Gut microbial production of lithocholic acid reprograms pro-resolutive macrophages to enhance vedolizumab responsiveness via the TGR5/FXR–NF-κB axis

TL;DR

This study shows that gut microbes produce a bile acid, lithocholic acid, which helps a drug called vedolizumab work better in treating Crohn's disease by reprogramming immune cells.

Contribution

The study identifies lithocholic acid as a key microbial metabolite that enhances vedolizumab efficacy via macrophage reprogramming through the TGR5/FXR–NF-κB axis.

Findings

Baseline gut microbiota-derived secondary bile acids predict vedolizumab efficacy in Crohn's disease.

Lithocholic acid reprograms macrophages toward a pro-resolutive M2 phenotype via the TGR5/FXR–NF-κB axis.

Fecal microbiota transplantation confirms microbial composition influences vedolizumab responsiveness.

Abstract

Crohn’s disease (CD) is a complex chronic transmural inflammatory bowel disease. Although vedolizumab (VDZ) markedly improves clinical outcomes in CD, treatment non-response remains a significant limitation, constraining its broader utility. Elucidating the mechanisms underlying VDZ responsiveness is thus critically needed. In this research, we employed a humanized mouse model of 2,4,6-trinitrobenzene sulfonic acid–induced colitis to investigate VDZ treatment response in CD. Our findings indicate that VDZ significantly alleviated disease phenotypes in a portion of CD mice. Integrated metagenomic and metabolomic profiling identified baseline gut microbiota–derived secondary bile acids as potential predictors of VDZ efficacy. Subsequent fecal microbiota transplantation from clinical donors into pseudo-germ-free mice confirmed that gut microbial composition critically influences VDZ responsiveness. Targeted metabolomics further pinpointed lithocholic acid (LCA) as a key microbially derived metabolite correlated with therapeutic remission. Single-cell RNA sequencing also revealed that intestinal macrophages serve as pivotal mediators of LCA-driven modulation of treatment outcomes. Furthermore, transcriptomic analyses demonstrated that LCA polarizes macrophages toward an M2-resolutive phenotype via concurrent engagement of the TGR5/FXR and their downstream nuclear factor kappa-B (NF-κB) pathways. Ultimately, using a conditioned medium co-culture system, we established that the regulatory effects of pro-resolutive macrophage niche on treatment response in a manner dependent on the TGR5/FXR–NF-κB axis. Taken together, our study elucidates a microbiota-immune circuit in which gut microbial metabolite LCA augments VDZ responsiveness in CD by reprogramming macrophages toward a pro-resolutive phenotype via the TGR5/FXR–NF-κB signaling network. These insights provide a mechanistic foundation for biomarker development and personalized therapeutic strategies in inflammatory bowel disease.

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