Butyrate ameliorated the intestinal barrier dysfunction and attenuated acute pancreatitis in mice fed with ketogenic diet

Butyrate, a short-chain fatty acid (SCFA), has demonstrated significant efficacy in preventing colitis-associated inflammation. Acute pancreatitis is an acute gastrointestinal disorder characterized by increased systemic inflammation, bacterial translocation, and disrupted intestinal barrier. However, the effects and mechanisms of butyrate in attenuating acute pancreatitis remain unclear. In this study, we established two mouse models of acute pancreatitis induced by cerulein (Cer) and taurocholate (TA), which were further exacerbated by a ketogenic diet (KD). The results suggested that butyrate supplementation effectively reduced mortality rates, systemic inflammation, and intestinal barrier disruption caused by Cer- and TA-induced acute pancreatitis in mice fed a KD. Furthermore, we observed a significant reduction in gut microbiota diversity as well as overgrowth of Lachnospirales and Erysipelotrichales along with depletion of SCFAs in mice fed a KD, and these alterations were reversed by butyrate supplement. To evaluate the role of microbiota and butyrate supplement, we conducted germ-depletion trials by antibiotics. The results showed that while systemic inflammation was attenuated in mice with TA-induced pancreatitis following antibiotic treatment, the reduction in mortality remained inconclusive (p = 0.055). Importantly, the key differential change between antibiotic treatment and butyrate supplementation was found to be related to intestinal barrier dysfunction and repairment. These results suggest that butyrate plays a central role in mitigating acute pancreatitis through amelioration of intestinal barrier dysfunction.