Altered profile of human gut microbiome is associated with cirrhosis and its complications

Abstract

Background & aims: 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.

Keywords: Acute-on-chronic liver failure; Cirrhosis dysbiosis ratio; Decompensation; Endotoxin; Hepatic encephalopathy; Infections; MELD score; Microbiota.

Fig. 1. PCO analysis of microbiota between groups

Fig. 1(A): Controls were clustered together (blue) compared to all cirrhotics (red) Fig. 1(B): Controls (blue) were clustered with outpatient cirrhotics (green) and far from inpatient cirrhotics (red) Each dot represents a subject in the graphs and the distance between the dots is proportional to the similarity in microbial abundance pattern. Therefore dots that are clustered together have similar microbial composition than those that are relatively further apart.

Fig. 2. PCO analysis of microbiota in the cohort study

Controls (red) were clustered with cirrhotics without infections (pink) but farther away from MELD-matched cirrhotics with infections (blue)

Fig. 3. PCO analysis of microbiota in patients with poor outcomes within 30 days

Fig. 3(A): Organ failure: Clustering of controls (red) with cirrhotics without (blue) and away from those with organ failure (green) Fig. 3(B): Death: Clustering of controls (blue) with cirrhotics without outcomes (red) and away from those who died (green)