Disease Severity and Proton Pump Inhibitor Use Impact Strongest on Faecal Microbiome Composition in Liver Cirrhosis

Vanessa Stadlbauer; Irina Komarova; Ingeborg Klymiuk; Marija Durdevic; Alexander Reisinger; Andreas Blesl; Florian Rainer; Angela Horvath


Liver International. 2020;40(4):866-877. 

In This Article

Abstract and Introduction


Background & Aims: Compositional changes of the faecal microbiome in cirrhosis are well described and have been associated with complications and prognosis. However, it is less well known, which disease or treatment-related factors affect microbiome composition most distinctively.

Methods: 16S rDNA sequencing data of 88 cirrhotic outpatients were investigated. Factors influencing microbiome composition were analysed by univariate and multivariate redundancy analysis. The association of the identified factors with changes in diversity and taxonomic composition was studied in depth using analysis of composition of microbiome, LDA-effect size and least absolute shrinkage and selection operator regularized regression.

Results: Disease severity and aetiology, proton pump inhibitor (PPI) use, nutritional status, age and C-reactive protein are significant explanatory variables for faecal microbiome composition in liver cirrhosis. Despite some taxonomic overlaps especially between disease severity and PPI use, we could show that the effects of disease severity, aetiology, PPI use and age are independent factors influencing microbiome composition also in subgroup analyses.

Conclusion: Our cross sectional system biology study identifies disease severity, aetiology, PPI use and age as independent factors that influence microbiome composition in liver cirrhosis. In chronic diseases with high morbidity, such as liver cirrhosis, precise patient metadata documentation is of utmost importance in microbiome analysis. Further studies with a higher sample size are necessary to validate this finding.


Liver cirrhosis is an increasingly common disease with high complication rates. It leads to reduced quality of life and a high burden of disease for patients, their family and the healthcare system.[1] Cirrhosis is associated with changes in the structure and functionality of the microbiome of the gut[2–5] and other body sites, such as skin or the mouth.[6] Compared to healthy individuals, a decrease in faecal microbial diversity and an imbalance between commensal and pathogenic taxa is seen in patients with cirrhosis. Furthermore, cirrhosis-associated dysbiosis goes hand in hand with increased gut permeability, intestinal bacterial translocation, intestinal and systemic inflammation leading to complications of cirrhosis and an increased mortality.[3,7–11] Dysbiosis in general and especially in cirrhosis may be caused by host and environmental factors, which shape the microbiome. These factors include alcohol consumption, aetiology and severity of liver disease, diet composition and medication.[5,12–18] Drug intake has emerged as one of the most important drivers of dysbiosis. It has recently been shown in vitro that, apart from classic antimicrobials, many other drugs have an extensive impact on human gut bacteria.[19] A population-based deep sequencing study of the faecal microbiome revealed that proton pump inhibitors (PPI) were associated with the most profound microbiome changes, followed by statins, antibiotics, laxatives and beta blockers.[20] Nearly 50% of older adults take one or more medications that are not medically indicated and 45% of patients over the age of 75 take five or more drugs per day.[21] The known consequences of polypharmacy and over-medication are increased healthcare costs, adverse drug reactions, increased rates of drug-drug interactions, decreased performance status of the patients, cognitive impairment, higher risk of falls and non-compliance. Interventions to reduce polypharmacy are difficult to implement.[22,23]

From the currently available data it is not known which of the above described factors may have the strongest impact on faecal microbiome composition in cirrhosis and would therefore be the most promising therapeutic goal.

We therefore conducted a systems biology analysis on a large dataset of cirrhotic patients of different aetiology and disease severity to analyse, which factors have the strongest influence on faecal microbiome composition and predicted metagenomics in patients with liver cirrhosis.