that of host metabolism, altering the pharmacokinetic and pharmacodynamic properties of xenobiotics and associated metabolites. The range of xenobiotics subject to gut microbial metabolism is impressive and expanding. Gut microbes modify many classes of dietary compounds, including complex polysaccharides, lipids, proteins, and phytochemicals. These metabolic reactions are linked to a variety of health benefits, as well as disease susceptibilities. Gut microbes are also able to transform industrial chemicals and pollutants, altering their toxicities and lifetimes in the body. Similarly, microbial transformations of drugs can change their pharmacokinetic properties, be critical for prodrug activation, and lead to undesirable side effects or loss of efficacy. In the vast majority of cases, the individual microbes and enzymes that mediate these reactions are unknown. Fueled by findings underscoring the relevance of microbial xenobiotic metabolism to human health, scientists are increasingly seeking to discover and manipulate the enzymatic chemistry involved in these transformations. Recent work exploring how gut microbes metabolize the drugs digoxin and irinotecan, as well as the dietary nutrient choline, provides guidance for such investigations. These studies, which combine traditional methods with modern approaches, illustrate how a molecular understanding of gut microbial xenobiotic metabolism can guide hypothesis-driven research into the roles these reactions play in both microbiota and host biology. OUTLOOK We still face a myriad of challenges in understanding the gut microbiota’s contribution to xenobiotic metabolism. It is imperative that we connect the many known microbial transformations with the genes and enzymes responsible for these activities, and knowledge of enzyme mechanism and biochemical logic will facilitate this objective. There also remains a great need to uncover currently unappreciated activities associated with this community. Revealing the full scope of microbially mediated transformations in the gut may give us new insights into the many variable and contradictory studies regarding the effects of diet, pollutants, and drugs on human health. Microbial genes and enzymes will provide both specific targets for manipulation and diagnostic markers that can be incorporated into clinical studies and practice. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will inform personalized nutrition, toxicology risk assessment, precision medicine, and drug development.