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

Laskaridou E, Steele CN, Reid GR, Rinehart JT, Marinik EL, Howard KR, Davy BM, Sweet MG, Neilson AP, Davy KP. Gut microbiota-generated trimethylamine N-oxide from dietary choline and glucose homeostasis in humans. Am J Physiol Endocrinol Metab. 2026 Aug 1;331(2):E148-E153. doi: 10.1152/ajpendo.00160.2026. Epub 2026 Jun 18. PMID: 42314769; PMCID: PMC13398441.

https://pubmed.ncbi.nlm.nih.gov/42314769/

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.