Gut microbiota-derived propionate mediates the protective effects of green banana resistant starch on ulcerative colitis by inhibiting HDAC1 to promote HIF-1α acetylation.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with increasing global incidence, lacking specific targeted drugs. Green banana resistant starch (RS) has been shown to possess antioxidant effects and alleviate gastric ulcers and diarrhea, suggesting its potential therapeutic value for UC. However, its specific efficacy and mechanism of action remain unclear. In a dextran sulfate sodium-induced mouse model of UC, this study demonstrated that RS attenuates inflammatory responses and oxidative stress, preserves intestinal barrier function, and enriches beneficial commensals including Muribaculaceae, with a concomitant increase in propionate (PA) production. Its protective effects were microbiota-dependent, as shown in pseudo-germ-free mice. PA activated GPR43, triggering the SP1 pathway to suppress HDAC1 expression. Reduced HDAC1 increased HIF-1α acetylation, upregulating tight junction proteins (ZO-1, Occludin) and MUC2 while inhibiting NFκB/NLRP3 signaling and improving oxidative markers. PA supplementation mimicked RS benefits, whereas an HDAC activator counteracted them, thereby highlighting the central role of the HDAC1/HIF-1α axis. These results establish the mechanistic basis by which RS-derived propionate targets the HDAC1/HIF-1α axis against colitis, highlighting the potential of RS as a gut microbiota-targeting nutraceutical for UC management.