Gut microbiota-derived lithocholic acid leads to intestinal barrier dysfunction via LPCAT1 in irritable bowel syndrome

Intestinal barrier dysfunction is widely observed in patients with irritable bowel syndrome (IBS) and significantly contributes to the persistence of IBS symptoms. The association between gut dysbiosis and the pathogenesis of IBS, as well as its connection to intestinal barrier dysfunction, has been established. However, the precise roles of gut bacteria in inducing intestinal barrier dysfunction and the underlying mechanisms of IBS remain unclear. In the present study, we showed that microbiota-derived lithocholic acid (LCA) is positively associated with intestinal barrier dysfunction biomarkers in patients with IBS-D. We found excessive LCA disrupts intestinal barrier function in normal mice and aggravates colonic inflammation in a mouse model of experimental colitis. Mechanistically, LCA modulates phospholipid metabolism and compromises the intestinal barrier by directly activating lysophosphatidylcholine acyltransferase 1 (LPCAT1). Our results demonstrated that LCA significantly upregulates LPCAT1 expression, and its overexpression leads to intestinal barrier dysfunction and promotes colonic inflammation via the activation of matrix metalloproteinase-1 (MMP1). Furthermore, we found inhibition of LPCAT1 ameliorates intestinal barrier dysfunction, diarrhea symptoms and colonic inflammation in LCA-treated mice and those with experimental colitis, highlighting LPCAT1 as a potential therapeutic target for gastrointestinal diseases characterized by intestinal barrier dysfunction and colonic inflammation. Additionally, our findings showed a positive correlation between LPCAT1 and biomarkers of intestinal barrier dysfunction and colonic inflammation in patients with ulcerative colitis. Collectively, these findings reveal the essential role of gut microbiota-derived LCA in the development of intestinal barrier dysfunction by activating LPCAT1, which worsens diarrhea symptoms in IBS and colonic inflammation in IBD. Inhibiting LPCAT1, therefore, presents a promising therapeutic strategy for both IBS-D and ulcerative colitis. This study provides insights into the molecular mechanisms involving LCA and an associated gut dysbiosis pattern in the pathogenesis of IBS-D, while also identifying new therapeutic targets aimed at maintaining intestinal homeostasis in gastrointestinal diseases, particularly in reducing IBD risks among the IBS-D population.