Abstract
Our gut harbors more microbes than any other body site, and accumulating evidence suggests that these organisms have a sizable impact on human health. Though efforts to classify the metabolic activities that define this microbial community have transformed the way we think about health and disease, our knowledge of gut microbially produced small molecules and their effects on host biology remains in its infancy. This Outlook surveys a range of approaches, hurdles, and advances in defining the chemical repertoire of the gut microbiota, drawing on examples with particularly strong links to human health. Progress toward understanding and manipulating this chemical language is being made with diverse chemical and biological expertise and could hold the key for combatting certain human diseases.
Highlights
In the late 1800s, the first germ-free (GF) guinea pig was delivered by aseptic caesarian section,[1] marking the first time a mammal, normally inoculated with billions of microbes upon birth, emerged without any
At every cycle, occurring multiple times per day, an estimated 5% of bile acids (BAs) skip reabsorption and are instead subject to gut microbial metabolism.[25−27] Known microbial BA biotransformations include oxidation and epimerization of hydroxy groups, dehydroxylation, and conjugation and deconjugation of the amino acid.[12,28−30] In addition to acting as a surfactant to aid in the absorption of dietary fats and lipophilic vitamins,[31] BAs act as ligands in host signaling processes
Despite its seemingly transparent genetic basis, the natural product generated by this gene cluster, colibactin, eluded isolation via traditional methods, and its complete structure has only recently been proposed
Summary
In the late 1800s, the first germ-free (GF) guinea pig was delivered by aseptic caesarian section,[1] marking the first time a mammal, normally inoculated with billions of microbes upon birth, emerged without any. Colonization of GF model organisms with both complex gut microbiotas and simplified, defined consortia have suggested that gut microbes can play causal roles in altering host phenotypes Despite these advances, the molecular mechanisms underlying the human gut microbiota’s influences on host biology have largely remained elusive. Growing evidence supports a key role for microbially derived small molecules in mediating the biological effects of the gut microbiota through interactions with host targets and pathways. In this Outlook, we discuss efforts to decipher the chemical repertoire of the gut microbiota and emphasize the integral role of chemistry in enabling the discovery and characterization of bioactive microbial metabolites. The approaches, challenges, and opportunities we explore apply not just to other human-associated microbial communities and to microbial and chemical ecology, more generally
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