Microbiota-derived bile acids (BAs) are associated with host biology/disease, yet their causal effects remain largely undefined. Herein, we speculate that characterizing previously undefined microbiota-derived BAs would uncover previously unknown BA-sensing receptors and their biological functions. We integrated BA metabolomics and microbial genetics to functionally profile >200 putative microbiota BA metabolic genes. We identified 56 less-characterized BAs, many of which are detected in humans/mammals. Notably, a subset of these BAs are potent antagonists of the human androgen receptor (hAR). They inhibit AR-related gene expression and are human-relevant. As a proof-of-principle, we demonstrate that one of these BAs suppresses tumor progression and potentiates the efficacy of anti-PD-1 treatment in an AR-dependent manner. Our findings show that an approach combining bioinformatics, BA metabolomics, and microbial genetics can expand our knowledge of the microbiota metabolic potential and reveal an unexpected microbiota BA-AR interaction and its role in regulating host biology.
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Hundreds of microbiota genes are associated with host biology/disease. Unraveling the causal contribution of a microbiota gene to host biology remains difficult because many are encoded by nonmodel gut commensals and not genetically targetable. A general approach to identify their gene transfer methodology and build their gene manipulation tools would enable mechanistic dissections of their impact on host physiology. We developed a pipeline that identifies the gene transfer methods for multiple nonmodel microbes spanning five phyla, and we demonstrated the utility of their genetic tools by modulating microbiome-derived short-chain fatty acids and bile acids in vitro and in the host. In a proof-of-principle study, by deleting a commensal gene for bile acid synthesis in a complex microbiome, we discovered an intriguing role of this gene in regulating colon inflammation. This technology will enable genetically engineering the nonmodel gut microbiome and facilitate mechanistic dissection of microbiota-host interactions.
Copyright © 2022 Elsevier Inc. All rights reserved.