Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research

Abstract

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10–20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.

Alcoholic Liver Disease and the co-triggering Role of MEOS with Its CYP 2E1 Catalytic Cycle and ROS

“…These results obtained in humans were subsequently confirmed in experimental animal studies, whereby rats received Teschke R, Neuman alcohol in a nutritionally adequate diet [2]. Therefore and based on the pioneering work of Charles S. Lieber and his associates, the conclusion was reached that the alcoholic beverage itself rather than malnutrition causes the early stages of ALD [3], a proposal that became mainstream recognition [4][5][6][7][8]. However, alcohol is not a stable chemical when present in the liver but undergoes biotransformation to acetaldehyde as the first oxidation product [9][10][11].…”

“…They may relate, for instance, to degradation products of ingested toxins such as reactive metabolites of alcohol formed as byproducts in response to the high oxidative state of the liver during ethanol metabolism [62]. Alternatively, they may relate to bacteria [71,72] in the context of the gut microbiome with their endotoxins as inducers of proinflammatory T helper cells and regulatory T cells in the intestinal tract [8], conditions of relevance for patients with ALD [22,23,30].…”

“…Compelling evidence exists that an immune component may be involved in the development and progression of ALD [8,[62][63][64][65][66], although non-immune mechanisms are also to be considered at least in some patients with acute alcoholic hepatitis (AH), who do not respond to treatment by cortisol [73]. Support for the immune component is provided by the detection of circulating autoantibodies, infiltration of immune cells in the liver, and the detection of hepatic aldehyde modified proteins in patients with ALD [62].…”

“…Support for the immune component is provided by the detection of circulating autoantibodies, infiltration of immune cells in the liver, and the detection of hepatic aldehyde modified proteins in patients with ALD [62]. The immune issue in ALD is known for three decades and is exhaustively considered in many publications including some selected ones [8,27,22,23,30,[62][63][64][65][66]. As expected, a broad range of different mechanistic steps have been proposed and variably covered, open for discussion [8,[62][63][64][65][66].…”

Obesity and accumulation of subcutaneous adipose tissue are poor prognostic factors in patients with alcoholic liver cirrhosis

“…When chronic inflammation and fibrosis of the liver were induced by nutritional disorder, oxidative stress, inflammatory cytokines, adipocytokines, and dysbiosis were observed in both alcoholic and nonalcoholic steatohepatitis [5,6]. In the pathogenic mechanisms of alcoholic liver injury, the biological metabolic changes and acetaldehyde metabolized by alcohol-induced injury [5], in particular, by dysbiosis and endotoxin via direct injury of gut mucosa by the alcohol, and are also notable factors of liver damage [7].…”