Rifaximin eases cirrhotic portal hypertension via DCA suppression

Microbiome-derived deoxycholic acid (DCA) worsens portal hypertension by boosting TPH1-dependent 5-hydroxytryptamine (5-HT) biosynthesis, which activates portal vein smooth muscle cell contraction via HTR1A-GIRK3 signalling, a study has found.

By reducing DCA levels, rifaximin improves cirrhotic portal hypertension, underscoring a potential therapeutic strategy for clinical management.

The researchers used thioacetamide (TAA) injection or bile duct ligation (BDL) to induce portal hypertension in mice, which were then treated with antibiotics or rifaximin, with or without exogenous DCA supplementation.

A cohort of 51 patients with cirrhosis and 19 healthy controls was analysed to confirm the associations among DCA, 5-HT, and hepatic venous pressure gradient (HVPG). In mechanistic studies, the research team used mice with tissue-specific knockout of gut epithelial Tph1 (Tph1^VKO), vascular smooth muscle cell (VSMC) Htr1a (Htr1a^ΔVSMC), or Kcnj9 (Kcnj9^ΔVSMC).

A positive association was observed between faecal DCA and portal pressure in TAA-induced portal hypertension mice (r, 0.631; p<0.001), as well as DCA and HVPG in patients (r, 0.5874; p<0.001).

Treatment with antibiotics reduced faecal DCA, serum 5-HT, and portal pressure in TAA- or BDL-induced portal hypertension mice. Such reductions were reversed by exogenous DCA, and this effect was eliminated in Tph1^VKO mice.

Upregulated GIRK3 (encoded by Kcnj9) was noted in portal veins from portal hypertension mice and patients. Deletion of VSMC-specific Kcnj9 reduced portal hypertension and prevented 5-HT-induced elevation of portal pressure.

“Mechanistically, 5-HT triggered portal vein smooth muscle cell contraction via the HTR1A-GIRK3-Ca²⁺-MLC2 pathway,” the researchers said.

Furthermore, rifaximin improved portal hypertension by reducing DCA in wild-type mice. However, the study drug had no added reduction in portal pressure in Tph1^VKO, Htr1a^ΔVSMC, or Kcnj9^ΔVSMC mice.