Effects and mechanisms of nobiletin on gut motility by coordinating bile acid signaling via dual ileal-colonic axes in STC model mice.

Slow transit constipation (STC) is a functional gastrointestinal disorder with complex etiology and limited therapeutic options. Nobiletin (NOB), a natural polymethoxyflavone derived from citrus, exhibits multiple pharmacological activities. However, its effects on STC remain unknown. Using a loperamide-induced STC mouse model, this study demonstrates that NOB administration significantly alleviates constipation symptoms, improves intestinal propulsion, and restores plasma neurotransmitter balance. NOB also enhanced intestinal barrier function by upregulating colonic MUC2 and tight junction proteins (Claudin-1, Occludin). Importantly, it is reported for the first time that NOB differentially modulates bile acid signaling along the gut axis: it normalized ileal bile acid reabsorption via the FXR/TGR5-ASBT pathway, while enhancing colonic motility through the FXR/TGR5/5-HT3R axis, which is a dual-regulatory mechanism that has not been previously described in the context of STC. In addition, NOB modulated gut microbiota composition by reducing the Firmicutes to Bacteroidota ratio (F/B ratio) and enriching beneficial bacteria such as Alloprevotella and Bacteroides. These results underscore NOB's multitarget and gut axis-coordinated role in alleviating STC, highlighting its promise as a novel therapeutic agent and providing new mechanistic insights into bile acid signaling in constipation.