Microbiota-dependent metabolite and cardiovascular disease marker trimethylamine-N-oxide (TMAO) is associated with monocyte activation but not platelet function in untreated HIV infection

Abstract

BackgroundHIV infection is associated with increased risk of cardiovascular disease beyond that explained by traditional risk factors. Altered gut microbiota, microbial translocation, and immune activation have been proposed as potential triggers. The microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) predicts myocardial infarction (MI) in the general population and has recently been shown to induce platelet hyperreactivity. In the present study, we investigated if TMAO was associated with platelet function, microbial translocation, and immune activation in both untreated and combination anti-retroviral therapy (cART) HIV infection.MethodsTMAO and the pre-cursors betaine, choline, and carnitine were quantified by mass-spectrometry in plasma samples from a previously established cross-sectional cohort of 50 untreated and 50 cART treated HIV-infected individuals. Whole-blood impedance aggregometry, C-reactive protein, sCD14, and lipopolysaccharide were assessed as measures of platelet function, inflammation, monocyte activation, and microbial translocation, respectively.ResultsTMAO was not associated with platelet aggregation response after stimulation with four different agonists, or with overall hypo- or hyperreactivity in untreated or treated HIV-infected individuals. In contrast, sCD14 a marker of both monocyte activation and microbial translocation was independently associated with TMAO in untreated HIV-infection (R = 0.381, P = 0.008). Lower levels of carnitine [32.2 (28.4–36.8) vs. 38.2 (33.6–42.0), P = 0.001] and betaine [33.1 (27.3–43.4) vs.37.4 (31.5–48.7, P = 0.02], but similar TMAO levels [3.8 (2.3–6.1), vs. 2.9 μM (1.9–4.8) P = 0.15] were found in cART treated compared to untreated HIV-infected individuals, resulting in higher ratios of TMAO/carnitine [0.12 (0.07–0.20) vs. 0.08 (0.05–0.11), P = 0.02] and TMAO/betaine [0.11 (0.07–0.17) vs. 0.08 (0.05–0.13), P 0.02].ConclusionsIn contrast to recent studies in HIV-uninfected populations, the present study found no evidence of TMAO-induced platelet hyperreactivity in HIV infected individuals. Microbial translocation and monocyte activation may affect TMAO levels in untreated individuals. Furthermore, the elevated ratios of TMAO/betaine and TMAO/carnitine in cART-treated individuals could possibly suggest a role of cART in TMAO metabolism.

Metformin effect on gut microbiota: insights for HIV-related inflammation

“…TMAO is converted in the liver from trimethylamine (TMA) which is an organic compound synthesized exclusively by the gut microbiota from dietary nutrients. Haissman et al [85] reported that microbiota-dependent TMAO levels are also associated with monocyte activation in untreated PLWH. By comparing PLWH with and without coronary heart disease, Kehrmann et al [86] showed that high circulating TMAO was a marker of coronary heart disease in association with the fecal abundance of Phascolarctobacterium, Desulfovibrio, Sutterella, and Faecalibacterium.…”

Gut microbial diversity in HIV infection post combined antiretroviral therapy

“…Significantly, a meta-analysis on 19 prospective studies showed that blood TMAO and its precursors are associated with elevated risk of major adverse cardiovascular events and a higher all-cause mortality independently of traditional risk factors [ 56 ▪ ]. However, a recent study in HIV infection failed to show any association between TMAO levels and platelet-hyperactivity in both treated and untreated patients [ 57 ▪ ], although TMAO levels were elevated. Rather, the study showed a significant association between TMAO and sCD14 and a higher ratio of TMAO to its precursors carnitine and betaine in treated patients.…”

“…In this last study, it was only the middle subpopulation within the second and third TMAO quartiles, compared with the first and fourth quartile, that showed an association with coronary stenosis, which suggests the involvement of other pathways. In this regard, Haissman et al [ 57 ▪ ] suggested a role for cART in TMAO metabolism. This observation together with the fact that not all patients with high TMAO levels will experience a cardiac complication limits the role of TMAO as a strong predictor of CVD.…”

Biomarkers of aging in HIV: inflammation and the microbiome

“…In particular, trimethylamine-N-oxide (TMAO), a metabolite of phosphatidylcholine, was linked to plaque burden [73,74], myocardial perfusion defects [75], coronary stenosis [76] in HIV-infected subjects. Although TMAO was independently associated with microbial translocation markers (LPS) [77] and macrophage activation (sCD14, CD163) [74,77], a recent report failed to find a relationship between the metabolite and inflammation [78], suggesting its limited use as clinical marker of cardiovascular risk in HIV infection given possible confounders.…”