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 antibioticresistant organisms. However, the impact of gut microbial antibiotic resistance gene (ARG) burden on clinical outcomes is unclear. The aims of the study were to 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 outpatients with cirrhosis who underwent metagenomics, we evaluated change in ARG abundances with progression and their multivariable impact on 90-day hospitalizations and deaths over 1 year. We also studied ARGs pre-and 8 weeks post-rifaximin in patients with compensated cirrhosis in an open-label trial. Finally, ARGs from CKD and diabetes studies were compared with cirrhosis on machine learning. RESULTS: A total of 163 patients with cirrhosis (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 with 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.

Multiple bacterial virulence factors focused on adherence and biofilm formation associate with outcomes in cirrhosis

“…These findings are interesting because, in addition to the prior studies showing altered metabolomics and antibiotic resistance genes, the higher prevalence of VF-containing bacteria likely reflect a hostile gut microbiome in cirrhosis. 51 , 52 …”

“…Whether these VF-expressing bacteria are a marker of poor prognosis, such as those with antibiotic resistance genes or whether they result in clinically apparent infections is an important question. 52 Therefore, we enrolled hospitalized patients with SBP and UTI, which are the most common infections in cirrhosis. 5 Reflecting clinical experience, the yield of causative organisms in UTI was higher than that in SBP on routine culture, and these organisms were consistent with recent literature.…”

Species-Level Analysis of the Human Gut Microbiome Shows Antibiotic Resistance Genes Associated With Colorectal Cancer

“…In another cohort of a healthy population, the highest abundance of ARG was TcR ( Hu et al, 2013 ). The ARG abundance difference in different populations may be due to the disease-specific variations in antibiotic resistance under different antibiotic exposures ( Shamsaddini et al, 2021 ).…”

“…Rifaximin, a rifamycin antibiotic, was popularly used in travelers’ diarrhea and irritable bowel syndrome. It had been reported to neither affect ARGs nor increase the ARG burden because the use of rifaximin would rarely bring about the development of drug resistance compared with other antibiotics ( Shamsaddini et al, 2021 ). The high ARG burden in CRC patients suggested that it is recommended to consider possible antibiotic resistance when selecting appropriate antibiotic treatments, such as short-term alternating antibiotics and microbiome-based interventions ( Dubinsky et al, 2020 ).…”

Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction

“…This may be due to the technique of sequencing used. A recent study demonstrates significant and profound changes in the microbiota in liver cirrhosis – using metagenomics and not only 16S sequencing – with a favorable effect of rifaximin unlike absorbable antibiotics ( Shamsaddini et al, 2021 ). The extent to which such antibiotic therapies shift individual bile acids in a favorable direction in humans is unclear.…”