Colonic inflammation and secondary bile acids in alcoholic cirrhosis.
Alcohol abuse with/without cirrhosis is associated with an impaired gut barrier and inflammation. Gut microbiota can transform primary bile acids (BA) to secondary BAs, which can adversely impact the gut barrier. The purpose of this study was to define the effect of active alcohol intake on fecal BA levels and ileal and colonic inflammation in cirrhosis. Five age-matched groups {two noncirrhotic (control and drinkers) and three cirrhotic [nondrinkers/nonalcoholics (NAlc), abstinent alcoholic for >3 mo (AbsAlc), currently drinking (CurrAlc)]} were included. Fecal and serum BA analysis, serum endotoxin, and stool microbiota using pyrosequencing were performed. A subgroup of controls, NAlc, and CurrAlc underwent ileal and sigmoid colonic biopsies on which mRNA expression of TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (Cox-2) were performed. One hundred three patients (19 healthy, 6 noncirrhotic drinkers, 10 CurrAlc, 38 AbsAlc, and 30 NAlc, age 56 yr, median MELD: 10.5) were included. Five each of healthy, CurrAlc, and NAlc underwent ileal/colonic biopsies. Endotoxin, serum-conjugated DCA and stool total BAs, and secondary-to-primary BA ratios were highest in current drinkers. On biopsies, a significantly higher mRNA expression of TNF-α, IL-1β, IL-6, and Cox-2 in colon but not ileum was seen in CurrAlc compared with NAlc and controls. Active alcohol use in cirrhosis is associated with a significant increase in the secondary BA formation compared with abstinent alcoholic cirrhotics and nonalcoholic cirrhotics. This increase in secondary BAs is associated with a significant increase in expression of inflammatory cytokines in colonic mucosa but not ileal mucosa, which may contribute to alcohol-induced gut barrier injury.
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Genta
G
Kakiyama
Department of Microbiology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Phillip B
PB
Hylemon
Department of Immunology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Huiping
H
Zhou
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
William M
WM
Pandak
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Douglas M
DM
Heuman
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Dae Joong
DJ
Kang
Junshin Clinic Bile Acid Institute, Tokyo, Japan; and.
Hajime
H
Takei
Junshin Clinic Bile Acid Institute, Tokyo, Japan; and.
Hiroshi
H
Nittono
Department of Microbiology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Jason M
JM
Ridlon
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Michael
M
Fuchs
Department of Microbiology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Emily C
EC
Gurley
Department of Immunology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Yun
Y
Wang
Department of Immunology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Runping
R
Liu
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia;
Arun J
AJ
Sanyal
Microbiome Analysis Center, George Mason University, Manassas, Virginia.
Patrick M
PM
Gillevet
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia; jsbajaj@vcu.edu.
Jasmohan S
JS
Bajaj
D000437:Alcoholism / Q000150:complications*; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism*; D003108:Colonic Diseases / Q000139:chemically induced* / Q000473:pathology; D005243:Feces / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged
D001647:Bile Acids and Salts
alcohol; cytokines; farnesoid X receptor; microbiome