Preclinical Insights into the Antifibrotic Potential of Butyrate

Fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition (ECM) deposition, which disrupts organ structure and function and can ultimately lead to organ failure. It can affect nearly all organs, and the associated morbidity and mortality increase with age. Nevertheless, few effective treatments are currently available for fibrosis. Targeting gut microbiota-derived metabolites has recently emerged as an active area of research. These metabolites participate in disease pathophysiology and profoundly affect host health. Butyrate, a major gut microbiota-derived metabolite, exerts diverse biological effects, including improving metabolism, mediating epigenetic modifications, regulating immune and inflammatory responses, and promoting gut health. Growing preclinical evidence suggests that butyrate has antifibrotic potential and may offer a promising therapeutic strategy for fibrotic diseases. The review first provides a concise overview of the sources, biosynthesis, and metabolism of butyrate in vivo. We then discuss its major biological functions and relationship with fibrosis. Subsequently, we summarize experimental evidence and the mechanisms underlying the effects of butyrate in models of liver, kidney, lung, and heart fibrosis. Finally, we assess the translational prospects of butyrate as an adjunctive therapy for fibrosis and discuss current challenges and future directions to guide further research.