Impact of Antibiotic Resistance Genes in Gut Microbiome of Patients with Cirrhosis.

Abstract Background and aims Cirrhosis is associated with changes in intestinal microbiota that can lead to hepatic encephalopathy (HE) and infections, especially with antibiotic-resistant organisms. However, the impact of gut microbial antibiotic resistance gene (ARG) burden on clinical outcomes is unclear. Aims: Determine the impact of ARGs in cirrhosis-related gut metagenome on outcomes and disease progression, study the effect of rifaximin on ARG burden, and compare ARGs in cirrhosis with chronic kidney disease (CKD) and diabetes. Methods In cirrhotic outpatients who underwent metagenomics, we evaluated change in ARG abundances with progression and their multi-variable impact on 90-day hospitalizations and deaths over 1 year. We also studied ARGs pre and 8-weeks post-rifaximin in compensated cirrhotics in an open-label trial. Finally, ARGs from CKD and diabetes studies were compared to cirrhosis on machine learning. Results 163 cirrhotics (43 compensated, 20 ascites-only, 30 HE-only, 70 both) and 40 controls were included. ARG abundances were higher in cirrhosis versus controls and worsened with advancing cirrhosis severity. 44 patients were hospitalized and 14 died. ARG abundances were associated with hospitalizations and mortality while controlling for cirrhosis complications, medications and demographics. Rifaximin trial: ARG abundance patterns were minimally affected in 19 patients post-rifaximin. CKD/diabetes comparison: ARG abundance patterns in cirrhosis are distinguishable on machine learning and include more gram-positive ARGs. Conclusions Cirrhosis is associated with high gut microbial ARG gene burden compared to controls, which worsens with disease progression and may be different from CKD and diabetes. ARGs are not affected by rifaximin and are associated with hospitalizations and death.