Short-chain fatty acids alleviate cholestatic liver injury by improving gut microbiota and bile acid metabolism

Cholestasis , characterized by the obstruction of bile flow and the accumulation of bile acids , can lead to severe liver damage. Current treatments, such as ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), are limited in effectiveness and have significant side effects , underscoring the need for new therapies. In our study, we investigated the effects of short-chain fatty acids (SCFAs) as a treatment in a mouse model of cholestasis induced by α-naphthylisothiocyanate (ANIT). Our findings demonstrated that SCFAs improved liver function, as indicated by reductions in liver function markers, decreased necrosis, and reduced bile duct proliferation and inflammation. Furthermore, SCFAs enhanced intestinal barrier function and increased the abundance of beneficial gut bacteria , such as Akkermansia muciniphila ( A. muciniphila ). SCFAs also triggered the FXR-Fgf15-Cyp7a1 pathway, reducing bile acid synthesis and improving bile acid metabolism . These findings indicate that SCFAs could offer a viable new treatment strategy for cholestatic liver conditions by improving gut-liver interactions, stabilizing bile acid metabolism , and alleviating inflammation. • SCFAs combat cholestasis via gut microbiota modulation and FXR-FGF15-Cyp7a1 activation, offering multi-target therapy. • SCFAs promote Akkermansia muciniphila growth, restoring gut barrier and hepatic anti-inflammation in cholestasis. • SCFAs inhibit Cyp7a1 via intestinal FXR-FGF15 to suppress bile acid synthesis . • SCFAs surpass UDCA/OCA by multi-targeting microbiota-bile acid axis, reducing fibrosis safely.