Distinct patterns of microbiota and its function in end-stage liver cirrhosis correlate with antibiotic treatment, intestinal barrier impairment and systemic inflammation

Abstract

Background: Decompensated liver cirrhosis (dLC) is associated with a dysbalanced microbiome, however, reasons for those observations and resulting consequences for patients are largely unexplored. We aimed to characterize bacterial and fungal components of gut microbiota applying quantitative genome-resolved metagenomics and investigate their relation with gut barrier integrity, inflammation and how this impacts the clinical outcome of dLC patients. Methods: Samples were collected prospectively from 95 consecutive hospitalized dLC patients between 2017 and 2022. Metagenomic shot-gun sequencing coupled to flow-cytometric analyses were performed for qualitative and quantitative insights into gut microbiota on a compositional and functional level. Plasma, CRP, Zonulin and CD163 were measured to investigate host functions. Competing risk analyses were performed to compare cirrhosis-related complications within 90 days. Results: Median baseline MELD was 16 and median age 57.6 years. Patients were clustered into three groups (G1-G3) showing greatly distinct microbial patterns. G1 displayed lowest diversity and highest Enterococcus relative abundance (77.97 %), whereas G2 was dominated by Bifidobacteria (52.31 %). G3 was most diverse and clustered most closely with HC. Bacterial concentrations in patients were lower compared with HC (median 2.65 x 109 cells/gram stool), especially for G1 (median of 2.65 x 109 cells/gram stool); G2 and G3 were in-between the two. Fungi were primarily detected in patient samples and an overgrowth in G1 that was dominated by Candida spp (51.63 %) was observed. Moreover, G1-patients most frequently received antibiotics (n=33; 86.8 %) at baseline and had higher plasma levels of Zonulin (p=0.044), CD163 (p=0.019) and a numerically higher incidence of infections (p=0.09). Conclusion: Different bacterial clusters were observed at qualitative and quantitative levels and correlated with fungal abundance. Antibiotic treatment contributed to dysbiosis in patients with dLC, which translated into impairment of the intestinal barrier, translocation and systemic inflammation.