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The microbial metabolite trimethylamine-N-oxide in association with inflammation and microbial dysregulation in three HIV cohorts at various disease stages

Missailidis, Catharinaa; Neogi, Ujjwala,b; Stenvinkel, Peterc; Trøseid, Mariusd,e,f; Nowak, Piotrg,*; Bergman, Petera,*

doi: 10.1097/QAD.0000000000001813

Objective: HIV-1-infection infers an increased cardiovascular risk where gut dysbiosis and microbial translocation may contribute. We assessed TMAO, a microbial metabolite with atherosclerotic properties, in plasma of HIV-1-infected individuals at different clinical stages in relation to inflammatory markers, cardiovascular events and gut microbiota.

Methods: Primary HIV-1-infected (n = 17) and chronic HIV-1-infected individuals (n = 22) were sampled before and after ART-initiation. In the chronic HIV-1-cohort, repeated faecal samples were analysed by 16SrRNA gene sequencing. HIV-1-infected individuals on longstanding ART (n = 101) and healthy HIV-1-negative individuals (n = 60), served as controls. TMAO and markers of immune activation were analysed by LC/MS/MS and immune assays, respectively.

Results: TMAO levels were lower in untreated HIV-1-infected individuals, increased significantly after ART-initiation (P = 0.040 and P < 0.001) but remained similar to healthy controls. TMAO levels were not affected by ART, immune status or degree of systemic inflammation. Higher TMAO in HIV-1-infected individuals on longstanding ART was not significantly associated with cardiovascular risk (P = 0.38). Additionally, TMAO levels correlated inversely with Bacteroidetes (Rho: −0.62, P = 0.002), and positively with Firmicutes (Rho: 0.65, P = 0.001) but held no correlation to TMA-producing genera. Notably gut dysbiosis at follow-up was more pronounced in patients without increase in TMAO levels after ART characterized by loss of Bacteroidetes (P = 0.023) and significantly elevated LPS levels (P = 0.01).

Conclusion: Our data does not support that TMAO is a significant link between gut dysbiosis and inflammation in HIV-1-infection. We propose that HIV-1, microbial composition and ART disparately confound TMAO levels, thus limiting its role as a cardiovascular risk marker in HIV-1-infected individuals.

aDivision of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge

bScience for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna

cDivision of Renal Medicine, Department of Clinical Science Intervention and Technology, Karolinska University Hospital Huddinge, Stockholm, Sweden

dResearch Institute of Internal Medicine, Oslo University Hospital Rikshospitalet

eInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo

fSection of Clinical Immunology and Infectious diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway

gDepartment of Medicine Huddinge, Unit of Infectious Disease, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Correspondence to Catharina Missailidis, MD, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden. E-mail:

Received 17 October, 2017

Revised 12 January, 2018

Accepted 15 January, 2018

Copyright © 2018 Wolters Kluwer Health, Inc.