Gut microbiota-generated trimethylamine N-oxide from dietary choline and glucose homeostasis in humans

The causal relationship between gut microbiota-generated trimethylamine N-oxide (TMAO) and type 2 diabetes remains unclear. We tested the hypothesis that gut microbiota-generated increases in plasma TMAO concentrations will impair insulin sensitivity and glucose tolerance in healthy, sedentary humans. To address this, we performed two studies utilizing a randomized double-blind, placebo-controlled, crossover design. Eligible participants (age of 35 ± 16 yr for the acute study and 46 ± 14 yr for the short-term study) consumed a 1,000 mg/day dose of choline bitartrate and placebo (maltodextrin) the night before each testing session (for the acute study, n = 20, 8 women) or for 4 wk (for the short-term study, n = 23, 13 women). An oral glucose tolerance test was performed the day after the acute study and before and after the short-term study. Insulin sensitivity was calculated using the Matsuda index. Plasma TMAO was increased (both P < 0.05) 400% and 110% following acute and 4 wk of daily ingestion of 1,000 mg of choline bitartrate, respectively. There were no statistically significant differences in insulin sensitivity (Matsuda index) or insulin resistance (HOMA-IR) between the interventions in both the acute study and short-term study. In addition, there were no significant differences between conditions in fasting glucose, 2-h glucose, area under the curve, and incremental area under the curve in the acute and short-term study. Taken together, the results of the present study suggest that the relationship between TMAO and glucose homeostasis may not be causal in nature.NEW & NOTEWORTHY Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been linked to impaired glucose homeostasis and type 2 diabetes, but causality is unclear. In two randomized, double-blind, placebo-controlled studies, acute and short-term dietary choline increased TMAO without affecting insulin sensitivity, glucose tolerance, or fasting glucose and insulin. These findings do not support a causal role for TMAO, though longer-term studies are needed.