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

Manuela G Neuman; Helmut Karl Seitz; Samuel W French; Stephen Malnick; Heidekazu Tsukamoto; Lawrence B Cohen; Paula Hoffman; Boris Tabakoff; Michael Fasullo; Laura E Nagy; Pamela L Tuma; Bernd Schnabl; Sebastian Mueller; Jennifer L Groebner; French A Barbara; Jia Yue; Afifiyan Nikko; Mendoza Alejandro; Tillman Brittany; Vitocruz Edward; Kylie Harrall; Laura Saba; Opris Mihai

doi:10.3390/biomedicines8030063

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

Biomedicines. 2020 Mar 18;8(3):63. doi: 10.3390/biomedicines8030063.

Authors

Manuela G Neuman^{1

2}, Helmut Karl Seitz³, Samuel W French⁴, Stephen Malnick⁵, Heidekazu Tsukamoto^{6

7}, Lawrence B Cohen⁸, Paula Hoffman⁹, Boris Tabakoff⁹, Michael Fasullo¹⁰, Laura E Nagy¹¹, Pamela L Tuma¹², Bernd Schnabl¹³, Sebastian Mueller³, Jennifer L Groebner¹², French A Barbara⁴, Jia Yue⁴, Afifiyan Nikko⁴, Mendoza Alejandro⁴, Tillman Brittany⁴, Vitocruz Edward⁴, Kylie Harrall⁹, Laura Saba⁹, Opris Mihai^{1

14}

Affiliations

¹ In Vitro Drug Safety and Biotechnology, Toronto, ON, M5G 1L5, Canada.
² Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, M5G 1L5, Canada.
³ Department of Medicine, Centre of Alcohol Research, University of Heidelberg, Salem Medical Centre, 337374 Heidelberg, Germany.
⁴ Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA.
⁵ Department Internal Medicine C, Kaplan Medical Centre and Hebrew University of Jerusalem, Rehovot 76100, Israel.
⁶ Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, CA 90089-5311, USA.
⁷ Department of Veterans; Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
⁸ Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON M4N 3M5, Canada.
⁹ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA.
¹⁰ College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12205, USA.
¹¹ Departments of Pathobiology and Gastroenterology, Center for Liver Disease Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
¹² Department of Biology, The Catholic University of America, Washington, DC 20064, USA.
¹³ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁴ Department Family Medicine Clinic CAR, Bucharest, Romania.

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.

Keywords: CYP 1A2; CYP2E1; acetaldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), CYP 1A1; alcoholic hepatitis; hepato-carcinogenesis; hepatocytotoxicity; his3-Δ3′ and his3- Δ5′; laboratory markers; microsomal ethanol oxidizing system (MEOS), immunohistochemistry; mithocondrion.

Publication types

Review

Abstract

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