Resistant starch alleviates intestinal fibrosis by reshaping gut microbiota to increase acetate production, which inhibits fibroblast activation through an HDAC2-H3K27ac epigenetic axis.
Resistant starch alleviated intestinal fibrosis in a DSS-induced chronic colitis mouse model.
Resistant starch reshaped gut microbiota composition and increased the abundance of short-chain fatty acid-producing beneficial bacteria.
Resistant starch treatment was associated with a marked increase in acetate levels as measured by targeted metabolomic analysis.
Acetate inhibited TGF-β-induced fibroblast activation in human and primary mouse intestinal fibroblasts.
Acetate inhibited fibroblast activation by inhibiting histone deacetylase 2 (HDAC2), thereby enhancing histone H3 acetylation at lysine 27 (H3K27ac).
This research suggests that resistant starch — a type of dietary fiber found in foods like unripe bananas, cooked and cooled potatoes, and whole grains — may help reduce intestinal fibrosis, a condition where excessive scar tissue builds up in the intestine and can cause dangerous narrowing. In mice with chronic colitis-like disease, resistant starch helped restore normal colon length and reduced the accumulation of scar tissue proteins. The researchers found that gut bacteria fermented the resistant starch and produced higher levels of a molecule called acetate (a short-chain fatty acid), and that beneficial bacteria including Bacteroides acidifaciens and Bifidobacterium pseudolongum were more abundant after resistant starch treatment. The study also investigated how acetate works at a molecular level using intestinal fibroblast cells — the cells primarily responsible for producing the scar tissue in fibrosis. The researchers found that acetate blocks the activity of an enzyme called HDAC2 (histone deacetylase 2), which in turn changes how genes are regulated through a process called histone acetylation (specifically at a site called H3K27). This epigenetic change appears to dampen the fibrosis-promoting signals driven by a molecule called TGF-β. This research suggests a chain of events connecting dietary fiber → gut bacteria → acetate production → epigenetic changes → reduced fibrosis. The authors caution that direct proof that acetate specifically causes the anti-fibrotic effects of resistant starch in living animals still needs to be established. Nevertheless, these findings open potential avenues for dietary or therapeutic strategies targeting the gut microbiome and epigenetic regulation to treat fibrotic intestinal diseases, such as those seen in Crohn's disease.
Zheng Y, Zhuang H, Dan L, Zhou Y, Yan B, Zhang Y, et al.. (2026). Resistant starch alleviates intestinal fibrosis involving an acetate-mediated HDAC2-H3K27ac axis in fibroblasts.. Food & function. https://doi.org/10.1039/d6fo01179a