Abstract
Among gut microbiota-derived metabolites, trimethylamine-N-oxide (TMAO) is receiving increased attention due to its possible role in the carcinogenesis of colorectal cancer (CRC). In spite of numerous reports implicating TMAO with CRC, there is a lack of empirical mechanistic evidences to concretize the involvement of TMAO in the carcinogenesis of CRC. Possible mechanisms such as inflammation, oxidative stress, DNA damage, and protein misfolding by TMAO have been discussed in this review in the light of the latest advancements in the field. This review is an attempt to discuss the probable correlation between TMAO and CRC but this linkage can be concretized only once we get sufficient empirical evidences from the mechanistic studies. We believe, this review will augment the understanding of linking TMAO with CRC and will motivate researchers to move towards mechanistic study for reinforcing the idea of implicating TMAO with CRC causation.
Key points
• TMAO is a gut bacterial metabolite which has been implicated in CRC in recent years.
• The valid mechanistic approach of CRC causation by TMAO is unknown.
• The article summarizes the possible mechanisms which need to be explored for validation.
This is a preview of subscription content, log in via an institution to check access.
source foods such as fish, eggs, and meat. Although dietary TMAO can skip the gut microbiome processing before absorption but choline and carnitine must be processed to TMA by gut bacteria. TMA can be processed and converted to TMAO by the hepatic enzyme, FMO3 after it has been formed. The liver can expel dietary and endogenously formed TMAO, which can be absorbed by extrahepatic tissues or excreted in urine (adapted with permission from Ref. Cho et al. 2017, © 2016 Elsevier)
Similar content being viewed by others
References
Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zheng Y, Cheng T-YD, Miller JW, Green R, Lane DS, Beresford SAA, Caudill MA (2014) Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res 74:7442–7452. https://doi.org/10.1158/0008-5472.CAN-14-1835
Bag S, Banerjee DR, Basak A, Das AK, Pal M, Banerjee R, Paul RR, Chatterjee J (2015) NMR ((1)H and (13)C) based signatures of abnormal choline metabolism in oral squamous cell carcinoma with no prominent Warburg effect. Biochem Biophys Res Commun 459:574–578. https://doi.org/10.1016/j.bbrc.2015.02.149
Baxter BA, Parker KD, Nosler MJ, Rao S, Craig R, Seiler C, Ryan EP (2020) Metabolite profile comparisons between ascending and descending colon tissue in healthy adults. World J Gastroenterol 26:335–352. https://doi.org/10.3748/wjg.v26.i3.335
Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ (2013) Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17:49–60. https://doi.org/10.1016/j.cmet.2012.12.011
Bennion BJ, DeMarco ML, Daggett V (2004) Preventing misfolding of the prion protein by trimethylamine N-oxide. Biochemistry 43:12955–12963. https://doi.org/10.1021/bi0486379
Bhat MY, Singh LR, Dar TA (2017) Trimethylamine N-oxide abolishes the chaperone activity of α-casein: an intrinsically disordered protein. Sci Rep 7. https://doi.org/10.1038/s41598-017-06836-2
Bjørndal B, Ramsvik MS, Lindquist C, Nordrehaug JE, Bruheim I, Svardal A, Nygård O, Berge RK (2015) A phospholipid-protein complex from antarctic krill reduced plasma homocysteine levels and increased plasma trimethylamine-n-oxide (TMAO) and carnitine levels in male Wistar rats. Mar Drugs 13:5706–5721. https://doi.org/10.3390/md13095706
Boutagy NE, Neilson AP, Osterberg KL, Smithson AT, Englund TR, Davy BM, Hulver MW, Davy KP (2015) Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity (silver Spring) 23:2357–2363. https://doi.org/10.1002/oby.21212
Chan CWH, Law BMH, Waye MMY, Chan JYW, So WKW, Chow KM (2019) Trimethylamine-N-oxide as one hypothetical link for the relationship between intestinal microbiota and cancer - where we are and where shall we go? J Cancer 10:5874–5882. https://doi.org/10.7150/jca.31737
Cho CE, Caudill MA (2017) Trimethylamine-N-oxide: friend, foe, or simply caught in the cross-fire? Trends Endocrinol Metab 28:121–130. https://doi.org/10.1016/j.tem.2016.10.005
Cho CE, Taesuwan S, Malysheva OV, Bender E, Tulchinsky NF, Yan J, Sutter JL, Caudill MA (2017a) Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial. Mol Nutr Food Res 61. https://doi.org/10.1002/mnfr.201600324
Drapala A, Szudzik M, Chabowski D, Mogilnicka I, Jaworska K, Kraszewska K, Samborowska E, Ufnal M (2020) Heart failure disturbs gut-blood barrier and increases plasma trimethylamine, a toxic bacterial metabolite. Int J Mol Sci 21. https://doi.org/10.3390/ijms21176161
Dumas M-E, Maibaum EC, Teague C, Ueshima H, Zhou B, Lindon JC, Nicholson JK, Stamler J, Elliott P, Chan Q, Holmes E (2006) Assessment of analytical reproducibility of 1h nmr spectroscopy based metabonomics for large-scale epidemiological research: the INTERMAP study. Anal Chem 78:2199–2208. https://doi.org/10.1021/ac0517085
Ey J, Schömig E, Taubert D (2007) Dietary sources and antioxidant effects of ergothioneine. J Agric Food Chem 55:6466–6474. https://doi.org/10.1021/jf071328f
Feller AG, Rudman D (1988) Role of carnitine in human nutrition. J Nutr 118:541–547. https://doi.org/10.1093/jn/118.5.541
Ganguly P, Boserman P, van der Vegt NFA, Shea J-E (2018) Trimethylamine N-oxide counteracts urea denaturation by inhibiting protein–urea preferential interaction. J Am Chem Soc 140:483–492. https://doi.org/10.1021/jacs.7b11695
Georgescauld F, Mocan I, Lacombe M-L, Lascu I (2009) Rescue of the neuroblastoma mutant of the human nucleoside diphosphate kinase A/nm23-H1 by the natural osmolyte trimethylamine-N-oxide. FEBS Lett 583:820–824. https://doi.org/10.1016/j.febslet.2009.01.043
Goldstein L, Funkhouser D (1972) Biosynthesis of trimethylamine oxide in the nurse shark, Ginglymostoma cirratum. Comp Biochem Physiol A Comp Physiol 42:51–57. https://doi.org/10.1016/0300-9629(72)90365-9
Guertin KA, Li XS, Graubard BI, Albanes D, Weinstein SJ, Goedert JJ, Wang Z, Hazen SL, Sinha R (2017) Serum trimethylamine N-oxide, carnitine, choline, and betaine in relation to colorectal cancer risk in the alpha tocopherol, beta carotene cancer prevention study. Cancer Epidemiol Biomarkers Prev 26:945–952. https://doi.org/10.1158/1055-9965.EPI-16-0948
van Hecke T, Jakobsen LMA, Vossen E, Guéraud F, de Vos F, Pierre F, Bertram HCS, de Smet S (2016) Short-term beef consumption promotes systemic oxidative stress, TMAO formation and inflammation in rats, and dietary fat content modulates these effects. Food Funct 7:3760–3771. https://doi.org/10.1039/c6fo00462h
Humbert JA, Hammond KB, Hathaway WE (1970) Trimethylaminuria: the fish-odour syndrome. Lancet 2:770–771. https://doi.org/10.1016/s0140-6736(70)90241-2
Iida T, Onodera K, Nakase H (2017) Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 23:1944–1953. https://doi.org/10.3748/wjg.v23.i11.1944
Janeiro MH, Ramírez MJ, Milagro FI, Martínez JA, Solas M (2018) Implication of trimethylamine N-oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients 10. https://doi.org/10.3390/nu10101398
Jaworska K, Huc T, Samborowska E, Dobrowolski L, Bielinska K, Gawlak M, Ufnal M (2017) Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite. PLoS ONE 12:e0189310. https://doi.org/10.1371/journal.pone.0189310
Ke Y, Li D, Zhao M, Liu C, Liu J, Zeng A, Shi X, Cheng S, Pan B, Zheng L, Hong H (2018) Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress. Free Radical Biol Med 116:88–100. https://doi.org/10.1016/j.freeradbiomed.2018.01.007
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WHW, Bushman FD, Lusis AJ, Hazen SL (2013a) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585. https://doi.org/10.1038/nm.3145
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WHW, Bushman FD, Lusis AJ, Hazen SL (2013b) Intestinal microbiota metabolism of l -carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585. https://doi.org/10.1038/nm.3145
Lakshmi GBVS, Yadav AK, Mehlawat N, Jalandra R, Solanki PR, Kumar A (2021) Gut microbiota derived trimethylamine N-oxide (TMAO) detection through molecularly imprinted polymer based sensor. Sci Rep 11:1338. https://doi.org/10.1038/s41598-020-80122-6
Lee JY, Sim T-B, Lee J-E, Na H-K (2017) Chemopreventive and chemotherapeutic effects of fish oil derived omega-3 polyunsaturated fatty acids on colon carcinogenesis. Clin Nutr Res 6:147–160. https://doi.org/10.7762/cnr.2017.6.3.147
Lim U, Lampe J TMAO, the gut microbiome, and colorectal cancer risk in the multiethnic cohort
Liu X, Liu H, Yuan C, Zhang Y, Wang W, Hu S, Liu L, Wang Y (2017) Preoperative serum TMAO level is a new prognostic marker for colorectal cancer. Biomark Med 11:443–447. https://doi.org/10.2217/bmm-2016-0262
Lv L, Shen Z, Zhang J, Zhang H, Dong J, Yan Y, Liu F, Jiang K, Ye Y, Wang S (2014) Clinicopathological significance of SIRT1 expression in colorectal adenocarcinoma. Med Oncol 31:965. https://doi.org/10.1007/s12032-014-0965-9
Man AWC, Zhou Y, Xia N, Li H (2020) Involvement of gut microbiota, microbial metabolites and interaction with polyphenol in host immunometabolism. Nutrients 12. https://doi.org/10.3390/nu12103054
Miller CA, Corbin KD, da Costa K-A, Zhang S, Zhao X, Galanko JA, Blevins T, Bennett BJ, O’Connor A, Zeisel SH (2014) Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr 100:778–786. https://doi.org/10.3945/ajcn.114.087692
Mondul AM, Moore SC, Weinstein SJ, Karoly ED, Sampson JN, Albanes D (2015) Metabolomic analysis of prostate cancer risk in a prospective cohort: the alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study. Int J Cancer 137:2124–2132. https://doi.org/10.1002/ijc.29576
Oellgaard J, Winther SA, Hansen TS, Rossing P, von Scholten BJ (2017) Trimethylamine N-oxide (TMAO) as a new potential therapeutic target for insulin resistance and cancer. Curr Pharm Des 23:3699–3712. https://doi.org/10.2174/1381612823666170622095324
Olek RA, Samulak JJ, Sawicka AK, Hartmane D, Grinberga S, Pugovics O, Lysiak-Szydlowska W (2019) Increased trimethylamine N-oxide is not associated with oxidative stress markers in healthy aged women. Oxid Med Cell Longev 2019:6247169. https://doi.org/10.1155/2019/6247169
Pachauri N, Dave K, Dinda A, Solanki PR (2018) Cubic CeO2 implanted reduced graphene oxide-based highly sensitive biosensor for non-invasive oral cancer biomarker detection. J Mater Chem B 6:3000–3012. https://doi.org/10.1039/C8TB00653A
Pachauri N, Lakshmi GBVS, Sri S, Gupta PK, Solanki PR (2020) Silver molybdate nanoparticles based immunosensor for the non-invasive detection of Interleukin-8 biomarker. Mater Sci Eng, C 113:110911. https://doi.org/10.1016/j.msec.2020.110911
Park JE, Miller M, Rhyne J, Wang Z, Hazen SL (2019) Differential effect of short-term popular diets on TMAO and other cardio-metabolic risk markers. Nutr Metab Cardiovasc Dis 29:513–517. https://doi.org/10.1016/j.numecd.2019.02.003
Parker KD, Maurya AK, Ibrahim H, Rao S, Hove PR, Kumar D, Kant R, Raina B, Agarwal R, Kuhn KA, Raina K, Ryan EP (2021) Dietary rice bran-modified human gut microbial consortia confers protection against colon carcinogenesis following fecal transfaunation. Biomedicines 9:144. https://doi.org/10.3390/biomedicines9020144
Rath S, Heidrich B, Pieper DH, Vital M (2017) Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome 5:54. https://doi.org/10.1186/s40168-017-0271-9
Rebouche CJ (2004) Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 1033:30–41. https://doi.org/10.1196/annals.1320.003
Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Zeisel SH, Willett WC, Chan JM (2012) Choline intake and risk of lethal prostate cancer: incidence and survival. Am J Clin Nutr 96:855–863. https://doi.org/10.3945/ajcn.112.039784
Romano KA, Vivas EI, Amador-Noguez D, Rey FE (2015) Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio 6:e02481. https://doi.org/10.1128/mBio.02481-14
Rombouts C, Van Meulebroek L, De Spiegeleer M, Goethals S, Van Hecke T, De Smet S, De Vos WH, Vanhaecke L (2021) Untargeted metabolomics reveals elevated L-carnitine metabolism in pig and rat colon tissue following red versus white meat intake. Mol Nutr Food Res 65:e2000463. https://doi.org/10.1002/mnfr.202000463
Sánchez-Alcoholado L, Ordóñez R, Otero A, Plaza-Andrade I, Laborda-Illanes A, Medina JA, Ramos-Molina B, Gómez-Millán J, Queipo-Ortuño MI (2020) Gut microbiota-mediated inflammation and gut permeability in patients with obesity and colorectal cancer. Int J Mol Sci 21:E6782. https://doi.org/10.3390/ijms21186782
Savi M, Bocchi L, Bresciani L, Falco A, Quaini F, Mena P, Brighenti F, Crozier A, Stilli D, Del Rio D (2018) Trimethylamine-N-Oxide (TMAO)-Induced impairment of cardiomyocyte function and the protective role of urolithin B-glucuronide. Molecules 23. https://doi.org/10.3390/molecules23030549
Sun X, Jiao X, Ma Y, Liu Y, Zhang L, He Y, Chen Y (2016) Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun 481:63–70. https://doi.org/10.1016/j.bbrc.2016.11.017
Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368:1575–1584. https://doi.org/10.1056/NEJMoa1109400
Tarashi S, Siadat SD, Ahmadi Badi S, Zali M, Biassoni R, Ponzoni M, Moshiri A (2019) Gut bacteria and their metabolites: which one is the defendant for colorectal cancer? Microorganisms 7:561. https://doi.org/10.3390/microorganisms7110561
Tatzelt J, Prusiner SB, Welch WJ (1996) Chemical chaperones interfere with the formation of scrapie prion protein. EMBO J 15:6363–6373
Tiwari S, Gupta PK, Bagbi Y, Sarkar T, Solanki PR (2017) L-cysteine capped lanthanum hydroxide nanostructures for non-invasive detection of oral cancer biomarker. Biosens Bioelectron 89:1042–1052. https://doi.org/10.1016/j.bios.2016.10.020
Xu R, Wang Q, Li L (2015) A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. BMC Genomics 16:S4. https://doi.org/10.1186/1471-2164-16-S7-S4
Yang S, Li X, Yang F, Zhao R, Pan X, Liang J, Tian L, Li X, Liu L, Xing Y, Wu M (2019) Gut microbiota-dependent marker TMAO in promoting cardiovascular disease: inflammation mechanism, clinical prognostic, and potential as a therapeutic target. Front Pharmacol 10. https://doi.org/10.3389/fphar.2019.01360
Yu X-F, Zou J, Dong J (2014) Fish consumption and risk of gastrointestinal cancers: a meta-analysis of cohort studies. World J Gastroenterol 20:15398–15412. https://doi.org/10.3748/wjg.v20.i41.15398
Zeisel SH, DaCosta KA, Fox JG (1985) Endogenous formation of dimethylamine. Biochem J 232:403–408. https://doi.org/10.1042/bj2320403
Zeisel SH, daCosta KA, LaMont JT (1988) Mono-, di- and trimethylamine in human gastric fluid: potential substrates for nitrosodimethylamine formation. Carcinogenesis 9:179–181. https://doi.org/10.1093/carcin/9.1.179
Zeisel SH, Mar M-H, Howe JC, Holden JM (2003) Concentrations of choline-containing compounds and betaine in common foods. J Nutr 133:1302–1307. https://doi.org/10.1093/jn/133.5.1302
Zhang AQ, Mitchell SC, Smith RL (1999) Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol 37:515–520. https://doi.org/10.1016/s0278-6915(99)00028-9
Funding
The study was funded by grant from SERB-DST (Grant No. CRG/2018/002957) and the Core grant of the National Institute of Immunology, New Delhi, India. PRS and AK are thankful to the Department of Biotechnology for Indo-Russia (DBT/IC-2/Indo-Russia/2017-19/02), and Indian Council of Medical Research (ICMR), India (34/13/2019-TF/Nano/BMS) for financial support.
Author information
Authors and Affiliations
Contributions
AK and PRS designed the study. RJ, ND, and AKY collected data and produced the initial draft of the manuscript. MS, RS, and DV contributed to drafting the manuscript. All authors have read and proved the final submitted manuscript.
Corresponding author
Ethics declarations
Ethics approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Jalandra, R., Dalal, N., Yadav, A.K. et al. Emerging role of trimethylamine-N-oxide (TMAO) in colorectal cancer. Appl Microbiol Biotechnol 105, 7651–7660 (2021). https://doi.org/10.1007/s00253-021-11582-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-021-11582-7