Colonic inflammation and secondary bile acids in alcoholic cirrhosis

Abstract

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.

Intestinal transport and metabolism of bile acids

“…Indeed, with the observation that CDCA inhibits Clostridium diffi cile spore germination, there is increasing interest in developing bile acid analogs that are resistant to bacterial transformations such as 7-dehydroxylation ( 196 ). Notably, levels of gut 7 ␣ / ␤ -dehydroxylation activity vary many fold between human populations ( 26 ) and under different pathophysiological conditions ( 197,198 ).…”

Microbiota, cirrhosis, and the emerging oral-gut-liver axis

“…There is an imbalance of BA synthesis and excretion in cirrhosis, with reduced levels of secondary BAs due to decreased colonic conversion (32,33). There is evidence that the Firmicutes, particularly those within the Clostridiales cluster, are responsible for the conversion of primary to secondary BAs in the colon (33)(34)(35). It is also possible that reduced BA secretion allows migration of oral microbiota downward to the distal gut, thereby potentiating small intestinal bacterial overgrowth.…”

Gut Microbiota, Cirrhosis, and Alcohol Regulate Bile Acid Metabolism in the Gut

“…Recently, it has been reported that alcohol induces bile acid synthesis through activation of hepatic cannabinoid receptor type 1 (Cb1r) and CREBH (32). Kakiyama et al (2014) have shown that cirrhotic patients who are currently drinking have significantly higher levels of fecal secondary bile acids compared to cirrhotic patients abstaining from alcohol (> 6 months), nonalcoholic cirrhotics, drinkers without cirrhosis and even healthy control who abstain from alcohol (33). Cirrhotic patients actively drinking also showed significant increases in mRNA of proinflammatory markers (TNF-α, IL-6, IL-1β, MCP-1) in colonic but not ileal tissue compared with all other groups (33).…”