Butyrate production in the large intestine and ruminant forestomach depends on bacterial butyryl‐CoA/acetate‐CoA transferase activity and is highest when fermentable fiber and nonstructural carbohydrates are balanced. Gastrointestinal epithelia seem to use butyrate and butyrate‐induced endocrine signals to adapt proliferation, apoptosis, and differentiation to the growth of the bacterial community. Butyrate has a potential clinical application in the treatment of inflammatory bowel disease (IBD; ulcerative colitis). Via inhibited release of tumor necrosis factor α and interleukin 13 and inhibition of histone deacetylase, butyrate may contribute to the restoration of the tight junction barrier in IBD by affecting the expression of claudin‐2, occludin, cingulin, and zonula occludens poteins (ZO‐1, ZO‐2). Further evaluation of the molecular events that link butyrate to an improved tight junction structure will allow for the elucidation of the cofactors affecting the reliability of butyrate as a clinical treatment tool.