Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance
Open accessAbstract
The influence of the gut microbiome on metabolic and behavioral traits is widely accepted, though the microbiome-derived metabolites involved remain unclear. We carried out untargeted urine 1 H-NMR spectroscopy-based metabolic phenotyping in an isogenic C57BL/6J mouse population (n = 50) and show that microbial-host co-metabolites are prodromal (i.e., early) markers predicting future divergence in metabolic (obesity and glucose homeostasis) and behavioral (anxiety and activity) outcomes with 94%–100% accuracy. Some of these metabolites also modulate disease phenotypes, best illustrated by trimethylamine- N -oxide (TMAO), a product of microbial-host co-metabolism predicting future obesity, impaired glucose tolerance (IGT), and behavior while reducing endoplasmic reticulum stress and lipogenesis in 3T3-L1 adipocytes. Chronic in vivo TMAO treatment limits IGT in HFD-fed mice and isolated pancreatic islets by increasing insulin secretion. We highlight the prodromal potential of microbial metabolites to predict disease outcomes and their potential in shaping mammalian phenotypic heterogeneity.
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L-carnitine present in red meat can be metabolized to trimethylamine oxide, which is associated with an increased incidence of atherosclerosis and obesity.
“Accordingly, L-carnitine present in red meat can be metabolized to trimethylamine oxide (TMAO), which is associated with an increased incidence of atherosclerosis [194] and obesity [195].”
From Impact of Protein Intake in Older Adults with Sarcopenia and Obesity: A Gut Microbiota Perspective (2020) · cites this paper as [195]
Chronic exposure of mice to TMAO attenuates diet-associated glucose tolerance, reducing endoplasmic stress and adipogenesis in adipocytes.
“Chronic exposure of mice to TMAO attenuates diet-associated glucose tolerance, reducing endoplasmic stress and adipogenesis in adipocytes (Dumas et al., 2017).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Dumas et al., 2017
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ResultGut metagenome in European women with normal, impaired and diabetic glucose control
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BackgroundSelf-citationDietary intervention impact on gut microbial gene richness
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ResultGut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor
Smith, M. I., Yatsunenko, T., Manary, M. J., Trehan, I., Mkakosya, R., Cheng, J., Kau, A. L., Rich, S. S., Concannon, P., Mychaleckyj, J. C., et al. (2013) · Science · doi:10.1126/science.1229000 · Cited by 1,173 · cited 2× · see citing works
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“(2013) is now accepted (Bennett et al., 2013; Koeth et al., 2013, 2014; Ussher et al., 2013; Wang et al., 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al.”
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“The dataset was then further aligned using recursive segment-wise peak alignment (RSPA) (Veselkov et al., 2009), and peak calling was performed using statistical recoupling of variables (SRVs) (Blaise et al., 2009).”
MethodSelf-citationDumas, M.-E., Barton, R. H., Toye, A., Cloarec, O., Blancher, C., Rothwell, A., Fearnside, J., Tatoud, R., Blanc, V., Lindon, J. C., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601056103 · Cited by 1,042 · cited 8× · see citing works
“Methylamines (TMA, DMA, MMA, and TMAO) and their pre-cursor choline are the major metabolites associated with HFD in the C57BL/6J mouse (Figure 2D), which is consistent with our previous report (Dumas et al., 2006).”
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“To evaluate microbial metabolites as prodromal markers, we repurposed a pharmaco-metabonomics framework (Clayton et al., 2006), which we developed initially for drug toxicity prediction using pre-dose metabolic phenotypes, to predict complex metabolic and behavior phenotype outcomes following HFD feeding in isogenic m…”
MethodSelf-citationMicrobial conversion of choline to trimethylamine requires a glycyl radical enzyme
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“138 Cell Reports 20, 136–148, July 5, 2017 commensal bacteria, and metabolized into TMAO, dimethylamine (DMA), and monomethylamine (MMA) in the liver (Figure 2D) (al-Waiz et al., 1992; Craciun and Balskus, 2012; Dolphin et al., 1997).”
BackgroundMetabolic adaptation to a high-fat diet is associated with a change in the gut microbiota
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“…the isogenic mouse population model with a pharmaco-metabonomic approach, phenotypic heterogeneity in absence of genetic variation can be directly predicted by specific microbial-host co-metabolites, which could not be inferred through 16 s rRNA phylogenetic analysis (Serino et al., 2012).”
BackgroundMethodInfluentialγ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO
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“While the association between TMAO and atherosclerosis initially reported by Tang et al. (2013) is now accepted (Bennett et al., 2013; Koeth et al., 2013, 2014; Ussher et al., 2013; Wang et al., 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al.,…”
BackgroundQuantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome
Shoaie, S., Ghaffari, P., Kovatcheva‐Datchary, P., Mardinoğlu, A., Sen, P., Pujos‐Guillot, E., de Wouters, T., Juste, C., Rizkalla, S. W., Chilloux, J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.001 · Cited by 417 · cited 1× · see citing works
“However, beyond beneficial bacteria (Dao et al., 2016; Shoaie et al., 2015), the microbiome-derived mediators promoting host health or disease remain elusive: a few microbial metabolite families (e.g., short-chain fatty acids or bile acids) are known to affect human health (Dumas et al., 2014;…”
BackgroundSelf-citationThe TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
Warrier, M., Shih, D. M., Burrows, A. C., Ferguson, D., Gromovsky, A. D., Brown, A. L., Marshall, S., McDaniel, A., Schugar, R. C., Wang, Z., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.036 · Cited by 414 · cited 2× · see citing works
“, 2013) and was shown to play a central role in the regulation of cholesterol balance and glucose homeostasis (Warrier et al., 2015).”
BackgroundFlavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
Miao, J., Ling, A. V., Manthena, P. V., Gearing, M. E., Graham, M. J., Crooke, R. M., Croce, K. J., Esquejo, R. M., Clish, C. B., Morbid Obesity Study Group, et al. (2015) · Nature Communications · doi:10.1038/ncomms7498 · Cited by 368 · see citing works
Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet
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“…initially reported by Tang et al. (2013) is now accepted (Bennett et al., 2013; Koeth et al., 2013, 2014; Ussher et al., 2013; Wang et al., 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al., 2014; Lever et al., 2014; McEntyre et al., 2015).”
BackgroundInfluentialColonic bacterial metabolites and human health
Russell, W. R., Hoyles, L., Flint, H. J., & Dumas, M. (2013) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.07.002 · Cited by 353 · cited 3× · see citing works
“TMA is synthesized by gut microbial degradation of nitrogen-rich nutrients such as choline, phosphatidylcholine, and L-carnitine in decreasing order (al-Waiz et al., 1992; Russell et al., 2013).”
BackgroundSelf-citationVeselkov, K., Lindon, J. C., Ebbels, T. M. D., Crockford, D. J., Volynkin, V., Holmes, E. C., Davies, D. B., & Nicholson, J. K. (2008) · Analytical Chemistry · doi:10.1021/ac8011544 · Cited by 338 · cited 1× · see citing works
“The dataset was then further aligned using recursive segment-wise peak alignment (RSPA) (Veselkov et al., 2009), and peak calling was performed using statistical recoupling of variables (SRVs) (Blaise et al., 2009).”
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Self-citationHeterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet
Burcelin, R., Crivelli, V., Dacosta, A., Roy-Tirelli, A., & Thorens, B. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00332.2001 · Cited by 292 · cited 4× · see citing works
“Phenotypic Heterogeneity Underpins IGT and Obesity in Isogenic Mouse Populations To study the phenomenon of heterogeneous metabolic adaptation to HFD in mice (Burcelin et al., 2002; Serino et al., 2012), we generated a large population of isogenic C57BL/6J mice fed either chow diet (CHD) or HFD (n = 193) for up to 5 m…”
BackgroundMethodInfluentialThe IRE1α-XBP1 Pathway of the Unfolded Protein Response Is Required for Adipogenesis
Sha, H., He, Y., Chen, H., Wang, C., Zenno, A., Shi, H., Yang, X., Zhang, X., & Qi, L. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.04.009 · Cited by 292 · cited 1× · see citing works
“Splicing of the Xbp1 transcript is also required for adipogenesis (Sha et al., 2009).”
BackgroundMissense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome
Dolphin, C. T., Janmohamed, A., Smith, R. L., Shephard, E. A., & Phillips, L. R. (1997) · Nature Genetics · doi:10.1038/ng1297-491 · Cited by 284 · cited 4× · see citing works
“, 1992) catabolized by FMO3 in humans (Dolphin et al., 1997).”
BackgroundInfluentialVeselkov, K., Karstens, L., Masson, P., Robinette, S. L., Want, E. J., Li, J. V., Barton, R. H., Boursier-Neyret, C., Walther, B., Ebbels, T. M. D., et al. (2011) · Analytical Chemistry · doi:10.1021/ac201065j · Cited by 267 · cited 2× · see citing works
“Variance-stabilizing logarithmic transform of the SRV clusters (Veselkov et al., 2011) and probabilistic quotient normalization (Dieterle et al.”
MethodSelf-citationMicroscopic insights into the protein-stabilizing effect of trimethylamine N-oxide (TMAO)
Ma, J., Pazos, I. M., & Gai, F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403224111 · Cited by 253 · cited 2× · see citing works
“This general protein stabilization mechanism (Ma et al., 2014) is thought to reduce ER stress, which is involved in inflammation and insulin resistance (Ozcan et al.”
BackgroundGenotype to phenotype: lessons from model organisms for human genetics
Lehner, B. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3404 · Cited by 228 · cited 2× · see citing works
“However, phenotype variability is also commonly observed in identical twins and in isogenicmodel systems (Lehner, 2013), which can be exacerbated by high-fat diet (HFD) feeding in mice (Burcelin et al.”
BackgroundLever, M., George, P. M., Slow, S., Bellamy, D., Young, J. M., Ho, M., McEntyre, C. J., Elmslie, J. L., Atkinson, W., Molyneux, S. L., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114969 · Cited by 223 · cited 2× · see citing works
“, 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al., 2014; Lever et al., 2014; McEntyre et al., 2015).”
BackgroundBasseri, S., Lhoták, Š., Sharma, A. M., & Austin, R. C. (2009) · Journal of Lipid Research · doi:10.1194/jlr.m900216-jlr200 · Cited by 223 · cited 2× · see citing works
“1 mM 4-phenylbutyrate (PBA) (Figure 4C), an ER stress inhibitor also known to inhibit lipogenesis (Basseri et al., 2009).”
BackgroundMethodInfluentialUrinary metabolic signatures of human adiposity
Elliott, P., Posma, J. M., Chan, Q. M., García‐Pérez, I., Wijeyesekera, A., Bictash, M., Ebbels, T. M. D., Ueshima, H., Zhao, L., Horn, L. V., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa5680 · Cited by 207 · cited 2× · see citing works
“We previously showed that hippurate is negatively associated with BMI in humans (Elliott et al., 2015) and that benzoate variation was 144 Cell Reports 20, 136–148, July 5, 2017 associated with a UGT2b polymorphism in the Goto-Kakizaki rat model of type 2 diabetes (Dumas et al., 2007).”
BackgroundSelf-citationGenetic and Environmental Effects on Complex Traits in Mice
Valdar, W. S. J., Solberg, L. C., Gauguier, D., Cookson, W., Rawlins, J. N. P., Mott, R., & Jonathan Flint, C. (2006) · Genetics · doi:10.1534/genetics.106.060004 · Cited by 206 · cited 2× · see citing works
“Behavioral Tests EPM and OF were used to assess rodent exploration, activity, and anxiety as previously described (Solberg et al., 2006; Valdar et al., 2006).”
MethodSelf-citationThe exogenous origin of trimethylamine in the mouse
Al-Waiz, M., Mikov, M., Mitchell, S. C., & Smith, R. L. (1992) · Metabolism · doi:10.1016/0026-0495(92)90140-6 · Cited by 196 · cited 5× · see citing works
“…al., 2006): TMA is derived from dietary choline fermentation by 138 Cell Reports 20, 136–148, July 5, 2017 commensal bacteria, and metabolized into TMAO, dimethylamine (DMA), and monomethylamine (MMA) in the liver (Figure 2D) (al-Waiz et al., 1992; Craciun and Balskus, 2012; Dolphin et al., 1997).”
BackgroundInfluentialDumas, M., Kinross, J. K., & Nicholson, J. K. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.11.001 · Cited by 186 · cited 2× · see citing works
“…bacteria (Dao et al., 2016; Shoaie et al., 2015), the microbiome-derived mediators promoting host health or disease remain elusive: a few microbial metabolite families (e.g., short-chain fatty acids or bile acids) are known to affect human health (Dumas et al., 2014; Russell et al., 2013).”
BackgroundSelf-citationGut microbiota metabolism of l-carnitine and cardiovascular risk
Ussher, J. R., Lopaschuk, G. D., & Arduini, A. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.10.013 · Cited by 170 · cited 2× · see citing works
“…between TMAO and atherosclerosis initially reported by Tang et al. (2013) is now accepted (Bennett et al., 2013; Koeth et al., 2013, 2014; Ussher et al., 2013; Wang et al., 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al., 2014; Lever…”
Backgroundvan Schadewijk, A. M., Wout, E. F. A. V. ’., Stolk, J. N., & Hiemstra, P. S. (2011) · Cell Stress and Chaperones · doi:10.1007/s12192-011-0306-2 · Cited by 158 · cited 1× · see citing works
“We first assessed Xbp1 splicing, because splicing of this central ER stress regulator is induced by ER stress and was validated as an ER stress marker recapitulating all other events in the IRE1a-XBP1 pathway (van Schadewijk et al., 2012).”
BackgroundDumas, M., Wilder, S. P., Bihoreau, M., Barton, R., Fearnside, J. F., Argoud, K., Damato, L., Wallis, R., Blancher, C., Keun, H., et al. (2007) · Nature Genetics · doi:10.1038/ng2026 · Cited by 153 · cited 1× · see citing works
“…bacteria (Dao et al., 2016; Shoaie et al., 2015), the microbiome-derived mediators promoting host health or disease remain elusive: a few microbial metabolite families (e.g., short-chain fatty acids or bile acids) are known to affect human health (Dumas et al., 2014; Russell et al., 2013).”
BackgroundSelf-citationRegulation of unfolded protein response modulator XBP1s by acetylation and deacetylation
Wang, F., Chen, Y., & Ouyang, H. (2010) · Biochemical Journal · doi:10.1042/bj20101293 · Cited by 144 · cited 3× · see citing works
“…and atherosclerosis initially reported by Tang et al. (2013) is now accepted (Bennett et al., 2013; Koeth et al., 2013, 2014; Ussher et al., 2013; Wang et al., 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al., 2014; Lever et al., 2014; McEntyre…”
BackgroundMethodCytokine-Induced β-Cell Death Is Independent of Endoplasmic Reticulum Stress Signaling
Åkerfeldt, M. C., Howes, J. E., Chan, J. Y., Stevens, V. A., Boubenna, N., McGuire, H. M., King, C., Biden, T. J., & Laybutt, D. R. (2008) · Diabetes · doi:10.2337/db07-1802 · Cited by 134 · cited 3× · see citing works
“Similarly, TMAO corrects ER stress and Xbp1 splicing induced by cytokines and palmitate in b cells (Akerfeldt et al., 2008).”
BackgroundResultInfluentialA protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice
Solberg, L. C., Valdar, W. S. J., Gauguier, D., Nunez, G., Taylor, A. M., Heyes, S. B., Arboledas-Hita, C., Hernandez-Pliego, P., Davidson, S. I., Burns, P., et al. (2006) · Mammalian Genome · doi:10.1007/s00335-005-0112-1 · Cited by 112 · cited 2× · see citing works
“Behavioral Tests EPM and OF were used to assess rodent exploration, activity, and anxiety as previously described (Solberg et al., 2006; Valdar et al., 2006).”
MethodSelf-citationPhylometabonomic Patterns of Adaptation to High Fat Diet Feeding in Inbred Mice
Fearnside, J., Dumas, M., Rothwell, A. R., Wilder, S. P., Cloarec, O., Toye, A. A., Blancher, C., Holmes, E. C., Tatoud, R., Barton, R. H., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001668 · Cited by 104 · cited 3× · see citing works
“Glucose Tolerance and Insulin Secretion Tests Body weight (BW) was recorded and intraperitoneal glucose tolerance tests (IP-GTT, 2 g/kg BW) were performed in overnight-fasted mice as previously described (Fearnside et al., 2008).”
MethodSelf-citationMetabotyping of Caenorhabditis elegans reveals latent phenotypes
Blaise, B., Giacomotto, J., Eléna, B., Dumas, M., Toulhoat, P., Ségalat, L., & Emsley, L. (2007) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0707393104 · Cited by 104 · cited 2× · see citing works
“Models were validated by permutations testing of the Q(2)Yhat goodness-of-prediction statistics parameter with 10,000 random iterations and calculation of an empirical p value (Blaise et al., 2007).”
MethodSelf-citationToye, A. A., Dumas, M., Blancher, C., Rothwell, A. R., Fearnside, J., Wilder, S. P., Bihoreau, M.-T., Cloarec, O., Azzouzi, I., Young, S., et al. (2007) · Diabetologia · doi:10.1007/s00125-007-0738-5 · Cited by 104 · cited 2× · see citing works
“Transcriptomics Experiments were performed according to Affymetrix protocols as previously described (Toye et al., 2007).”
MethodSelf-citationBlaise, B. J., Shintu, L., Elena‐Herrmann, B., Emsley, L., Dumas, M., & Toulhoat, P. (2009) · Analytical Chemistry · doi:10.1021/ac9007754 · Cited by 88 · cited 2× · see citing works
“The dataset was then further aligned using recursive segment-wise peak alignment (RSPA) (Veselkov et al., 2009), and peak calling was performed using statistical recoupling of variables (SRVs) (Blaise et al., 2009).”
MethodSelf-citationThe Role of Adipocyte XBP1 in Metabolic Regulation during Lactation
Gregor, M. F., Misch, E. S., Yang, L., Hummasti, S., Inouye, K., Lee, A., Bierie, B., & Hotamışlıgil, G. S. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.03.042 · Cited by 81 · cited 1× · see citing works
“The lack of effect of TMAO treatment on BW and BMI in HFD-fed mice supports the view that despite Xbp1’s central role in ER stress, adipocyte-specific Xbp1 deletion does not affect obesity (Gregor et al., 2013).”
BackgroundMcEntyre, C. J., Lever, M., Chambers, S. T., George, P. M., Slow, S., Elmslie, J. L., Florkowski, C. M., Lunt, H., & Krebs, J. D. (2014) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/0004563214545346 · Cited by 67 · cited 2× · see citing works
“, 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al., 2014; Lever et al., 2014; McEntyre et al., 2015).”
BackgroundA mouse model to test the in vivo efficacy of chemical chaperones
Bai, C., Biwersi, J., Verkman, A. S., & Matthay, M. A. (1998) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/s1056-8719(98)00034-3 · Cited by 59 · cited 4× · see citing works
“, 2011b), the roles played by TMAO in glucose homeostasis are less clear (Bai et al., 1998; Gao et al., 2014; Lever et al., 2014; McEntyre et al., 2015).”
BackgroundInfluentialAl-Waiz, M. M., Ayesh, R., Mitchell, S. C., Idle, J. R., & Smith, R. L. (1987) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1987.207 · Cited by 56 · cited 2× · see citing works
“, 2015) triggered by potential microbial retroversion (Al-Waiz et al., 1987), we performed subcutaneous TMAO administration.”
BackgroundThe microbial-mammalian metabolic axis: beyond simple metabolism.
Dumas, M. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.04.005 · Cited by 43 · see citing works
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Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women
Hoyles, L., Fernández-Real, J.-M., Federici, M., Serino, M., Abbott, J., Charpentier, J., Heymes, C., Luque, J. L., Anthony, E., Barton, R. H., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0061-3 · Cited by 720 · see citing works
Self-citationGut microbes and metabolites as modulators of blood-brain barrier integrity and brain health
Parker, A., Fonseca, S., & Carding, S. R. (2019) · Gut Microbes · doi:10.1080/19490976.2019.1638722 · Cited by 722 · see citing works
“TMAO’s beneficial effects include reducing endoplasmic reticulum stress and lipogenesis in adipocytes, increasing insulin secretion in pancreatic islets, and attenuating diet-induced impaired glucose tolerance.(59,60) Again, by extension, such therapies may also be beneficial in protecting against neurodegenerative di…”
BackgroundMicrobiota-derived metabolites as drivers of gut–brain communication
Ahmed, H., Leyrolle, Q., Koistinen, V., Kärkkäinen, O., Layé, S., Delzenne, N., & Hanhineva, K. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2102878 · Cited by 462 · see citing works
Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., Schell, M., Sandoval-Espinola, W. J., Tao, J., Sha, B., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.021 · Cited by 427 · see citing works
Gut reactions: Breaking down xenobiotic–microbiome interactions
Clarke, G., Sandhu, K. V., Griffin, B. T., Dinan, T. G., Cryan, J. F., & Hyland, N. P. (2019) · Pharmacological Reviews · doi:10.1124/pr.118.015768 · Cited by 319 · see citing works
“Chronic exposure of mice to TMAO attenuates diet-associated glucose tolerance, reducing endoplasmic stress and adipogenesis in adipocytes (Dumas et al., 2017).”
BackgroundKoh, A., & Bäckhed, F. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.005 · Cited by 307 · see citing works
Feeding gut microbes to nourish the brain: unravelling the diet–microbiota–gut–brain axis
Schneider, E., O'Riordan, K. J., Clarke, G., & Cryan, J. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01108-6 · Cited by 258 · see citing works
“It has been shown that TMAO plays a key role in forecasting and modulating obesity, glucose tolerance and host behaviour, while also enhancing insulin secretion and reducing metabolic stress 197 .”
Interplay between food and gut microbiota in health and disease
Danneskiold‐Samsøe, N. B., Barros, H. D. D. F. Q., dos Santos, R., Bicas, J. L., Cazarin, C. B. B., Madsen, L., Kristiansen, K., Pastore, G. M., Brix, S., & Maróstica, M. R. (2018) · Food Research International · doi:10.1016/j.foodres.2018.07.043 · Cited by 271 · see citing works
Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota
Hoyles, L., Jiménez-Pranteda, M. L., Chilloux, J., Brial, F., Myridakis, A., Aranias, T., Magnan, C., Gibson, G. R., Sanderson, J. D., Nicholson, J. K., et al. (2018) · Microbiome · doi:10.1186/s40168-018-0461-0 · Cited by 251 · see citing works
Self-citationHoyles, L., Pontifex, M. G., Rodriguez-Ramiro, I., Anis-Alavi, M. A., Jelane, K. S., Snelling, T., Solito, E., Fonseca, S., Carvalho, A. L., Carding, S. R., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01181-z · Cited by 221 · see citing works
“Moreover, protective roles for TMAO have been reported in rodent models of hypertension [18], atherosclerosis [19] and non-alcoholic steatohepatitis [20] and we have previously shown TMAO to improve glucose homeostasis and insulin secretion in mice fed a high-fat diet [21].”
BackgroundSelf-citationImplication of gut microbiota metabolites in cardiovascular and metabolic diseases
Brial, F., Lay, A. L., Dumas, M., & Gauguier, D. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2901-1 · Cited by 197 · see citing works
Self-citationHeianza, Y., Sun, D., Li, X., DiDonato, J. A., Bray, G. A., Sacks, F. M., & Qi, L. (2019) · Gut · doi:10.1136/gutjnl-2018-316155 · Cited by 177 · see citing works
Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids
Yue, S., Liu, J., Wang, A.-T., Meng, X., Yang, Z.-R., Peng, C. Y., Guan, H., Wang, C., & Yan, D. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00256.2018 · Cited by 130 · see citing works
“Also, the dysbiotic microbiome profiles affect the functional output of the gut microbiota, in particular bacterial metabolites, such as short-chain fatty acids (SCFAs) (19), trimethylamineN-oxide (11), and branched-chain amino acids (BCAAs, i.”
BackgroundRahim, M. B. H. A., Chilloux, J., Martínez-Gili, L., Neves, A. L., Myridakis, A., Gooderham, N. J., & Dumas, M. (2019) · Acta Diabetologica · doi:10.1007/s00592-019-01312-x · Cited by 124 · see citing works
Self-citationLinks between Dietary Protein Sources, the Gut Microbiota, and Obesity
Madsen, L., Myrmel, L. S., Fjære, E., Liaset, B., & Kristiansen, K. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.01047 · Cited by 110 · see citing works
“, 2013) and recently also linked to obesity (Dumas et al., 2017).”
BackgroundPraveenraj, S. S., Sonali, S., Anand, N., Hediyal, T. A., Vichitra, C., Kalyan, M., Kanna, P. V., Chandana, K. A., Paneyala, S., Mahalakshmi, A. M., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02990-5 · Cited by 112 · see citing works
Prokopidis, K., Chambers, E. S., Lochlainn, M. N., & Witard, O. C. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.770455 · Cited by 109 · see citing works
Impact of Protein Intake in Older Adults with Sarcopenia and Obesity: A Gut Microbiota Perspective
Prokopidis, K., Cervo, M. M., Gandham, A., & Scott, D. (2020) · Nutrients · doi:10.3390/nu12082285 · Cited by 99 · see citing works
“Accordingly, L-carnitine present in red meat can be metabolized to trimethylamine oxide (TMAO), which is associated with an increased incidence of atherosclerosis [194] and obesity [195].”
BackgroundMicrobial metabolites in non-alcoholic fatty liver disease
Zhou, D., & Fan, J. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i17.2019 · Cited by 94 · see citing works
Chen, R., Wang, J., Zhan, R., Zhang, L., & Wang, X. (2019) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2019.112139 · Cited by 94 · see citing works
Zhao, Z., Xin, F., Zhou, D., Xue, Y., Liu, X., Yang, R., Pan, Q., & Fan, J. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i20.2450 · Cited by 85 · see citing works
Local and systemic effects of microbiome‐derived metabolites
Spivak, I., Fluhr, L., & Elinav, E. (2022) · EMBO Reports · doi:10.15252/embr.202255664 · Cited by 74 · see citing works
“Work by Dumas et al (2017) suggests that TMAO induces an improved insulin secretion and glucose tolerance in mouse models of metabolic dysfunction, while others (Chen et al , 2019b) argue that TMAO interacts with the UPR-effector PERK, thereby disrupting glucose tolerance.”
Leyrolle, Q., Cserjési, R., Mulders, M. D. G. H., Zamariola, G., Hiel, S., Gianfrancesco, M. A., Rodriguez, J., Portheault, D., Amadieu, C., Leclercq, S., et al. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.09.025 · Cited by 69 · see citing works
An Integrated Approach to Skeletal Muscle Health in Aging
Agostini, D., Gervasi, M., Ferrini, F., Bartolacci, A., Stranieri, A., Piccoli, G., Barbieri, E., Sestili, P., Patti, A., Stocchi, V., et al. (2023) · Nutrients · doi:10.3390/nu15081802 · Cited by 76 · see citing works
Zhou, D., Zhang, J., Xiao, C., Mo, C., & Ding, B. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.964477 · Cited by 57 · see citing works
“Others have pointed out that TMAO functions as a chemical chaperone (22) and could actually be beneficial.”
BackgroundThe Relationship between Fish Intake and Urinary Trimethylamine‐ N ‐Oxide
Yin, X., Gibbons, H., Rundle, M., Frost, G. S., McNulty, B. A., Nugent, A. P., Walton, J., Flynn, A., & Brennan, L. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900799 · Cited by 54 · see citing works
Integration of the human exposome with the human genome to advance medicine
Barouki, R., Audouze, K., Coumoul, X., Démenais, F., & Gauguier, D. (2018) · Biochimie · doi:10.1016/j.biochi.2018.06.023 · Cited by 52 · see citing works
Self-citationPancreas–Microbiota Cross Talk in Health and Disease
Adolph, T. E., Mayr, L., Grabherr, F., Schwärzler, J., & Tilg, H. (2019) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082018-124306 · Cited by 47 · see citing works
Raad, G., Serra, F., Martin, L., Derieppe, M., Gilleron, J., Costa, V. L., Pisani, D. F., Amri, E., Trabucchi, M., & Grandjean, V. (2021) · eLife · doi:10.7554/elife.61736 · Cited by 49 · see citing works
Trimethylamine/Trimethylamine-N-Oxide as a Key Between Diet and Cardiovascular Diseases
He, S., Jiang, H., Zhuo, C., & Jiang, W. (2021) · Cardiovascular Toxicology · doi:10.1007/s12012-021-09656-z · Cited by 45 · see citing works
“The possible explanation is that TMAO can work as a chaperone, help fold protein and alleviate ERS [72].”
BackgroundInfluentialYadav, H., Jaldhi, Bhardwaj, R., Anamika, A., Bakshi, A., Gupta, S., & Maurya, S. K. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122022 · Cited by 46 · see citing works
A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression
Iruzubieta, P., Medina, J. M., Fernández-López, R., Crespo, J., & de la Cruz, F. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051369 · Cited by 44 · see citing works
“In one study where mice were fed with a high-fat diet, TMAO supplementation reduced glucose tolerance, whereas other studies reported improvements in glucose tolerance after chronic TMAO administration [81,82].”
ResultGut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD
Termite, F., Archilei, S., D’Ambrosio, F., Petrucci, L., Viceconti, N., Iaccarino, R., Liguori, A., Gasbarrini, A., & Miele, L. (2025) · Antioxidants · doi:10.3390/antiox14010056 · Cited by 46 · see citing works
Krueger, E. S., Lloyd, T. S., & Tessem, J. S. (2021) · Nutrients · doi:10.3390/nu13082873 · Cited by 40 · see citing works
“In humans and mice, TMAO levels increase with body mass index and visceral adiposity [237,239].”
BackgroundResultInfluentialTMAO and diabetes: from the gut feeling to the heart of the problem
Jaworska, K., Kuś, M., & Ufnal, M. (2025) · Nutrition and Diabetes · doi:10.1038/s41387-025-00377-8 · Cited by 39 · see citing works
Ma, R., Shi, G.-Y., Li, Y., & Shi, H. (2024) · British Journal Of Nutrition · doi:10.1017/s0007114524000631 · Cited by 37 · see citing works
“Researchers have conducted a cross-sectional study among more than 3000 ordinary residents in Guangzhou, China, and the results showed that the severity of NAFLD was correlated with an increase in TMAO and betaine concentrations and a decrease in the betaine:choline ratio (30) .”
BackgroundIntestinal Flora Derived Metabolites Affect the Occurrence and Development of Cardiovascular Disease
Wen, Y., Sun, Z., Xie, S., Hu, Z., Lan, Q., Sun, Y., Yuan, L., & Zhai, C. (2022) · Journal of Multidisciplinary Healthcare · doi:10.2147/jmdh.s367591 · Cited by 39 · see citing works
Koppe, L., & Soulage, C. O. (2022) · Kidney International · doi:10.1016/j.kint.2022.06.025 · Cited by 37 · see citing works
Barretto, S. A., Lasserre, F., Huillet, M., Régnier, M., Polizzi, A., Lippi, Y., Fougerat, A., Person, E., Bruel, S., Bétoulières, C., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01050-9 · Cited by 36 · see citing works
Gut microbiota-related metabolome analysis based on chromatography-mass spectrometry
Zhou, L., Yu, D., Zheng, S., Ouyang, R., Wang, Y., & Xu, G. (2021) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2021.116375 · Cited by 34 · see citing works
Krueger, E. S., Beales, J. L., Russon, K. B., Elison, W. S., Davis, J., Hansen, J. M., Neilson, A. P., Hansen, J. M., & Tessem, J. S. (2021) · Biomolecules · doi:10.3390/biom11121892 · Cited by 32 · see citing works
Fadhlaoui, K., Arnal, M.-É., Martineau, M., Camponova, P., Ollivier, B., O’Toole, P. W., & Brugère, J. (2020) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-020-10599-8 · Cited by 30 · see citing works
Introduction to the Microbiome and Metabolome
Faintuch, J., & Faintuch, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-815249-2.02001-7 · Cited by 29 · see citing works
Role of gut microbial metabolites in nonalcoholic fatty liver disease
Zhao, Z. H., Lai, J. K., Qiao, L., & Fan, J. (2019) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12709 · Cited by 28 · see citing works
Huang, L., Ren, P., Ouyang, Z., Tao, W., Kong, X., Li, T., Yin, Y., He, S., Yang, C., & He, Q. (2020) · Animal Feed Science and Technology · doi:10.1016/j.anifeedsci.2020.114505 · Cited by 26 · see citing works
Smith, L., Klément, W., Dopavogui, L., de Bock, F., Lasserre, F., Barretto, S. A., Lukowicz, C., Fougerat, A., Polizzi, A., Schaal, B., et al. (2020) · Environment International · doi:10.1016/j.envint.2020.106010 · Cited by 25 · see citing works
Lei, D., Yu, W., Liu, Y. F., Jiang, Y., Li, X., Lv, J., & Li, Y. (2023) · Molecules · doi:10.3390/molecules28093817 · Cited by 24 · see citing works
“Others pointed out that TMAO acts as a chemical chaperone [41].”
BackgroundGut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke
Li, Z., He, X., Fang, Q., & Yin, X. (2024) · Biomolecules · doi:10.3390/biom14111463 · Cited by 26 · see citing works
“Additionally, the TMAO concentration is predictive of future obesity [75].”
Host–Microbiota Mutualism in Metabolic Diseases
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BackgroundInfluence of the Human Gut Microbiome on the Metabolic Phenotype
Hoyles, L., & Swann, J. R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812293-8.00018-9 · Cited by 21 · see citing works
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“1c), consistent with our previous reports using this diet 13,28 .”
Self-citationTrimethylamine N-oxide: role in cell senescence and age-related diseases
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“In addition, they also proved that TMAO directly accelerates insulin secretion in isolated islets [111].”
BackgroundTrimethylamine N-Oxide as a Mediator Linking Peripheral to Central Inflammation: An In Vitro Study
Janeiro, M. H., Solas, M., Orbe, J., Rodríguez, J. A., de Muniain, L. S., Escalada, P., Yip, P. K., & Ramírez, M. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417557 · Cited by 18 · see citing works
“…1000 µ M. Based on this evidence and on the concentration of TMAO used in vitro experiments in the literature for other cell lines [7,9,10,16,21,27,39,40], all of our experiments included the concentration of 200 µ M because recent epidemiological studies have shown that TMAO in plasma ranges…”
MethodLützhøft, D. O., Bækgård, C., Wimborne, E. A., Straarup, E. M., Pedersen, K., Swann, J. R., Pedersen, H. D., Kristensen, K., Morgills, L., Nielsen, D. S., et al. (2024) · PLoS ONE · doi:10.1371/journal.pone.0298602 · Cited by 18 · see citing works
“TMAO has been associated with attenuated ER stress, reduced lipogenesis in adipocytes, improved insulin secretion and restored glucose tolerance in mice [77].”
α-synuclein overexpression and the microbiome shape the gut and brain metabolome in mice
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Interplay between gut microbiota and p66Shc affects obesity‐associated insulin resistance
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Self-citationImplications of Gut Microbiota-Derived Metabolites in Neurological Disorders
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“Moreover, administration of TMAO to mice fed a high fat diet improved glucose tolerance [29].”
BackgroundRegulation of Physiological Barrier Function by the Commensal Microbiota
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“It has been reported that TMAO acts as a chemical chaperone, facilitating protein folding, and stabilising protein structure, hence alleviating endoplasmic reticulum stress (Achard and Laybutt 2012; Dumas et al. 2017).”
BackgroundHe, G., Liu, X., Lu, A.-S., & Feng, Y. (2022) · Cardiovascular Therapeutics · doi:10.1155/2022/9512401 · Cited by 9 · see citing works
“Finally, the mechanism of the effect of gut microbial-related choline metabolite TMAO on hypertension required further study on not only the diuretic effect but also others, such as protein structure protective effect [50] and endoplasmic reticulum stress-alleviating effect [51].”
BackgroundBi-clustering of metabolic data using matrix factorization tools
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“Novel beneficial roles for TMAO in glucose homoeostasis and insulin secretion have been reported, and the improvement of impaired glucose tolerance mediated by increased insulinemia was related to ER-stress improvement, which was confirmed in vitro by treating isolated pancreatic islets with subcutaneous TMAO infusion…”
BackgroundLees, H., Swann, J. R., Poucher, S. M., Holmes, E. C., Wilson, I. D., & Nicholson, J. K. (2019) · Journal of Proteome Research · doi:10.1021/acs.jproteome.9b00040 · Cited by 8 · see citing works
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“Protective roles have been observed for TMAO in rodent models of hypertension (Huc et al., 2018), glucose homeostasis (Dumas et al., 2017), atherosclerosis (Collins et al., 2016), non-alcoholic steatohepatitis (Zhao et al., 2019) and BBB integrity (Hoyles et al., 2021), with elevated levels acting…”
Gut Microbiota Metabolite TMAO and Adolescent Cardiometabolic Health: A Cross-sectional Analysis
Iorra, F. D. Q., Rodrigues, P. G., Bock, P. M., Guahnon, M. P., Eller, S. C. W. D. S., de Oliveira, T. F., Birk, L., Schwarz, P. D. S., Drehmer, M., Bloch, K. V., et al. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf055 · Cited by 7 · see citing works
“…example, studies involving chronic in vivo TMAO administration have shown that it can reduce impaired glucose tolerance in mice fed a high-fat diet [60], while the acute treatment of rat islets with TMAO has been found to reduce β -cell damage and normalize islet function under glycolipotoxic…”
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Sarcopenic Obesity: The Underlying Molecular Pathophysiology and Prospect Therapies
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“(141-143 141-143) That being said, trimethylamine oxide (TMAO), which is produced during the metabolism of L-carnitine found in red meat, has been linked to a higher risk of atherosclerosis (144) and obesity (145).”
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Diet dependent impact of benzoate on diabetes and obesity in mice
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“For example, beneficial or protective effects have been reported in glucose homeostasis [13, 14], carcinogenesis [15] atherosclerosis and cardiovascular function [16, 17], steatohepatitis [18], and inflammatory insults [19].”
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“Increasing evidence suggests that plasma TMAO is a marker of cardiovascular, renal, and metabolic diseases [1–7 , 60 ].”
The Gut Microbiota as a Therapeutic Approach for Obesity
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“9,40 45 Several studies have suggested that TMAO can cause memory impairment by promoting pathological injuries in the brain.”
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Self-citationUnraveling the mechanisms of PCOS: the interplay between gut microbiota and the immune system
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“For instance, co-metabolites such as trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG), and hippurate have been identified as predictive features in the outcomes of diabetes and obesity, demonstrating a strong potential to predict metabolic risks associated with PCOS [102].”
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“…suggested potential benefits depending on the sites of accumulation, with some studies showing that TMAO can ameliorate high-fat-diet-induced adiposity by modulating ER stress responses and improving insulin sensitivity in tissues such as skeletal muscle, liver, and pancreatic β -cells [54,55].”
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“Experimental and animal studies indicated that TMAO impaired glucose tolerance (35,36) and activated PERK to promote metabolic dysfunction (10) .”
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- Authors
- Dumas, M.-E., Rothwell, A. R., Hoyles, L., Aranias, T., Chilloux, J., Calderari, S., Noll, E. M., Péan, N., Boulangé, C. L., Blancher, C., Barton, R. H., Gu, Q., Fearnside, J. F., Deshayes, C., Hue, C., Scott, J., Nicholson, J. K., & Gauguier, D.
- Affiliations
- Imperial College London (GB)
- Centre for Human Genetics (GB)
- Inserm (FR)
- Faculté de médecine de Tunis (TN)
- Corresponding author
- Dumas, Marc-Emmanuel
- Gauguier, Dominique
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 20
- Issue
- 1
- Pages
- 136-148
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5507771
- OpenAlex
- W2732316158
- Cited by
- 114
- References
- 71
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 11 · 2021: 21 · 2020: 13 · 2019: 17 · 2018: 13 · 2017: 2
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- HAL (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- European Commission
- Wellcome Trust
- Medical Research Council (MR/L01632X/1, RDLS015375)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- gut microbiota, prodromal biomarkers, phenotypic heterogeneity, obesity, impaired glucose tolerance, anxiety-like behavior, locomotor activity, trimethylamine N-oxide, endoplasmic reticulum stress, lipogenesis, insulin secretion, pancreatic islets, high-fat diet, C57BL/6J mice
- MeSH terms
- Gastrointestinal Microbiome, Insulin Secretion, Animals, Anxiety, Blood Glucose, Cell Line, Insulin, Male, Methylamines, Mice, Inbred C57BL, Obesity, Phenotype, Biomarkers, Oxidants, Adipocytes, Glucose Intolerance, Lipogenesis, Insulin-Secreting Cells, Mice, Host-Pathogen Interactions, Metabolome, Endoplasmic Reticulum Stress
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