Increased plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, are associated with higher cardiovascular risk and incidence of diabetes in clinical studies. Metformin is the most widely prescribed type 2 diabetes drug, but its effects on the turnover of TMAO in the organism have not been evaluated. This study aimed to investigate the effects of metformin in vitro on the microbial metabolism of choline, a dietary precursor of TMAO, and plasma TMAO levels in vivo in an experimental model of diabetes. Metformin was administered to diabetic db/db mice and age-matched nondiabetic controls at a dose of 250 mg/kg for up to 8 weeks. Mice were fed either standard chow or choline-enriched diet that mimics meat and dairy product intake. Subsequent plasma sampling was carried out, faecal samples were collected from choline-supplemented mice. Moreover, the effects of metformin on bacterial growth and the production of TMAO precursor trimethylamine (TMA) in vitro were studied. Quantification of TMA, TMAO, and choline in the collected samples was performed by UPLC/MS/MS. Diabetic mice presented 10-13 times higher plasma TMAO concentrations than nondiabetic mice. The administration of metformin resulted in a twofold decrease in TMAO levels compared to db/db control mice. Metformin selectively affected the growth of various bacterial genera and significantly decreased the production of TMA by gut bacteria in vitro. When choline was administered to facilitate microbiota-dependent TMA/TMAO production in vivo, metformin decreased plasma TMAO by ~50%. Our data provide evidence that metformin suppresses bacterial TMA production and significantly decreases TMAO levels in db/db mice. These data support the hypothesis of TMAO as a metabolic disease risk marker and warrant further investigation of TMAO for diabetes research applications.
Acknowledgement: Latvian Council of Science project “Trimethylamine-N-oxide as a link between unhealthy diet and cardiometabolic risks” No. Izp-2018/1-0081.
- 3.2 Clinical medicine
- 3.1 Basic medicine
- 3.4. Other publications in conference proceedings (including local)