Microbiota-fibroblasts interactions in multi-organ fibrosis

Fibrosis, driven by persistent fibroblast activation and excessive extracellular matrix deposition, constitutes a universal pathological hallmark of chronic diseases affecting multiple organs. Emerging evidence suggests that the human host and its commensal microbiota function as an integrated biological system, wherein microbial signals dictate tissue remodeling both locally and across organ boundaries. In this review, we delineate the microbiota-fibroblast axis to examine how bacteria, viruses, microbial metabolites, and microbial-derived components regulate fibroblast activation, differentiation, and fibrogenesis across different organs. From a holobiont perspective, we integrate evidence from multiple microbial niches, including the oral cavity, gut, and lung, to elucidate their contributions to fibrosis in the intestine, liver, lung, heart, kidney, and spleen. We further organize these interactions within interconnected regulatory networks, including the gut-liver, gut-kidney-heart, oral-heart, and spleen-liver axes. Additionally, we critically evaluate direct fibroblast-targeting mechanisms, indirect effects mediated through other cell types, and correlative evidence linking microbial dysbiosis to fibrosis progression. Collectively, this conceptual framework highlights the therapeutic potential of targeting microbiota-fibroblast interactions in fibrotic diseases.