Microbial bile acid modifications: current understandings, key problems, and future perspectives

Increasing evidence has established the gut microbiota as a central driver of BA modification. Gut microbiota is involved in extensive BA modifications through various processes, including deconjugation, 7α-dehydroxylation, oxidation, epimerization, as well as emerging pathways like re-conjugation and succinylation. This review examined these microbial transformations, delineating the specific microbial species and metabolic enzymes involved. Focusing on the association between microbial modified BAs and human physiology, we investigated the existing therapeutic strategies targeting the microbiota-BA axis. These strategies can be categorized into two main domains: regulation of microbial composition (e.g., probiotics, FMT) and BA modifications (e.g., enzyme inhibitors). BA receptors, including canonical receptors (FXR, TGR5) and non-canonical (PXR, CAR, VDR, S1PR2, RORγt) receptors, further mediated the effects of BAs on various physiological functions, such as BA homeostasis, intestinal barrier integrity, and immune responses. We also summarized emerging tools, such as reverse metabolomics, source tracking algorithms, and organoid models, which facilitated knowledge discovery of novel BA modifications and their biological roles. Collectively, this review offers a comprehensive perspective on microbial BA modifications and underscores the significant potential of the gut microbiota-BA axis for disease management.