title: Altered profile of human gut microbiome is associated with cirrhosis and its complications.
abstract: OBJECTIVE
  The gut microbiome is altered in cirrhosis; however its evolution with disease progression is only partly understood. We aimed to study changes in the 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. The ratio of autochthonous to non-autochthonous taxa was calculated as the cirrhosis dysbiosis ratio (CDR); a low number indicating dysbiosis. Firstly, the microbiome was compared between controls and cirrhotic sub-groups. Secondly, for stability assessment, stool collected twice within 6months 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 30days.
  
  
  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) followed by 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 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 30days.
  
  
  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.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States. Electronic address: jsbajaj@vcu.edu.
authors.forename: Jasmohan S
authors.initials: JS
authors.lastname: Bajaj
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heuman
authors.affiliation: Department of Microbiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Melanie B
authors.initials: MB
authors.lastname: White
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Monteith
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Noble
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Ariel B
authors.initials: AB
authors.lastname: Unser
authors.affiliation: Department of Microbiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Daita
authors.affiliation: Microbiome Analysis Center, George Mason University, Manassas, VA, United States.
authors.forename: Andmorgan R
authors.initials: AR
authors.lastname: Fisher
authors.affiliation: Microbiome Analysis Center, George Mason University, Manassas, VA, United States.
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Sikaroodi
authors.affiliation: Microbiome Analysis Center, George Mason University, Manassas, VA, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gillevet
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D004064:Digestive System / Q000382:microbiology*; D018450:Disease Progression; D058625:End Stage Liver Disease / Q000209:etiology / Q000382:microbiology; D005260:Female; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000382:microbiology; D006801:Humans; D007239:Infections / Q000209:etiology / Q000382:microbiology; D008103:Liver Cirrhosis / Q000150:complications* / Q000382:microbiology*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications / Q000382:microbiology; D008137:Longitudinal Studies; D008297:Male; D064307:Microbiota; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000382:microbiology; D011446:Prospective Studies; D012720:Severity of Illness Index
keywords: Acute-on-chronic liver failure; Cirrhosis dysbiosis ratio; Decompensation; Endotoxin; Hepatic encephalopathy; Infections; MELD score; Microbiota