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Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial
Open accessAbstract
Objective Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention. Design We included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated. Results Greater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (p interaction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids. Conclusion Our findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism. Trial registration number NCT00072995 .
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“Changes in TMAO and choline associated with increased insulin sensitivity in a weight-loss intervention study of obese individuals.155”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [155]
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Plant-Forward Diets Lower Circulating TMAO in Adults: A Systematic Review and Meta-AnalysisPreprint
Zupo, R., Castellana, F., Catino, F., Lampignano, L., Zheng, Y., Lip, G. Y. H., Mastrangelo, A., Ikram, M. A., Rodriguez‐Mateos, A., Menni, C., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9382739/v1
Wang, B., Yang, Y., Ho, Y. M., Lin, H., Yuan, J., Long, K., Cheng, K. K. Y., & Li, X. (2026) · Nature Communications · doi:10.1038/s41467-026-76075-5
“The TMAO reduction positively associates with improved insulin sensitivity in humans receiving dietary intervention and weight loss 20 .”
Self-citationTong, B., Wang, M., Yang, X., & Liu, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1868837
“Several mechanisms may explain how TMAO contributes to DR: (1) TMAO may exacerbate the metabolic abnormalities of diabetes by enhancing insulin resistance and altering liver cholesterol metabolism, thereby promoting DR (31).”
Sun, L., Zhang, S., Hu, H., Xu, B., Qian, S., Huang, Y., Yang, X. P., Liang, Y., & Chen, X. (2026) · Nutrients · doi:10.3390/nu18182950
“A high-fat diet can alter gut microbial diversity and community structure, thereby affecting the production and transformation of short-chain fatty acids, bile acid derivatives, choline metabolites, branched-chain amino acids, and lipid-related small molecules [15,16].”
Metadata
- Authors
- Heianza, Y., Sun, D., Li, X., DiDonato, J. A., Bray, G. A., Sacks, F. M., & Qi, L.
- Affiliations
- Tulane University (US)
- Cleveland Clinic (US)
- Pennington Biomedical Research Center (US)
- Harvard University (US)
- Corresponding author
- Qi, Lu
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2018-06-02
- Volume
- 68
- Issue
- 2
- Pages
- 263-270
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC6275143
- OpenAlex
- W2806227292
- Cited by
- 177
- References
- 52
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 22 · 2023: 22 · 2022: 25 · 2021: 32 · 2020: 18 · 2019: 16 · 2018: 6
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute
- Japan Society for the Promotion of Science
- United States-Israel Binational Science Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases
- Boston Obesity Nutrition Research Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- gut microbiota metabolites, trimethylamine N-oxide, choline, L-carnitine, insulin resistance, insulin sensitivity, glucose metabolism, weight loss diet, macronutrient composition, dietary fat intake, branched-chain amino acids, aromatic amino acids, obesity, POUNDS Lost trial
- MeSH terms
- Gastrointestinal Microbiome, Adult, Amino Acids, Carnitine, Choline, Diet, Reducing, Female, Glucose, Humans, Insulin Resistance, Male, Massachusetts, Methylamines, Obesity, Overweight
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