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

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.