The role of intestinal gp130 in alcohol-associated liver disease

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Project Summary/Abstract The most prominent consequence of alcohol use disorder is alcohol-associated liver disease (ALD). Alcohol abuse is associated with intestinal dysbiosis, bacterial overgrowth, increased gut permeability, and bacterial translocation to the liver, promoting liver inflammation. This insult to the liver, exacerbates ALD. The gut-liver axis plays a crucial role on the pathogenesis of ALD. Within this axis the intestinal microbiota composition, the mucosal immune system and intestinal specialized cells are fundamental regulators. These components are disturbed during ALD. Alcohol consumption decreases the pool of interleukin (IL)-22 secreting type 3 innate lymphoid cells (ILC3). IL-22 leads to the production of antimicrobial regenerating islet-derived protein 3 (REG3) lectins mediated by activation of the signal transducer and activator of transcription 3 (STAT3) signaling in the intestine. Antimicrobial REG3 lectins regulate the intestinal microbial composition and prevent from bacterial translocation. Expression of REG3 lectins is reduced in small intestines of ethanol-fed mice and in the duodenum of patients with alcohol use disorder (AUD). Therefore, we hypothesize that restoring the expression of intestinal REG3 lectins would be an effective therapy for patients with ALD. Phosphorylation of STAT3-REG3 axis also occurs through activation of the IL-6 signal transducer (IL6ST/gp130) coreceptor. We preliminarily determined the protective role of overactive intestinal gp130 in ethanol-induced liver disease in mice. gp130 pathway signals through four different signaling transduction pathways, among them the most prominent is gp130-STAT3 pathway. Hence, we aim to define the exact signaling transduction cassette involved in the preventive role of gp130 in ethanol-induced liver disease and define the use of an engineered gp130 receptor ligand as a novel translational interventional strategy to prevent ALD. To explore the proposed hypothesis, aim 1 will investigate whether gp130-STAT3-REG3 signaling cassette is involved in the prevention against ethanol-induced liver disease. This approach proposes to use ethanol-fed mice overexpressing active intestinal gp130 but with specific deletion of intestinal STAT3. It will assess the role of gp130-STAT3-REG3 axis in the prevention of ethanol-mediated dysregulation of microbiota composition, intestinal permeability, bacterial translocation to the liver, and steatohepatitis. Aim 2 will define whether the use of a novel engineered chimeric gp130 ligand is effective as a therapy to prevent ethanol-induced liver disease preclinically in mice and test its intestinal effects in human small intestinal organoids from AUD patients. The proposed study will characterize the role of gp130-STAT3-REG3 axis in preclinical models of ethanol- induced liver disease and in patients with alcohol use disorder using cutting edge microbiomics and state-of-the- art technology. The proposed intervention will find innovative strategies to prevent alcohol-associated liver disease in patients.