Pasteurized Akkermansia muciniphila mitigates 5-FU-induced intestinal mucositis in tumor-bearing mice through suppression of the cGAS-STING pathway and epithelial cell apoptosis

Abstract

The aim of this study was to examine whether pasteurized Akkermansia muciniphila (pAkk) could protect mice from chemotherapy-induced mucositis (CIM) in tumor-bearing mice. Mice were pretreated with pAkk and then treated with 5-fluorouracil (5-FU). pAkk mitigates symptoms of 5-FU-induced CIM, including slowing the rate of weight loss (14.2%) and increasing the villus height to crypt depth ratio (1.54%) in the ileum, while not impacting the antitumor efficacy of 5-FU. Furthermore, pAkk diminished the levels of proteins associated with apoptosis, including Bax, caspase-3, and Bcl-2, both in vivo and in vitro, and decreased the number of TUNEL-positive cells. pAkk further alleviated the disruption of cell barrier function and inflammation induced by 5-FU in a Caco-2/RAW264.7 co-culture model. Further exploration revealed that the cGAS-STING signaling pathway plays a crucial role in improving CIM by pAkk, with the expression of its related proteins being reversed upon pAkk treatment. The protective effect of pAkk was partially nullified after using a STING activator, further confirming that pAkk exerts its function at least partly through cGAS-STING signaling pathway. These findings provide support for developing Akkermansia muciniphila-based strategies to mitigate chemotherapy-related intestinal toxicity for patients with cancer.