Target the intestinal microbiota by prebiotics to improve alcoholic hepatitis progression: from molecular mechanisms to bedside – TIMPAH

Alcoholic liver disease (ALD) is the leading cause of cirrhosis worldwide with no specific therapeutic options other than alcohol withdrawal. Patients with alcohol misuse have an individual susceptibility to develop an ALD. This susceptibility, but also the severity of the ALD, depends, at least in part, on the intestinal microbiota (IM). Indeed, the IM of patients with severe ALD worsens liver damage in a mouse model of ALD. In this model, pectin, an alimentary fiber, changes IM and its metabolites (bile acids and indoles), decreasing the severity of liver injury and improving gut barrier which is disrupted by alcohol consumption. Pectin induces an increase in indoles, agonists of the AhR receptor, decreasing liver and intestinal barrier alcohol-induced injury. In AhR deficient mice, the effects of pectin are decreased but not completely abolished, suggesting that pectin also acts via other bacterial metabolites. Indeed, we showed that bile acids modified by pectin contribute to liver injury alleviation through the FXR receptor, which controls bile acid synthesis and metabolism. Overall, the improvement of liver and gut injuries in ALD is partially dependent on intestinal immune cells and their response to MI and its metabolites.
Our project proposes an innovative approach for the treatment of ALD based on the intake of pectin. The aim is to establish the proof of concept that pectin treatment in patients with ALD leads to metabolic changes similar to those observed in our mouse model.
This validation is particularly important in the case of bile acids, which differ between mice and humans. The effect of pectin in ALD patients will also be studied by measuring different parameters that assess the IM evolution, the intestinal barrier and liver inflammation. In addition, our partnership with immunologists expert in the in-depth and unsupervised analysis of immune cells will allow us to identify the subpopulations modified by pectin and the nature of the modifications induced. Fibers consumption, including pectin, has the advantage of being harmless but can be associated with poor tolerance, inducing bloating or abdominal distension, which can lead to low compliance. Therefore, identifying the molecular mechanisms by which pectin exerts its effects will provide new-targeted therapeutics. In our model of alcohol-fed mice, we will use diets enriched i) in pectin to target the bile acids and indole pathway or ii) in tryptophan to selectively target the indole pathway. The comparison of these diets in mice deficient in AhR in different cell types (innate immune cells, digestive epithelial cells and hepatocytes) will allow the study of the specific effect(s) of these metabolites on different cell populations. In particular, we will investigate changes in bile acid metabolism and AhR signaling via indoles and their impact on gut barrier and liver injury.
Unsupervised high dimensional analysis of systemic, intestinal and hepatic immune populations, combined with in situ analysis of intestinal immune cell populations will identify cells mediating the effect of pectin as well as the underlying mechanisms responsible for the beneficial effects of pectin in ALD, providing novel therapeutic targets beyond pectin.