Butyrate Inhibits\nthe HDAC8/NF-κB Pathway to\nEnhance Slc26a3 Expression and Improve the Intestinal Epithelial Barrier\nto Relieve Colitis

Dietary fiber is known to promote the production of short-chain\nfatty acids (SCFAs) by gut bacteria, which can enhance intestinal\nepithelial barrier function and ameliorate intestinal inflammation\nin patients with inflammatory bowel disease (IBD). Interestingly,\nsome IBD patients show reduced expression of solute carrier family\nmember 3 (Slc26a3) in intestinal epithelial cells. The objective of\nthis research was to investigate the interaction between SCFAs and\nSlc26a3 during colitis and assess how this interaction affects intestinal\nepithelial barrier function. We showed that butyrate alleviated colonic\ninflammation in a dose-dependent manner in a dextran sulfate sodium\nsalt (DSS)-induced colitis model. Consistent with this, butyrate increased\nSlc26a3 and tight junction protein levels. In addition, butyrate inhibited\nhistone deacetylase (HDAC) levels and significantly increased the\nexpression of Slc26a3 by the acetylation of histones in Caco-2BBe\ncells. The utilization of a pan-HDAC inhibitor or inhibitors specific\nto certain classes of HDACs revealed that butyrate primarily suppressed\nHDAC8 to blunt the NF-κB pathways and enhance the expression\nof Slc26a3. Notably, we demonstrated that HDAC8 activation counteracted\nthe beneficial effect of butyrate in DSS-induced colitis. Therefore,\nwe concluded that butyrate improves the expression of Slc26a3 via\ninhibition of the HDAC8/NF-κB pathway, leading to increased\nintestinal epithelial barrier function.