Multitarget actions of TongXie-Ning granules against the gut dysfunctions of diarrhea-predominant irritable bowel syndrome.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: TongXie-Ning (TXN), a traditional Chinese herbal medicine (TCM) that modified from TongXie YaoFang had long been used to treat diarrhea-predominant irritable bowel syndrome (IBS-D). However, the underlying mechanisms require further scientific elucidation. AIM OF THE STUDY: This study aimed to elucidate the multitarget actions of TXN in relieving gut dysfunction against IBS-D. MATERIALS AND METHODS: The therapeutic effect of TXN on a postinfectious (PI)-IBS rat model, induced by Trichinella spiralis infection, was assessed. Subsequently, the effects of TXN on intestinal smooth muscle activity, epithelial chloride and fluid secretion, and visceral sensory activity were assessed using isometric muscle contraction assays, transepithelial short-circuit current measurements, and recordings of intestinal mesenteric afferent nerves firing, respectively. RESULTS: TXN effectively increased colonic transit time, reduced fecal water content and enhanced visceral pain threshold in PI-IBS rats. Ex vivo, TXN inhibited the spontaneous and induced colonic smooth muscle activity in a concentration-dependent manner. Specially, it suppressed myogenic contraction by blocking extracellular Cainflux and opening Kchannels, and attenuated neurogenic contraction by enhancing nitrergic signaling and adrenergic β2-like effect. Furthermore, TXN reduced intestinal mucosal secretion and fluid outflow, by inhibiting epithelial Clsecretion via a Ca-related way, without affecting Clabsorption. TXN also alleviated the spontaneous activity of mesenteric afferents and suppressed firing induced by chemical (capsaicin)/mechanical (intraluminal pressure) stimuli. CONCLUSIONS: As a botanical compound, TXN exhibits multitarget effects on intestinal motility, secretion, and sensation, thereby effectively ameliorating the gut dysfunctions underlying diarrhea and pain in IBS-D. This study provides a scientific basis for the clinical application of TXN and helps developing IBS-D therapeutics based on TXN.