Resistant starch alleviates intestinal fibrosis involving an acetate-mediated HDAC2-H3K27ac axis in fibroblasts.

Dietary fibre-based interventions are of growing interest for the prevention and treatment of digestive diseases. In this study, we investigated the effect of resistant starch (RS) on intestinal fibrosis, a stricturing condition driven by excessive extracellular matrix (ECM) accumulation. RS was found to alleviate intestinal fibrosis in a dextran sulfate sodium (DSS)-induced chronic colitis mouse model, as evidenced by restored colon length, reduced ECM deposition (fibronectin and collagen I), and decreased levels of α-smooth muscle actin. Given that RS is fermented by the gut microbiota in the colon, metagenomic sequencing revealed that RS reshaped the composition of the gut microbiota and increased the abundance of beneficial gut bacteria, including Bacteroides acidifaciens, Faecalibaculum rodentium, and Bifidobacterium pseudolongum, which are known to enhance the production of short-chain fatty acids. Targeted metabolomic analysis further showed a marked increase in acetate levels, which was associated with reduced intestinal fibrosis. However, direct in vivo evidence that acetate is required for the anti-fibrotic effect of RS remains lacking. Using human (CCD-18Co) and primary mouse intestinal fibroblasts, the major ECM-producing cells that drive fibrosis progression, we demonstrated that acetate inhibited TGF-β-induced fibroblast activation by inhibiting histone deacetylase 2, thereby enhancing the acetylation level of histone H3 at lysine 27. Collectively, these results suggest a potential microbial-metabolic-epigenetic axis linking RS and acetate to fibrosis attenuation, which awaits causal validation in vivo. This axis holds promise as a therapeutic target for fibrotic diseases.