Interaction of bacterial metagenome and virome in patients with cirrhosis and hepatic encephalopathy

Jasmohan S. Bajaj, Masoumeh Sikaroodi, Amirhossein Shamsaddini, Zachariah Henseler, Tasha Santiago-Rodriguez, Chathur Acharya, Andrew Fagan, Phillip B. Hylemon, Michael Fuchs, Edith Gavis, Tonya Ward, Dan Knights, Patrick M. Gillevet

Research output: Contribution to journalArticlepeer-review

Abstract

Objective Altered bacterial composition is associated with disease progression in cirrhosis but the role of virome, especially phages, is unclear. Design Cross-sectional and pre/post rifaximin cohorts were enrolled. Cross-sectional: controls and cirrhotic outpatients (compensated, on lactulose (Cirr-L), on rifaximin (Cirr-LR)) were included and followed for 90-day hospitalisations. Pre/post: compensated cirrhotics underwent stool collection pre/post 8 weeks of rifaximin. Stool metagenomics for bacteria and phages and their correlation networks were analysed in controls versus cirrhosis, within cirrhotics, hospitalised/not and pre/post rifaximin. Results Cross-sectional: 40 controls and 163 cirrhotics (63 compensated, 43 Cirr-L, 57 Cirr-LR) were enrolled. Cirr-L/LR groups were similar on model for end-stage liver disease (MELD) score but Cirr-L developed greater hospitalisations versus Cirr-LR (56% vs 30%, p=0.008). Bacterial alpha/beta diversity worsened from controls through Cirr-LR. While phage alpha diversity was similar, beta diversity was different between groups. Autochthonous bacteria linked negatively, pathobionts linked positively with MELD but only modest phage-MELD correlations were seen. Phage-bacterial correlation network complexity was highest in controls, lowest in Cirr-L and increased in Cirr-LR. Microviridae and Faecalibacterium phages were linked with autochthonous bacteria in Cirr-LR, but not Cirr-L hospitalised patients had greater pathobionts, lower commensal bacteria and phages focused on Streptococcus, Lactococcus and Myoviridae. Pre/post: No changes in alpha/beta diversity of phages or bacteria were seen postrifaximin. Phage-bacterial linkages centred around urease-producing Streptococcus species collapsed postrifaximin. Conclusion Unlike bacteria, faecal phages are sparsely linked with cirrhosis characteristics and 90-day outcomes. Phage and bacterial linkages centred on urease-producing, ammonia-generating Streptococcus species were affected by disease progression and rifaximin therapy and were altered in patients who experienced 90-day hospitalisations.

Original languageEnglish (US)
Pages (from-to)1162-1173
Number of pages12
JournalGut
Volume70
Issue number6
DOIs
StatePublished - Jun 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
Funding Partly supported by VA Merit Review I0CX00176, NCATS R21TR002024 and R21TR003095,AHRQ RO1HS025412 and an investigator-initiated grant from Bausch Health.

Publisher Copyright:
© 2021 Author(s).

Keywords

  • cirrhosis
  • hepatic encephalopathy
  • intestinal microbiology
  • liver

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