Targeting the gut microbiota-bile acid axis: Therapeutic strategies for cholestatic liver disease and metabolic dysfunction-associated steatotic liver disease

Le résumé fourni par la source

Cholestatic liver disease (CSLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both associated with abnormal bile acid (BA) metabolism and have a steadily increasing incidence and prevalence worldwide. BAs are amphiphilic cholesterol metabolites that are pivotal in the regulation of their own biosynthesis as well as gut microbiota, indirectly affecting both host immunity and metabolic homeostasis. Conversely, the composition and function of BAs, including their reabsorption and excretion, are regulated by gut microbiota. Thus, regulating gut microbiota or targeting BA metabolic pathways is expected to provide novel strategies for the treatment of liver diseases. The present review focuses on elucidating the critical roles of the gut microbiota-BA axis in CSLD and MASLD and its potential as a therapeutic target. First, we clarify the roles of gut microbiota, BAs, and BA receptors, mainly farnesoid X receptor (FXR) and G protein-coupled BA receptor 1 (TGR5), in the modulation of hepatic glucose, lipid, and amino acid metabolism and intestinal barrier function, which effectively maintains the balance of the host immunoinflammatory response, as well as different cell death pathways. We also summarize recent preclinical and clinical studies involving the gut microbiota-BA axis. Subsequently, we emphasize the indirect regulation of BA metabolism by targeting gut microbiota through dietary interventions, fecal microbiota transplantation (FMT), and bacteriophage therapy and direct regulation of BA signaling by targeting secondary BAs, BA receptor agonists (fibroblast growth factor [FGF]19/21), and inhibitors of BA transporters (apical sodium-dependent BA transporter [ASBT], sodium taurocholate co-transporting polypeptide [NTCP]). Finally, we summarize and discuss mainly nanoparticle-based therapeutic strategies for modulating BA metabolism and the composition and function of the gut microbiota. Therefore, this review provides new insights to better understand the gut microbiota-BA axis in the context of treating CSLD and MASLD. • The gut microbiota modulates BAs to regulate hepatic metabolism. • Diversity of BA modifications affect the intestinal microenvironment. • Targeting the gut-BA axis could lead to promising treatments for CSLD and MASLD.

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