Alcohol-associated bowel disease: new insights into pathogenesis

Abstract

Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine, but the underlying mechanisms are not fully understood. In this review, we discuss the effects of alcohol on small and large intestinal functions, such as leaky gut, dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions, commonly referred to as alcohol-associated bowel disease (ABD). To date, detailed mechanistic insights into ABD are lacking. Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract. Ethanol metabolism generates acetaldehyde and acetate, which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract. The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD, including cancer, is discussed. We also highlight some gaps in knowledge existing in the field of ABD. Finally, we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.

Alcohol-associated liver disease

“…The detrimental effects of macrophages in ALD are likely due to production of a variety of inflammatory mediators (17), while neutrophils exacerbate ALD by producing ROS, inflammatory mediators, and neutrophil extracellular traps (27,28). On the other hand, macrophages and neutrophils play some beneficial roles in ameliorating ALD by promoting liver regeneration, fibrosis resolution, and antibacterial immuni- num, increased intestinal permeability, reduced production of antimicrobial molecules, increased mucus thickness, a striking diminution of mucosal immune cells, and gut microbiomerelated changes (44). In general, reduction of immune cells in the intestine is a unique feature of alcohol-associated bowel disease, which is different from other intestinal diseases (e.g., celiac disease, inflammatory bowel disease) characterized by intestinal inflammation (45).…”

“…In general, reduction of immune cells in the intestine is a unique feature of alcohol-associated bowel disease, which is different from other intestinal diseases (e.g., celiac disease, inflammatory bowel disease) characterized by intestinal inflammation (45). Alcohol-mediated reduction of intestinal immune cells results in intestinal immune dysfunction and subsequently contributes to gut barrier disruption (44). However, how chronic alcohol consumption exactly affects different pro-and antiinflammatory immune cell populations in different intestinal tracts still remains unclear.…”

“…Gut dysfunction and dysbiosis. Alcohol misuse can cause a profound impairment of intestinal functions, including a disease called alcohol-associated bowel disease (44). Alcohol-induced intestinal dysfunctions include malabsorption of nutrients, reduced villus-to-crypt ratio restricted to the duode-Figure 3.…”

Inflammation in Steatotic Liver Diseases: Pathogenesis and Therapeutic Targets

“…Recently, significant attention has been directed toward the gut–liver axis in ALD. 84 Microbial dysbiosis and intestinal permeability have emerged as focal points in the development of ALD therapeutics. As previously mentioned, bacterial LPS is a crucial factor in the initiation of ALD.…”

Minibioreactor arrays to model microbiome response to alcohol and tryptophan in the context of alcohol-associated liver disease

“…The disease progression and the severity of lesions are tightly linked to the gut-liver axis. This includes alterations in the composition and function of the gut microbiota and a gut barrier dysfunction characterized by a disruption of the homeostasis between intestinal epithelial cells, mucosal immune cells, and IM, inducing an increase in gut permeability (leaky gut) [4][5][6] . Both the sensitivity to and the protection from ALD are transmissible from patients to mice by fecal transplantation, emphasizing the critical role of IM in this condition 7 .…”