Effects of choline metabolite-trimethylamine N-oxide on immunometabolism in inflammatory bowel disease

Abstract

Trimethylamine N-oxide (TMAO), a key metabolite derived from the gut microbial metabolism of choline, has recently been implicated as a significant contributor to the development of several chronic diseases, including diabetes, cardiovascular disease, and chronic kidney disease. Its detrimental effects have garnered widespread attention in the scientific community. Inflammatory bowel disease (IBD), marked by persistent and recurring gastrointestinal inflammation, is a significant global health issue. Emerging evidence highlights a critical role for TMAO in the pathogenesis of IBD. This review comprehensively summarizes current research on the association between TMAO and IBD, with a particular focus on the mechanisms by which TMAO regulates immunometabolism in diseases.

Keywords: gut microbiota; immunometabolism; inflammatory bowel disease; metabolites; trimethylamine N-oxide.

Figure 1

Synthesis and metabolism of TMAO. Precursors of TMA (including L-carnitine, choline, ergothionein) can be ingested from foods such as red meat, eggs, and mushrooms, and then they are converted to TMA by various enzymes under the action of gut microbiota. TMA is absorbed into the bloodstream in the intestine and rapidly oxidized by FMO3 in the liver to form TMAO. Finally, transported through the systemic circulation to other organs, about 95% of TMAO is excreted in the urine, only 4% in the feces, and less than 1% in the breath. TMA, trimethylamine; FMO3, flavin-containing monooxygenase 3; TMAO, Trimethylamine oxide; CHDH, Choline dehydrogenase; BADH, Betaine-aldehyde dehydrogenase; BHMT, Betaine-homocysteine methyltransferase; CDH, L-carnitine dehydrogenase; CaiB, γ-butyrobetainyl-CoA:carnitine CoA transferase.

Figure 2

The effect of TMAO on the immunometabolism of IBD. TMAO affects intestinal homeostasis and immune response through PERK, NF-κB, and NLRP3 signaling pathways. TMAO, Trimethylamine oxide; PERK, protein kinase R-like ER kinase; eIF2α, eukaryotic initiation factor 2α; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; PPARγ, peroxisome proliferator-activated receptor γ; HSP60: Heat shock protein 60; GRP78: glucose regulated protein 78kD; Iκκ, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa-B; SIRT3, NAD-dependent protein deacetylase sirtuin-3; ROS, reactive oxygen species; mtROS, mitochondrial reactive oxygen species; SOD, Superoxide dismutase; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; Caspase-1, cysteinyl aspartate specific proteinase 1; (IL)-1β, 4, 8, 18, (Interleukins) -1β, 4, 8, 18; TNF-α, tumor necrosis factor-α; IBD, inflammatory bowel disease.

Figure 3

Immunomodulatory effects of TMAO in a variety of chronic diseases. TMAO is involved in cardiovascular disease, MAFLD, chronic kidney disease, type 2 diabetes mellitus, and nervous system diseases by triggering inflammatory responses and regulating the immune system through various mechanisms. The upper arrow indicates increased, the lower arrow indicates decreased, and the horizontal arrow indicates activated. TMAO, Trimethylamine oxide; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; TGF-β, transforming growth factor-β; Smad3, Mothers against decapentaplegic homolog 3; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; (IL)-1β, 18, (Interleukins) -1β, 18; ERS, endoplasmic reticulum stress; FoxO1, Forkhead box protein O1; TLR4, Toll-like receptor 4; Cox-2, Cyclooxygenase-2; GFR, glomerular filtration rate; MAFLD, metabolic associated fatty liver disease.