Low-molecular-weight xylan induces acute watery diarrhea in mice via osmotic stress-mediated intestinal epithelial apoptosis and microbial dysbiosis

While dietary fiber is beneficial for health, excessive intake can cause adverse effects, such as bloating, abdominal pain, and diarrhea. The role of fiber molecular weight (Mw) and the underlying molecular mechanisms driving these effects remain unclear. Here, we screened dietary fibers of various types and Mws in mice and found that low-Mw xylan specifically induced acute watery diarrhea, whereas high-Mw xylan did not. We demonstrated using intestinal epithelial cells and a mouse model that low-Mw xylan acts as an intestinal osmotic stressor, triggering epithelial cell apoptosis via caspase-3 activation. This effect was accompanied by a restructuring of the cecal microbiota towards a gas-producing, pro-inflammatory and mucolytic profile. Our findings reveal a causal pathway in a mouse model linking low-Mw fiber intake to diarrhea through osmotic stress-induced apoptosis and microbial dysbiosis, establishing Mw as a critical parameter for evaluating fiber safety and formulating dietary recommendations.