Characterization of TMAO productivity from carnitine challenge facilitates personalized nutrition and microbiome signatures discovery

Abstract

The capability of gut microbiota in degrading foods and drugs administered orally can result in diversified efficacies and toxicity interpersonally and cause significant impact on human health. Production of atherogenic trimethylamine N-oxide (TMAO) from carnitine is a gut microbiota-directed pathway and varies widely among individuals. Here, we demonstrated a personalized TMAO formation and carnitine bioavailability from carnitine supplements by differentiating individual TMAO productivities with a recently developed oral carnitine challenge test (OCCT). By exploring gut microbiome in subjects characterized by TMAO producer phenotypes, we identified 39 operational taxonomy units that were highly correlated to TMAO productivity, including Emergencia timonensis, which has been recently discovered to convert γ-butyrobetaine to TMA in vitro. A microbiome-based random forest classifier was therefore constructed to predict the TMAO producer phenotype (AUROC = 0.81) which was then validated with an external cohort (AUROC = 0.80). A novel bacterium called Ihubacter massiliensis was also discovered to be a key microbe for TMA/TMAO production by using an OCCT-based humanized gnotobiotic mice model. Simply combining the presence of E. timonensis and I. massiliensis could account for 43% of high TMAO producers with 97% specificity. Collectively, this human gut microbiota phenotype-directed approach offers potential for developing precision medicine and provides insights into translational research.

Atherosclerosis Amelioration by Allicin in Raw Garlic through Gut Microbiota and Trimethylamine-N-Oxide Modulation

“…41,42,43,44 Previously, in a human study, we developed the OCCT, which can robustly distinguish the low-and high-TMAO producers. 37 In this study, high-TMAO producers were de ned as individuals exhibiting OCCT plasma TMAO MAX level ≥ 10 µM 20 . There is currently a lack of studies on the effect of garlic on the gut microbiota in the human body; this study is the rst to demonstrate the impact of garlic on TMAO production by the gut microbiota.…”

“…The current study demonstrated that plasma and urine TMAO exhibited a high positive correlation that was consistent with the results from previous studies. 20,37 Currently, the primary genes responsible for converting carnitine to TMA by the gut microbiota remains unclear. A Rieske-type microbial CntA/B enzyme was reported to convert carnitine to TMA.…”

“…Participants with plasma TMAO ≥ 10 μM after the OCCT were de ned as high-TMAO producers and allowed to proceed for the garlic juice intervention. 20…”

“…18,19 A novel gut bacterium, Emergencia timonensis, was found to be capable of transforming γBB to TMA anaerobically and was reported to partially explain the phenotype of high-TMAO producers among human beings. 18,20 Investigations on how different food components interact with the gut microbiota have improved our understanding of modifying our dietary behaviors to achieve a health-promoting state. 8,21 Certain approaches were proposed for reducing TMAO production by the gut microbiota such as antibiotic use, fecal microbiota transplantation, and administration of TMA lyase inhibitor.…”

The Interface of Vibrio cholerae and the Gut Microbiome

“…Gut microbes can affect TMAO levels through the fermentation of choline or L-carnitine to the intermediate compound trimethylamine (TMA), followed by oxidization of TMA by flavin monooxygenases to TMAO in the liver. 167 The addition of TMAO to an infant mouse model of V. cholerae infection promoted CT production during colonization, a process that accelerated in the presence of reactive oxygen species (Figure 4). 168 Since several commensal gut microbes have been implicated in the accumulation of TMAO, 169,170 the differential ability of different microbiomes to affect TMAO levels may thus be a metabolic factor in promoting or inhibiting V. cholerae pathogenesis.…”