Journal of hepatology · 2026
Rifaximin ameliorates cirrhotic portal hypertension through suppression of microbiome-derived deoxycholic acid.
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Xiong Hai-Lin, Zhao Qi, Liu Shu-Qing, Chen Li-Lin, Nie Mei-Tong, Hong Xia-Lu, Ding Chen-Hong, Huang Ru, Jiang Nan, Chen Fei, Song Yu-Hao, Zhang Xin, Wang Ke-Qi, Zhu Chang-Peng, Xie Wei-Fen
Аннотация
BACKGROUND & AIMS: Microbiome-derived deoxycholic acid (DCA) elevates serum 5-hydroxytryptamine (5-HT), a mediator of portal hypertension (PH). Rifaximin, a non-absorbable antibiotic, is known to reduce DCA levels. We aimed to elucidate the role of DCA in cirrhotic PH and evaluate the therapeutic potential of rifaximin.
METHODS: PH was induced in mice by thioacetamide (TAA) injection or bile duct ligation (BDL). Mice were treated with antibiotics (ABX) or rifaximin, with or without exogenous DCA supplementation. A cohort of 51 patients with cirrhosis and 19 healthy controls was analyzed to validate correlations among DCA, 5-HT, and hepatic venous pressure gradient (HVPG). Mice with tissue-specific knockout of gut epithelial Tph1 (Tph1VKO), vascular smooth muscle cell Htr1a (Htr1aΔVSMC), or Kcnj9 (Kcnj9ΔVSMC) were used for mechanistic studies.
RESULTS: Fecal DCA positively correlated with portal pressure (PP) in TAA-induced PH mice (r = 0.631, p <0.001) and with HVPG in patients (r = 0.5874, p <0.001). ABX treatment reduced fecal DCA, serum 5-HT, and PP in TAA- or BDL-induced PH mice. Exogenous DCA reversed the ABX-induced reductions in serum 5-HT and PP, an effect abolished in Tph1VKO mice. GIRK3 (encoded by Kcnj9) was upregulated in portal veins from PH mice and patients. VSMC-specific Kcnj9 deletion attenuated PH and prevented 5-HT-induced PP elevation. Mechanistically, 5-HT triggered portal vein smooth muscle cell contraction via the HTR1A-GIRK3-Ca2+-MLC2 pathway. Rifaximin alleviated PH by reducing DCA in wild-type mice but showed no additional PP reduction in Tph1VKO, Htr1aΔVSMC, or Kcnj9ΔVSMC mice.
CONCLUSIONS: Microbiome-derived DCA exacerbates PH by enhancing TPH1-dependent 5-HT biosynthesis, which activates portal vein smooth muscle cell contraction via HTR1A-GIRK3 signaling. Rifaximin alleviates cirrhotic PH by reducing DCA levels, highlighting a potential therapeutic strategy for clinical PH management.
IMPACT AND IMPLICATIONS: Portal hypertension is a key driver of cirrhosis-related complications, yet current therapies exhibit suboptimal efficacy. Herein, we elucidate the role of the gut microbial metabolite deoxycholic acid in the pathophysiology of cirrhotic portal hypertension through the TPH1-5-HT/HTR1A-GIRK3 axis and provide preclinical evidence that rifaximin ameliorates cirrhotic portal hypertension by reducing deoxycholic acid. These insights may open a new avenue for the clinical management of cirrhotic portal hypertension.
METHODS: PH was induced in mice by thioacetamide (TAA) injection or bile duct ligation (BDL). Mice were treated with antibiotics (ABX) or rifaximin, with or without exogenous DCA supplementation. A cohort of 51 patients with cirrhosis and 19 healthy controls was analyzed to validate correlations among DCA, 5-HT, and hepatic venous pressure gradient (HVPG). Mice with tissue-specific knockout of gut epithelial Tph1 (Tph1VKO), vascular smooth muscle cell Htr1a (Htr1aΔVSMC), or Kcnj9 (Kcnj9ΔVSMC) were used for mechanistic studies.
RESULTS: Fecal DCA positively correlated with portal pressure (PP) in TAA-induced PH mice (r = 0.631, p <0.001) and with HVPG in patients (r = 0.5874, p <0.001). ABX treatment reduced fecal DCA, serum 5-HT, and PP in TAA- or BDL-induced PH mice. Exogenous DCA reversed the ABX-induced reductions in serum 5-HT and PP, an effect abolished in Tph1VKO mice. GIRK3 (encoded by Kcnj9) was upregulated in portal veins from PH mice and patients. VSMC-specific Kcnj9 deletion attenuated PH and prevented 5-HT-induced PP elevation. Mechanistically, 5-HT triggered portal vein smooth muscle cell contraction via the HTR1A-GIRK3-Ca2+-MLC2 pathway. Rifaximin alleviated PH by reducing DCA in wild-type mice but showed no additional PP reduction in Tph1VKO, Htr1aΔVSMC, or Kcnj9ΔVSMC mice.
CONCLUSIONS: Microbiome-derived DCA exacerbates PH by enhancing TPH1-dependent 5-HT biosynthesis, which activates portal vein smooth muscle cell contraction via HTR1A-GIRK3 signaling. Rifaximin alleviates cirrhotic PH by reducing DCA levels, highlighting a potential therapeutic strategy for clinical PH management.
IMPACT AND IMPLICATIONS: Portal hypertension is a key driver of cirrhosis-related complications, yet current therapies exhibit suboptimal efficacy. Herein, we elucidate the role of the gut microbial metabolite deoxycholic acid in the pathophysiology of cirrhotic portal hypertension through the TPH1-5-HT/HTR1A-GIRK3 axis and provide preclinical evidence that rifaximin ameliorates cirrhotic portal hypertension by reducing deoxycholic acid. These insights may open a new avenue for the clinical management of cirrhotic portal hypertension.