Alcohol's Impact on the Gut and Liver

Abstract

Alcohol is inextricably linked with the digestive system. It is absorbed through the gut and metabolised by hepatocytes within the liver. Excessive alcohol use results in alterations to the gut microbiome and gut epithelial integrity. It contributes to important micronutrient deficiencies including short-chain fatty acids and trace elements that can influence immune function and lead to liver damage. In some people, long-term alcohol misuse results in liver disease progressing from fatty liver to cirrhosis and hepatocellular carcinoma, and results in over half of all deaths from chronic liver disease, over half a million globally per year. In this review, we will describe the effect of alcohol on the gut, the gut microbiome and liver function and structure, with a specific focus on micronutrients and areas for future research.

Keywords: alcohol; cirrhosis; gut; hepatocellular carcinoma; liver; microbiome.

Figure 1

The effect of alcohol on the gut. (a) The histological effects of alcohol on the gut mucosa (cell death, mucosal erosions and loss of epithelium at villi tips). (b) Alcohol-induced disruption of tight junctions, exacerbated by reduced luminal SCFA concentrations. (c) Alcohol-induced dysbiosis leading to reduced SCFA and amino acid concentrations. (d) Increased concentration of secondary bile acids, and increased proportion conjugated with glycine. (e) Nutrient deficiencies as a consequence of (a–d). CTP: Connexin transmembrane proteins; JAM: Junctional adhesion molecule; EtOH: alcohol.

Figure 2

Alcohol-induced liver injury. Acetaldehyde (AA) is responsible for the majority of the toxic effects of alcohol on the liver. Acetaldehyde is extremely lipophilic, leading to the formation of acetaldehyde adducts—malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). This along with reactive oxygen species (ROS) leads to DNA damage and genotoxicity. Acetaldehyde also induces functional and structural alterations in various cell organelles (e.g., mitochondria and endoplasmic reticulum). MEOS: mitochondrial enzyme oxidation system; ADH: alcohol dehydrogenase. Image created at biorender.com (accessed on 20 August 2021).

Figure 3

Alcohol-induced steatosis. Alcohol induces hepatic steatosis by multiple mechanisms. It alters the redox ratio in the cell (NADH/NAD+), thereby inhibiting fatty acid oxidation and promoting its accumulation. It increases transcription factor SREBP1c, which leads to increased fatty acid synthesis and deposition. Alcohol inactivates PPARα, a nuclear hormone receptor that regulates many of the genes involved in fatty acid transport and oxidation. Alcohol has a direct inhibitory effect on fatty acid clearance and mobilisation. ↑: increased; ↓: decreased; HSC: hepatic stellate cell. Image created at biorender.com (accessed on 20 August 2021).

Figure 4

Alcohol-induced inflammation. Alcohol exerts its effects on both the innate and adaptive immunity. Alcohol not only induces enteric dysbiosis, but also increases intestinal permeability. Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) interact with TLR4 receptor on Kupffer cells and produce proinflammatory cytokines and chemokines via the NF-κB pathway, leading to liver inflammation. Acetaldehyde induces structural changes in various proteins and generates neoantigens, which elicit an adaptive immune response and contribute to liver inflammation. CCL2: C-C motif chemokine ligand 2; DAMPs: damage-associated molecular patterns; 4-HNE: 4-hydroxynonenal; IL: interleukin; MDA: malondialdehyde; NF-κB: nuclear factor kappa B; ROS: reactive oxygen species; TLR4: toll-like receptor 4; TNFα: tumor necrosis factor alpha; ↑: increased; ↓: decreased. Image created at biorender.com (accessed on 20 August 2021).