Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension.

BACKGROUND & AIMS: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH. METHODS: Carbon tetrachloride or bile duct ligation surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses. RESULTS: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice. CONCLUSIONS: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

Serum sPD-1 and sPD-L1 as predictive biomarkers for HBsAg clearance in HBeAg-negative CHB patients undergoing IFN-based therapy.

BACKGROUND AND AIMS: For chronic hepatitis B (CHB) patients, there is still a need to improve hepatitis B surface antigen (HBsAg) clearance rates. This study aimed to assess the predictive effectiveness of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for HBsAg clearance in HBeAg-negative CHB patients undergoing peginterferon (Peg-IFN)-based antiviral treatment. METHODS: This study encompassed 280 patients undergoing treatment with Peg-IFNα. Serum levels of sPD-1 and sPD-L1 were measured using ELISA kits at baseline, as well as at 12, 24 and 48 weeks. The primary endpoint of the study was the determination of HBsAg clearance at 48 weeks. Logistic regression analysis was employed to identify predictors of HBsAg clearance. RESULTS: The clearance group demonstrated significantly lower serum sPD-L1 levels compared to the non-clearance group. While both groups exhibited an increase in sPD-1 levels, only the clearance group showed a rise in sPD-L1 levels. Multivariate analysis identified sPD-L1 increase at 24 weeks, and HBsAg decline at 24 weeks as predictors for HBsAg clearance at 48 weeks. The combined use of these indicators showed a predictive performance for HBsAg clearance with an AUROC of 0.907 (95% CI: 0.861-0.953, p < 0.001). CONCLUSIONS: The study revealed an inverse relationship between the trends of sPD-1/sPD-L1 and HBsAg clearance during combined IFN and NAs treatment. Moreover, the magnitude of HBsAg reduction and sPD-L1 increase emerged as significant predictors for HBsAg clearance.