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. 2017 Nov;41(11):1857-1865.
doi: 10.1111/acer.13498. Epub 2017 Oct 11.

Continued Alcohol Misuse in Human Cirrhosis is Associated with an Impaired Gut-Liver Axis

Jasmohan S Bajaj  1 , Genta Kakiyama  1 , Derrick Zhao  1 , Hajime Takei  2 , Andrew Fagan  1 , Phillip Hylemon  1 , Huiping Zhou  1 , William M Pandak  1 , Hiroshi Nittono  2 , Oliver Fiehn  3 , Nita Salzman  4 , Mary Holtz  4 , Pippa Simpson  4 , Edith A Gavis  1 , Douglas M Heuman  1 , Runping Liu  1 , Dae Joong Kang  1 , Masoumeh Sikaroodi  5 , Patrick M Gillevet  5
Affiliations

Continued Alcohol Misuse in Human Cirrhosis is Associated with an Impaired Gut-Liver Axis

Jasmohan S Bajaj et al. Alcohol Clin Exp Res. 2017 Nov.

Abstract

Background: Cirrhosis and alcohol can independently affect the gut-liver axis with systemic inflammation. However, their concurrent impact in humans is unclear.

Methods: Our aim was to determine the effect of continued alcohol misuse on the gut-liver axis in cirrhotic patients. Age- and MELD-balanced cirrhotic patients who were currently drinking (Alc) or abstinent (NAlc) and healthy controls underwent serum and stool collection. A subset underwent upper endoscopy and colonoscopy for biopsies and duodenal fluid collection. The groups were compared regarding (i) inflammation/intestinal barrier: systemic tumor necrosis factor levels, intestinal inflammatory cytokine (duodenum, ileum, sigmoid), and ileal antimicrobial peptide expression; (ii) microbiota composition: 16SrRNA sequencing of duodenal, ileal, and colonic mucosal and fecal microbiota; and (iii) microbial functionality: duodenal fluid and fecal bile acid (BA) profile (conjugation and dehydroxylation status), intestinal BA transporter (ASBT, FXR, FGF-19, SHP) expression, and stool metabolomics using gas chromatography/mass spectrometry.

Results: Alc patients demonstrated a significant duodenal, ileal, and colonic mucosal and fecal dysbiosis, compared to NAlc and controls with lower autochthonous bacterial taxa. BA profile skewed toward a potentially toxic profile (higher secondary and glycine-conjugated BAs) in duodenal fluid and stool in Alc patients. Duodenal fluid demonstrated conjugated secondary BAs only in the Alc group. There was a greater expression of all ileal BA transporters in Alc patients. This group also showed higher endotoxemia, systemic and ileal inflammatory expression, and lower amino acid and bioenergetic-associated metabolites, without change in antimicrobial peptide expression.

Conclusions: Despite cirrhosis, continued alcohol misuse predisposes patients to widespread dysbiosis with alterations in microbial functionality such as a toxic BA profile, which can lead to intestinal and systemic inflammation.

Keywords: Bile Acids; Functionality; Inflammation; Metabolomics; Microbiota.

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