The Microbial Metabolite Trimethylamine N-Oxide Links Vascular Dysfunctions and the Autoimmune Disease Rheumatoid Arthritis

Abstract

Diet and microbiota each have a direct impact on many chronic, inflammatory, and metabolic diseases. As the field develops, a new perspective is emerging. The effects of diet may depend on the microbiota composition of the intestine. A diet that is rich in choline, red meat, dairy, or egg may promote the growth, or change the composition, of microbial species. The microbiota, in turn, may produce metabolites that increase the risk of cardiovascular disease. This article reviews our current understanding of the effects of the molecule trimethylamine-N-oxide (TMAO) obtained from food or produced by the microbiota. We review the mechanisms of actions of TMAO, and studies that associate it with cardiovascular and chronic kidney diseases. We introduce a novel concept: TMAO is one among a group of selective uremic toxins that may rise to high levels in the circulation or accumulate in various organs. Based on this information, we evaluate how TMAO may harm, by exacerbating inflammation, or may protect, by attenuating amyloid formation, in autoimmune diseases such as rheumatoid arthritis.

The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases

“…Average plasma TMAO in humans is around 3.3 µM; however, this can vary greatly after the intake of certain foods that are rich in choline and returns to the baseline within a few hours [ 35 ]. CKD sufferers often have persistent exaggerated levels of plasma TMAO, although, following a kidney transplant, the TMAO concentration was shown to reduce to almost control levels [ 91 , 92 ].…”

“…There, it will be metabolized into trimethylamine N-oxide (TMAO) by host hepatic monooxygenases [ 31 , 32 ] such as flavin-containing monooxygenases 3 (FMO3) [ 33 ]. Ultimately, TMAO is distributed throughout the body so that it can accumulate in tissues as an osmolyte [ 34 , 35 ] whilst the rest of it is mostly cleared by the kidney, which is in charge of excreting it through the urine (overviewed in Figure 1 ) [ 34 ].…”

TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology

“…Though the number of publications on TMAO are rapidly growing—only in the last three-to-four years, over 600 papers have been published according to PubMed—the mechanisms linking increased plasma levels of TMAO to cardiovascular diseases remain unknown [12]. Furthermore, conflicting results exist whether TMAO exerts beneficial or harmful effects on living organisms [13,14,15,16]. Previously, we demonstrated that chronic, low-dose oral TMAO treatment exerted positive effects on a pressure-overloaded heart in rats and was associated with a decrease in the plasma level of TMA, suggesting that not only TMAO but also TMA may exert biological effects on the circulatory system [17].…”

Involvement of Gut Microbiota, Microbial Metabolites and Interaction with Polyphenol in Host Immunometabolism

“…Elevated serum TMAO contributes to the pathogenesis of atherosclerosis by interfering with cholesterol metabolism, inducing inflammation, as well as altering the functions of endothelial cells, foam cells and macrophages [ 132 , 133 ]. TMAO increases TLR4 expression in endothelial cells.…”

“…Plasma proteins associated with inflammation, cardiometabolic disease, and kidney disease also correlate with TMAO. Increased TMAO-producing bacteria are found in patients with rheumatoid arthritis, a chronic inflammatory disease which shares similar pathogenesis to atherosclerosis [ 133 , 138 ]. Elevated TMAO level is also detected in the animal model of arthritis [ 139 ].…”