The Cirrhosis Dysbiosis Ratio defines Changes in the Gut Microbiome Associated with Cirrhosis and its Complications

Background & Aims—The gut microbiome is altered in cirrhosis; however its evolution with disease progression is partly understood. We aimed to study changes in microbiome over cirrhosis severity, its stability over time and its longitudinal alterations with decompensation. Methods—Controls and age-matched cirrhotics (compensated/decompensated/hospitalized) were included. Their stool microbiota was quantified using multi-tagged pyrosequencing. Ratio of autochthonous to non-autochthonous taxa was calculated as the cirrhosis dysbiosis ratio(CDR); a low number indicating dysbiosis. Firstly, microbiome was compared between controls and cirrhotic sub-groups. Second, for stability assessment, stool collected twice within 6 months in compensated outpatients was analyzed. Thirdly, changes after decompensation were assessed using (a) longitudinal comparison in patients before/after hepatic encephalopathy development (HE), (b) longitudinal cohort of hospitalized infected cirrhotics MELD-matched to uninfected cirrhotics followed for 30 days. Results—244 subjects [219 cirrhotics (121 compensated outpatients,54 decompensated outpatients,44 inpatients) and 25 age-matched controls)] were included. CDR was highest in controls(2.05) than compensated(0.89), decompensated(0.66) and inpatients(0.32,p<0.0001) and negatively correlated with endotoxin. Microbiota and CDR remained unchanged in stable © 2013 European Association of the Study of the Liver. Published by Elsevier B.V. All rights reserved. Corresponding Author: Jasmohan S Bajaj, MD, MS, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, Telephone: (804)-675-5802, Fax: (804)-675-5816, jsbajaj@vcu.edu. Conflict of Interest: None for any author Presentations: Portions of this paper were presented as an oral presentation at the Liver Meeting 2013 in Washington DC. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript J Hepatol. Author manuscript; available in PMC 2015 May 01. Published in final edited form as: J Hepatol. 2014 May ; 60(5): 940–947. doi:10.1016/j.jhep. 2013.12. 019. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript outpatient cirrhotics (0.91 vs. 0.86, p=0.45). In patients studied before/after HE development, dysbiosis occurred post-HE(CDR:1.2 to 0.42, p=0.03). In the longitudinal matched-cohort, microbiota were significantly different between infected/uninfected cirrhotics at baseline and a low CDR was associated with death and organ failures within 30 days. Conclusions—Progressive changes in the gut microbiome accompany cirrhosis and become more severe in the setting of decompensation. The cirrhosis dysbiosis ratio may be a useful quantitative index to describe microbiome alterations accompanying cirrhosis progression.