Impact of bacterial infections and spontaneous bacterial peritonitis prophylaxis on phage‐bacterial dynamics in cirrhosis

Abstract

Background and Aims Gut microbiota, including bacteria and phages, are altered in cirrhosis, but their role during infections and spontaneous bacterial peritonitis (SBP) prophylaxis is unclear. Our aim was determine metagenomic changes in gut bacteria; phages and their linkages centered around Gram‐negative and Gram‐positive pathobionts in patients with cirrhosis with/without infections or SBP prophylaxis. Approach and Results We included uninfected (n = 231) and infected (n = 30, SBP n = 19 and urinary tract infection n = 11 before antibiotics) patients who gave stool for bacterial and phage metagenomics. We matched uninfected to infected patients 1:1 on a model for end‐stage liver disease (MELD). We also analyzed subgroups of patients with ascites matched on an MELD (n = 73) to patients on SBP prophylaxis (n = 7) and then to SBP infection. Phage and bacterial taxa differences (DESeq2) and correlation networks centered around Escherichia coli and Enterococcus faecium were analyzed. Infections were mostly due to Enterobacteriaceae and Enterococcus spp. On metagenomics, higher fold changes of Enterobacteriaceae members, Enterococcus and Streptococcus spp., and Escherichia phages were seen in infected patients. Correlation networks showed more complex bacteria‐phage linkages in infected patients compared with uninfected ones overall and centered around E. coli and E. faecium. SBP prophylaxis induced higher Gram‐positive bacteria. In SBP, Enterococcus and Escherichia were higher versus ascites. Correlation networks around E. coli were complex in ascites but sparse with SBP prophylaxis, whereas the reverse was seen with E. faecium. Lytic phages and those associated with antibiotic resistance were correlated with E. faecium. Conclusion In cirrhosis, there are significant changes in phage‐bacterial linkages in infected patients and those on SBP prophylaxis compared to the remaining patients. SBP prophylaxis enriches complexity of E. faecium–centered but induces a collapse in E. coli–centered phage‐bacterial correlations.

Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis

“…The overall impact of this interaction is unclear but the functional implications of lactate, SCFA and methane could be important in modulating therapeutic approaches. These differential interactions could also explain the greater cohesion of the transkingdom correlation network in those who ultimately decompensated versud those who remained stable, which has been shown in studies of infected patients with cirrhosis 9. In addition, the relative stability of bacteria-archaea interaction in stable patients over both time points versus a collapse in those who were postoutcomes, also suggests an important role of non-bacterial components of the microbiome in cirrhosis.,…”

“…Defining the bacteria, archaea and viruses in patients with cirrhosis would help individualise prognostic strategies and refine eligibility and selection for success for faecal microbiota transplant and treatments for HE and SBP. In addition, knowledge of the interactions of bacteria with phages could help define therapies to protect against decompensation and development of infections 9…”

“…The gut microbiome is a major contributor towards hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP) 5–7. However, the impact of the microbiome on development of all-cause decompensation as a whole is unclear 8 9. The current literature in cirrhosis and microbiota are mainly comprised short-term trials of microbially modified therapies and projections of data on follow-up without longitudinal collections 10 11.…”

Primary prophylaxis for spontaneous bacterial peritonitis is linked to antibiotic resistance in the Veterans Health Administration

“…[8,15] Although the mechanisms of these are unclear, there is evidence of antibiotic-resistance genes in the gut microbiota that are expressed after ciprofloxacin therapy and that are resistant to correction with a fecal transplant, as well as changes in phage-bacterial dynamics that could lead to this altered gut milieu. [22,23] Persistence of the ciprofloxacin resistance-related genes despite fecal transplant is particularly concerning since this modality is being increasingly explored to reduce the gut reservoir of resistant organisms. [23,24] When assessing national-level antibiotic sensitivity data using VA antibiograms, we observed hospital and regional variability in E. coli and K. pneumoniae resistance to fluoroquinolones and TMP-SMX.…”

“…The decreasing efficacy of fluoroquinolones calls into question their continued use in high-resistance settings, especially in light of recent clinical trials showing a reduction in SBP without showing a mortality benefit in those receiving fluoroquinolones for SBPPr 8,15. Although the mechanisms of these are unclear, there is evidence of antibiotic-resistance genes in the gut microbiota that are expressed after ciprofloxacin therapy and that are resistant to correction with a fecal transplant, as well as changes in phage-bacterial dynamics that could lead to this altered gut milieu 22,23. Persistence of the ciprofloxacin resistance-related genes despite fecal transplant is particularly concerning since this modality is being increasingly explored to reduce the gut reservoir of resistant organisms 23,24…”