Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease

Abstract

Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.

Keywords: antioxidant; dysbiosis; endotoxemia; ethanol; fatty liver disease; gut microbiome; inflammation; leaky gut; oxidative stress; phytochemicals.

Figure 1

Schematic overview of gut–liver communication and damage prompted by intestinal disorders or consumption of exogenous agents. Numerous exogenous agents (e.g., alcohol, high-fat diet (HFD), fructose, etc.) or underlying intestinal disorders (e.g., Crohn’s disease, ulcerative colitis, etc.) can elicit changes to the abundance and/or composition of the gut microbiota. Elevated gut CYP2E1 and NADPH oxidases (NOXs) can increase oxidative stress. The resulting gut dysbiosis alters gut metabolism and damages the intestinal barrier through various mechanisms, including the oxidative stress-mediated post-translational modifications (PTMs), leading to decreases in paracellular junction complex proteins. Sustained damage to the barrier causes gut leakiness and, subsequently, a gut-localized immune response and increased levels of harmful gut-derived compounds (e.g., lipopolysaccharide (LPS), peptidoglycan, exosomes, etc.) into the circulation. LPS (and other gut-derived metabolites) and alcohol will reach the liver and drive alcoholic liver disease (ALD) pathogenesis and progression. Kupffer cell activation, mediated by LPS and oxidative stress driven by metabolism of the ethanol by hepatic CYP2E1 and from activated NOXs, increases inflammatory cytokine levels (e.g., TNF-α, etc.) and instigates hepatocyte apoptosis. Eventually, sustained oxidative stress, LPS infiltration, and hepatocyte damage will lead to the activation of hepatic stellate cells, driving liver fibrosis and continued liver damage.

Figure 2

Proposed mechanisms of the beneficial effects of antioxidant phytochemicals on gut dysbiosis and oxidative stress-mediated intestinal barrier dysfunction and inflammatory liver injury. As described in the text, many phytochemicals contained in various fruits, vegetables and dietary supplements can be metabolized by gut microbiota for improved absorption, leading to greater bioavailability. By improving the oxidative stress and gut dysbiosis, these antioxidant phytochemicals and/or their metabolites prevent leaky gut, endotoxemia, inflammation, and alcoholic and/or non-alcoholic fatty liver disease.