Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis

Alcoholic liver disease (ALD)—one of the most common liver diseases — involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis (AH), liver fibrosis, and cirrhosis. Alcohol consumption induces a weakened gut barrier and changes in the composition of the gut microbiota. The presence of CYP2E1 and its elevated levels in the gastrointestinal tract after alcohol exposure lead to elevated levels of ROS and acetaldehyde, inducing inflammation and oxidative damage in the gut. At the same time, the influx of harmful molecules such as the bacterial endotoxin LPS and peptidogly from gut dysbiosis can induce intestinal inflammation and oxidative damage, further compromising the intestinal mucosal barrier. In this process, various oxidative stress-mediated post-translational modifications (PTMs) play an important role in the integrity of the barrier, eg, the presence of acetaldehyde will result in the sustained phosphorylation of several paracellular proteins (occludin and zona occludens-1), which can lead to intestinal leakage. Eventually, persistent oxidative stress, LPS infiltration and hepatocyte damage through the enterohepatic circulation will lead to hepatic stellate cell activation and hepatic fibrosis. In addition, probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), bioengineered bacteria, gut-restricted FXR agonists and others are promising therapeutic approaches that can alter gut microbiota composition to improve ALD. In the future, there will be new challenges to study the interactions between the genetics of individuals with ALD and their gut microbiome, to provide personalized interventions targeting the gut-liver axis, and to develop better techniques to measure microbial communities and metabolites in the body.

Objective: To compare the potential efficacy and safety of dual therapy and quadruple therapy with vonoprazan (VPZ) as well as the standard quadruple therapy of proton pump inhibitor (PPI) for the eradication of Helicobacter pylori (Hp) infection in Hainan province. Methods: A single-centre, non-blinded, non-inferiority randomized controlled trial was conducted at the outpatient department of gastroenterology at the Second Affiliated Hospital of Hainan Medical University from June 2022 to February 2023. 135 patients aged 18–75 years with Hp infection were enrolled and randomized into three different groups (group V1: VPZ 20 mg twice a day and amoxicillin 1.0 g three times a day for 14 days V2: vonoprazan 20 mg, amoxicillin capsules 1.0 g, furazolidone 0.1 g and bismuth potassiulm citrate 240 mg, twice daily for 14 days;; group V3: ilaprazole 5 mg, Amoxicillin 1.0 g, Furazolidone 100 mg, bismuth potassiulm citrate 240 mg, twice a day for 14 days). Four weeks after the end of treatment, Hp eradication was confirmed by rechecking ¹³C-urea breath test (UBT). Results: The eradication efficacy of V1 and V3 was non-inferior to that of V2, which is consistent with the results obtained from the Kruskal-Wallis H test. The eradication rate by intentional analysis was 84.4% (38/45, 95%CI 73.4%–95.5%, P>0.05) for all the three groups. If analyzed by per-protocol, the eradication rates were 88.4% (38/43, 95%CI 78.4%–98.4%), 92.7% (38/41, 95%CI 84.4%–101.0%),88.4% (38/43，95%CI 78.4%–98.4%) in groups V1, V2 and V3, respectively, which did not show a significant difference (P > 0.05). The incidence of adverse effects was significantly lower in VPZ dual therapy compared to the other two treatment regimens (P < 0.05). VPZ dual therapy or quadruple therapy was also relatively less costly than standard quadruple therapy. Conclusion: VPZ dual therapy and quadruple therapy shows promise of not being worse than the standard quadruple therapy by a clinically relevant margin. More studies might be needed to definitively determine if the new therapy is equally effective or even superior.