Contribution of Trimethylamine N-Oxide (TMAO) to Chronic Inflammatory and Degenerative Diseases

Abstract

Trimethylamine N-oxide (TMAO) is a metabolite produced by the gut microbiota and has been mainly associated with an increased incidence of cardiovascular diseases (CVDs) in humans. There are factors that affect one’s TMAO level, such as diet, drugs, age, and hormones, among others. Gut dysbiosis in the host has been studied recently as a new approach to understanding chronic inflammatory and degenerative diseases, including cardiovascular diseases, metabolic diseases, and Alzheimer’s disease. These disease types as well as COVID-19 are known to modulate host immunity. Diabetic and obese patients have been observed to have an increase in their level of TMAO, which has a direct correlation with CVDs. This metabolite is attributed to enhancing the inflammatory pathways through cholesterol and bile acid dysregulation, promoting foam cell formation. Additionally, TMAO activates the transcription factor NF-κB, which, in turn, triggers cytokine production. The result can be an exaggerated inflammatory response capable of inducing endoplasmic reticulum stress, which is responsible for various diseases. Due to the deleterious effects that this metabolite causes in its host, it is important to search for new therapeutic agents that allow a reduction in the TMAO levels of patients and that, thus, allow patients to be able to avoid a severe cardiovascular event. The present review discussed the synthesis of TMAO and its contribution to the pathogenesis of various inflammatory diseases.

Microbial Metabolite Trimethylamine N-Oxide PromotesCampylobacter jejuniInfection by Escalating Intestinal Inflammation, Epithelial Damage, and Barrier Disruption

“…In Metabolic Syndrome related diseases, TMAO was implicated in causing endoplasmic reticulum stress and insulin resistance in patients at risk for diabetes 99 , and also implicated in promoting de novo lipogenesis in the liver of metabolic-dysfunction-associated fatty liver disease 100 . Increased serum levels of TMAO in colorectal cancer are correlated to increased tumors, worse stage and incidence of metastasis and overall lower disease survival 40 . Increasing amount of studies are also highlighting that TMAO may be linked to other cancers as well, such breast, ovarian and gastric cancers 101 .…”

“…TMAO is a microbial metabolite that is implicated in multiple different chronic inflammatory diseases, including but not limited to kidney diseases, metabolic syndrome and related conditions, cardiovascular disease, and cancer 40 . TMAO causes platelet hyperreactivity, foam cell formation and adhesion, cardiac fibroblast migration and proliferation, and cellular apoptosis that all contribute to cardiovascular disease progression.…”

“…Recently, it has been reported that some intestinal microorganisms, including E. coli, anaerobically metabolize diet-derived choline to TMA by choline TMA-lyase (cutC). Furthermore, TMA is oxidized to TMAO by flavin-dependent monooxygenase 3 (FMO3) in the host liver 38,40 . BLAST search and C. jejuni genome analysis confirmed that C. jejuni 81-176 does not encode a homologous gene to E. coli ’s cutC gene.…”

“…One key microbial metabolite that becomes highly enriched during gut dysbiosis is trimethylamine N-oxide (TMAO). The dysbiotic gut microbiota, especially proteobacteria, including E. coli, catabolize choline, carnitine, and betaine into the precursor TMA [37][38][39] , which is converted to TMAO by flavin monooxygenase 3 (FMO3) in the host liver 38,40 . Human studies demonstrated that the serum levels of TMAO is directly correlated to the increased intestinal levels of the Proteobacteria phylum and Bacteroides phylum 41,42 .…”

Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response

“…Although activation of AHR with TCDD has been shown to strongly upregulate Fmo3 expression (necessary to produce TMAO) in adult male mice, effects were minimal in juveniles [86], warranting followup studies to determine whether maternal WD exposure has long-lasting effects on the gut microbiome and AHR activity, with potential risks for increased TMAO-associated diabetes and cardiovascular disease [87]. Finally, in vitro studies have shown that TMAO signals through Toll-like receptors (TLRs) and the NLRP3 inflammasome and induces expression of proinflammatory cytokines in macrophages and endothelial cells [92,93]. Whether TMAO in early life plays a role in immune education remains to be determined.…”