Atractylodes macrocephala Koidz . Polysaccharide Ameliorates Colitis via Microbiota-Independent Activation of Autophagy and Induction of Mucin 2 Secretion

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease featured by impaired colonic mucus barrier dominated by MUC2. Dietary polysaccharides alleviate UC mainly via gut microbiota fermentation, but their direct effects on goblet cells remain unclear. Here, we identified a low-molecular-weight (2.68 kDa) inulin-type fructan from Atractylodes macrocephala Koidz. (AMKP). In DSS-induced colitis model, AMKP administration significantly ameliorated clinical symptoms while robustly upregulating MUC2 expression. Crucially, the therapeutic benefits of AMKP and its promotion of MUC2 secretion persisted even after exhaustive microbiota depletion via antibiotic (ABX) treatment, suggesting a microbiota-independent mechanism. In vitro mechanistic assays using LS174T goblet cells revealed that AMKP directly stimulates MUC2 synthesis and secretion. Further investigation demonstrated that AMKP-mediated mucosal restoration is driven by the activation of autophagy and the subsequent alleviation of endoplasmic reticulum (ER) stress. Notably, through the use of the autophagy inhibitor 3-MA and the ER stress inducer TUN, we confirmed that AMKP’s protective effect is strictly dependent on the autophagy-MUC2 axis. Our findings shift the paradigm of polysaccharide action from “microbial fermentation” to “direct host cell modulation”. By identifying AMKP as a direct secretagogue for goblet cells, this study provides a novel, microbiota-independent therapeutic strategy for restoring intestinal homeostasis in UC.