A butyrate-producing bacterium Clostridium butyricum prevents Clostridioides difficile infection independent of GPR43/109a

Abstract

Abstract Short-chain fatty acids, such as butyrate, are microbial metabolites that harbor bioactivities beneficial to the gastrointestinal health. Clostridium butyricum MIYAIRI588 (CBM) is a bacterium that produces a robust amount of butyrate and therefore used as a live biotherapeutic product in clinical settings. Clostridioides difficile (C. diff) is a bacterium that causes life-threatening diarrhea and colitis. The gut resident microbiota plays a critical role in the prevention of C. diff infection (CDI), as the disruption of the healthy microbiota by antibiotics greatly increases the risk of CDI. In this study, we examined how CBM protects the host from CDI, the mechanism which is not yet completely understood. Mice were pre-treated with cefoperazone to disrupt the gut microbiota and then infected with the C. diff VPI10463 strain to induce CDI. CBM treatment significantly improved body weight loss and mortality caused by CDI and increased neutrophils in colonic lamina propria (cLP) in the early phase of CDI. The protective effect of CBM was canceled when neutrophils were depleted by an anti-Ly6G antibody, suggesting that neutrophils may play a key role in the process. The administration of tributyrin, which elevates the concentration of butyrate in the colon, increased neutrophils in the cLP, indicating that increased butyrate produced by CBM regulates the neutrophil pool. Since it has been reported that butyrate-GPR43 signaling is crucial for neutrophils migration, we next examined the effect of CBM on CDI in GPR43/109a double knockout mice. Unexpectedly, the protective effect of CBM was retained in these mice. These results indicated that CBM prevents CDI possibly through butyrate but independent of GPR43/109a-mediated signaling.