Title:Trimethylamine N-oxide (TMAO) as a New Potential Therapeutic Target for Insulin Resistance and Cancer
Volume: 23
Issue: 25
Author(s): Jens Oellgaard*, Signe Abitz Winther, Tobias Schmidt Hansen, Peter Rossing and Bernt Johan von Scholten
Affiliation:
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, NSK 2.11, DK-2820,Denmark
Keywords:
Trimethylamine N-oxide, insulin resistance, type 2 diabetes, cardiovascular disease, diet, colorectal cancer, malignant neoplasms,
gut microbiota, microbiome, biomarkers.
Abstract: Background: The intake of animal products in food has been associated with both the development of
insulin resistance and gastrointestinal cancers (GIC). Through the digestion of animal protein and other constituents
of animal products, the commensal bacteria in the gut (the gut microbiota) forms metabolites that can contribute
to the development of both insulin resistance and cancer. Trimethylamine-N-Oxide (TMAO) is such a
molecule and has recently drawn a lot of attention as it may be a risk factor for - and a link between - the gut
microbiota and cardiovascular and renal disease. Further, TMAO is anticipated to have significance as a biomarker
of - or even an independent risk factor for - other undesirable conditions, including insulin resistance and
GIC. TMAO originates from a precursor, trimethylamine (TMA) that is a metabolite of various precursors;
mainly choline and carnitine from ingested foods.
Methods: We review the literature on TMAO as a shared risk factor and/or pathway between insulin resistance
and GIC risk and take the reader through the literature of interventions that could reduce formation of TMAO and
thereby the risk of insulin resistance and GIC. The purpose of the work is to generate a hypothesis to be tested in
preclinical and clinical studies.
Results: TMAO seems to be associated with both insulin resistance and GIC risk and also with atherosclerotic
cardiovascular disease. One shared pathway is the formation of N-Nitroso compounds, a group of metabolites that
can cause DNA-damage and epigenetic changes. Levels of TMAO can be reduced by limiting the dietary intake
of certain foods, most importantly animal products. Further, certain drugs, namely Meldonium and 3,3-dimethyl-
1-butanol, may inhibit the formation of TMAO by inhibiting bacterial enzymes.
Conclusions: The TMAO pathway and its metabolites are possibly involved in the development of two major
health problems: insulin resistance and cancer. Within these pathways novel therapeutic targets may be identified.
Further research is needed in order to verify existing or develop new pharmacological agents that modify these
pathways and reduce the risk of insulin resistance and GIC.
