Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease

Abstract

The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.

Figure 1:. Alcohol-induced intestinal component alterations.

Alcohol-associated liver disease (ALD) is characterized by gut dysbiosis, involving the overgrowth of harmful bacteria a decrease in bacterial and fungal, and an increase in viral diversity. Ethanol-induced dysbiosis contributes to intestinal barrier dysfunction, tight junction disruption, bacterial translocation, and increased levels and translocation of microorganism-derived toxins such as cytolysin and candidalysin. Additionally, there is a decrease in the release of short-chain (SCFA) and long-chain fatty acids (LCFA) and elevated production of trimethylamine (TMA). Ethanol-induced alterations in intestinal epithelial cells (IECs) include reduced levels of α1–2-fucosylation, and reduced numbers of tuft cells, disruption of intestinal stem cell (ISC) function, structural changes of M cells, and an increased number of Paneth cells. Goblet cells enhance their production of mucin-2 (MUC2) contributing to the thickening of the mucus layer. The production of various antimicrobial peptides (AMPs) like REG3, α-defensins, and CRAMP by enterocytes and Paneth cells decreases, while enterocytes produce more human beta-defensin (hBD). Enteroendocrine epithelial cells (EEC) increase their production of glucagon and gastric inhibitory peptide (GIP) and show alterations in the production of somatostatin and diuretic hormone 31 (Dh31). The gut immune system is also affected during ALD, resulting in an elevated number of macrophages, and intraepithelial lymphocytes (IELs) with reduced production of interferon-gamma (IFN-γ), as well as reduced numbers of T and B cells in the Peyer’s Patches, CD8+ T resident memory cells (CD8+ TRM cells), and Mucosal-associated invariant T cells (MAIT cells). Ethanol abuse is also related to a reduced production of secretory immunoglobulin A (sIgA). Mast cells and invariant natural killer T cells (iNKT cells) increase their migration to the liver. There is an impaired intestinal ILC3-secreting IL-22 production and decreased REG3 expression. Administration of the aryl hydrocarbon receptor (AhR) ligand indole-3-acetic acid (IAA) reverts this effect. Conventional type 1 dendritic cells (cDC1s) play a preventive role in ethanol-induced liver disease by preserving the levels of Akkermansia muciniphila in the intestine. Ethanol induces changes in Th1 and CD8 T cell responses, leading to a decrease in A. muciniphila and the disturbance of tight junctions, facilitating bacterial translocation. Prolonged alcohol consumption also results in increased levels of BAs. In ALD, there is a reduction of VIPergic neurons in the gut that results in the expansion of Enterococcus faecalis and the reduction of α1,2-fucosylation. This figure was created using Biorender.com. Abbreviations: APC: Antigen presenting cell; ILC3: Innate lymphoid cell 3; SCFA: Short-chain fatty acid; LCFA: Long-chain fatty acid; TMA: Trimethylamine; AMP: anti-microbial peptide; pIGR: poly immunoglobulin receptor; sIgA: secretory immunoglobulin A; IFN- γ: Interferon-gamma; IL-12: Interleukin 12; IL-17: interleukin 17; IL-22: interleukin 22; M cell: microfold cell; REG3: regenerating islet-derived protein 3; CRAMP: cathelicidin-related antimicrobial peptide; hBD: human ß-defensin; AhR: Aryl-hydrocarbon receptor-ligand.

Figure 2:. Gut-liver axis: impact on liver

Alcohol can directly impact hepatocytes leading to hepatocellular injury, steatosis, inflammation. These effects are exacerbated by the release of bacteria and bacterial products from the gut (PAMPs). Injury to hepatocytes releases of DAMPs, which along with PAMPs, activate resident and infiltrating immune cells in the liver and hepatic stellate cells (HSCs). In turn, pro-inflammatory cytokines/chemokines and pro-fibrogenic cytokines are released, at least in part by scar associated macrophages, that further stimulate the differentiation, migration, and activity of HSC, culminating in the development of fibrosis.