Gut microbiota and immunometabolic response to Choline and Betaine supplementation in a Mouse Model of Diet-Induced Obesity
Main Article Content
Abstract
Obesity is a chronic, recurring and multifactorial disease characterized by systemic inflammation, visceral adipose tissue dysfunction and gut microbiota dysbiosis. While Omega-3 fatty acids have shown beneficial effects in this context, the potential of other dietary modulators remains underexplored.
Our aim was to investigate the effects of dietary supplementation with choline and betaine on weight gain, gut microbiota composition and visceral immunometabolic profiles in a mouse model of diet-induced obesity.
Mice fed with choline and betaine supplemented diets, exhibited significantly reduced weight gain compared to obesity fat diet, at weeks 4, 12 and 24 after differential feeding was started. Beta-diversity analyses revealed sustained divergence in microbial communities between diet groups. Fat diet supplemented with choline and betaine feeding generated enrichment of SCFA-producing taxa such as Parabacteroides, Oscillospira, Flavonifractor, Harryflintia and Christensenellaceae R7 group while Fat diet feeding promoted the expansion of pro-inflammatory genera such as Helicobacter and Negativibacillus. In parallel, in the choline and betaine supplementation group immune data point toward an anti-inflammatory visceral adipose tissue phenotype, with IL-10–skewed T regulatory cell signatures producing high levels of IL-10.
Choline and betaine supplementation modulates the gut–adipose–immune axis by reshaping gut microbial community and enhancing host immunometabolic homeostasis. These findings support the potential of methyl-donor nutrients as dietary strategy to mitigate obesity-related inflammation and metabolic dysfunction.
Multiblock analysis with DIABLO identified a coordinated microbial–immune–metabolic signature that distinguished diet groups, linking Fat diet supplemented with choline and betaine-enriched taxa with IL-10–producing Tregs and adiponectin levels. These findings highlight the systemic impact of choline and betaine supplementation.
Keywords:
Obesity, choline, betaine, gut microbiota, visceral adipose tissue, methyl donors, short-chain fatty acids, regulatory T cells, diet-induced obesity, immunometabolism
Article Details
How to Cite
PORTELA, Néstor D. et al.
Gut microbiota and immunometabolic response to Choline and Betaine supplementation in a Mouse Model of Diet-Induced Obesity.
Medical Research Archives, [S.l.], v. 13, n. 8, aug. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6877>. Date accessed: 14 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i8.6877.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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51. Kuerbanjiang M, Yu W, Shang T, et al. Association between dietary betaine intake and overweight or obesity. Sci Rep. 2024;14:32031. doi:10.1038/s41598-024-83646-3
2. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808. doi:10.1172/JCI2 00319246
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7. Nishimura S, Manabe I, Nagasaki M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15(8):914-920. doi:10.1038/nm.1964
8. Zatterale F, Longo M, Naderi J, et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2020;10:1607. doi:10.3389/fphys.2019.01607
9. Agans R, Gordon A, Kramer DL, Perez-Burillo S, Rufián-Henares JA, Paliy O. Dietary Fatty Acids Sustain the Growth of the Human Gut Microbiota. Appl Environ Microbiol. 2018;84(21):e01525-18. doi:10.1128/AEM.01525-18
10. Daniel H, Gholami AM, Berry D, et al. High-fat diet alters gut microbiota physiology in mice. ISME J. 2014;8(2):295-308. doi:10.1038/ismej.2013.155
11. Shen W, Gaskins HR, McIntosh MK. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem. 2014;25(3):270-280. doi:10.1016/j.jnutbi o.2013.09.009
12. Xu AA, Kennedy LK, Hoffman K, et al. Dietary Fatty Acid Intake and the Colonic Gut Microbiota in Humans. Nutrients. 2022;14(13):2722. doi:10.3390/n u14132722
13. Schoeler M, Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord. 2019;20(4):461-472. doi:10.1007/s11154-019-09512-0
14. Portela ND, Galván C, Sanmarco LM, et al. Omega-3-Supplemented Fat Diet Drives Immune Metabolic Response in Visceral Adipose Tissue by Modulating Gut Microbiota in a Mouse Model of Obesity. Nutrients. 2023;15(6):1404. doi:10.3390/n u15061404
15. Portela ND, Eberhardt N, Bergero G, et al. Dietary Omega-3 Supplementation Shapes Gut Microbiota and Regulates Immunometabolism in a Mouse Model of Obesity. Medical Research Archives. 2025;13(5). doi:10.18103/mra.v13i5.6623
16. Choi SW, Friso S. Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging. Nutr Res Pract. 2023;17(4):597-615. doi:10.41 62/nrp.2023.17.4.597
17. Sivanesan S, Taylor A, Zhang J, Bakovic M. Betaine and Choline Improve Lipid Homeostasis in Obesity by Participation in Mitochondrial Oxidative Demethylation. Front Nutr. 2018;5:61. doi:10.338 9/fnut.2018.00061
18. Chen Q, Wang Y, Jiao F, et al. Betaine inhibits Toll-like receptor 4 responses and restores intestinal microbiota in acute liver failure mice. Scientific Reports. 2020;10(1):21850. doi:10.1038/s41598-020-78935-6
19. Zhao G, He F, Wu C, et al. Betaine in Inflammation: Mechanistic Aspects and Applications. Front Immunol. 2018;9:1070. doi:10.3389/fimmu.2018.01070
20. Ellacott KLJ, Morton GJ, Woods SC, Tso P, Schwartz MW. Assessment of feeding behavior in laboratory mice. Cell Metab. 2010;12(1):10-17. doi:10.1016/j.cmet.2010.06.001
21. Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA, Holmes SP. DADA2: High resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13(7):581-583. doi:10.1038/nmet h.3869
22. McMurdie PJ, Holmes S. phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data. PLOS ONE. 2013;8(4):e61217. doi:10.1371/journal.pone.0061217
23. Leo Lahti SS. microbiome R package. Published online 2019 2012. http://microbiome.github.io
24. Quast C, Pruesse E, Yilmaz P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Research. 2013;41(D1):D590-D596. doi:10.1093/n ar/gks1219
25. R Core Team. R Core Team (2022). R: A language and environment for statistical computing. Published online 2021. https://www.R-project.org/.
26. Wickham H. ggplot2: Elegant Graphics for Data Analysis. 2016. Accessed January 25, 2023. https://link.springer.com/book/10.1007/978-3-319-24277-4
27. Kassambara A. ggpubr: “ggplot2“ Based Publication Ready Plots. R package version 0.5.0. Published online 2022. https://CRAN.R-project.org/package=ggpubr
28. Cao Y, Dong Q, Wang D, Zhang P, Liu Y, Niu C. microbiomeMarker: an R/Bioconductor package for microbiome marker identification and visualization. Bioinformatics. 2022;38(16):4027-4029. doi:10.109 3/b ioinformatics/btac438
29. Wei T SV. R package “corrplot“: Visualization of a Correlation Matrix. Published online 2021. https://github.com/taiyun/corrplot.
30. Rohart F, Gautier B, Singh A, Cao KAL. mixOmics: An R package for ‘omics feature selection and multiple data integration. Published online 2017. doi:10.1371/journal.pcbi.1005752
31. Hu H, Tan L, Li X, et al. Betaine Reduces Lipid Anabolism and Promotes Lipid Transport in Mice Fed a High-Fat Diet by Influencing Intestinal Protein Expression. Foods. 2022;11(16):2421. doi:10.339 0/foods11162421
32. Wang X, Shang X, Pan Y, Fu Y, Zhu H, Yan S. Frontiers | Betaine alleviates obesity-related metabolic disorders in rats: insights from microbiomes, lipidomics, and transcriptomics. Published online 2025. doi:10.3389/fnut.2025.1604801
33. Kathirvel E, Morgan K, Malysheva OV, Caudill MA, Morgan TR. Betaine for the prevention and treatment of insulin resistance and fatty liver in a high-fat dietary model of insulin resistance in C57BL mice. Front Nutr. 2024;11:1409972. doi:10.3389/fnut.2 024.1409972
34. Zeng Q, Zhao M, Wang F, et al. Integrating Choline and Specific Intestinal Microbiota to Classify Type 2 Diabetes in Adults: A Machine Learning Based Metagenomics Study. Front Endocrinol (Lausanne). 2022;13:906310. doi:10.3389/fendo.2022.906310
35. Corbin KD, Zeisel SH. Choline Metabolism Provides Novel Insights into Non-alcoholic Fatty Liver Disease and its Progression. Curr Opin Gastroenterol. 2012;28 (2):159-165. doi:10.1097/MOG.0b013e32834e7b4b
36. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504 (7480):451-455. doi:10.1038/nature12726
37. Sun M, Wu W, Chen L, et al. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun. 2018;9(1):3555. doi:10.1038/s41467-018-05901-2
38. Chen L, Sun M, Wu W, et al. Microbiota Metabolite Butyrate Differentially Regulates Th1 and Th17 Cells’ Differentiation and Function in Induction of Colitis. Inflamm Bowel Dis. 2019;25(9):1450-1461. doi:10.1093/ibd/izz046
39. Romano KA, Campo AM del, Kasahara K, et al. Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption. Cell Host Microbe. 2017;22(3):279-290.e7. doi:10.1016/j.ch om.2017.07.021
40. Kropp C, Le Corf K, Relizani K, et al. The Keystone commensal bacterium Christensenella minuta DSM 22607 displays anti-inflammatory properties both in vitro and in vivo. Sci Rep. 2021; 11:11494. doi:10.1038/s41598-021-90885-1
41. Tavella T, Rampelli S, Guidarelli G, et al. Elevated gut microbiome abundance of Christensenellaceae, Porphyromonadaceae and Rikenellaceae is associated with reduced visceral adipose tissue and healthier metabolic profile in Italian elderly. Gut Microbes. 2021;13(1):1880221. doi:10.1080/19490 976.2021.1880221
42. Yang J, Li Y, Wen Z, Liu W, Meng L, Huang H. Oscillospira - a candidate for the next-generation probiotics. Gut Microbes. 2021;13(1):1987783. doi:10.1080/19490976.2021.1987783
43. Cui Y, Zhang L, Wang X, et al. Roles of intestinal Parabacteroides in human health and diseases. FEMS Microbiology Letters. 2022;369(1):fnac072. doi:10.1093/femsle/fnac072
44. Wang K, Liao M, Zhou N, et al. Parabacteroides distasonis Alleviates Obesity and Metabolic Dysfunctions via Production of Succinate and Secondary Bile Acids. Published online 2019. Accessed July 16, 2025. https://www.cell.com/cell-reports/abstract/S2211-1247(18)31958-2
45. Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. The Genus Alistipes: Gut Bacteria With Emerging Implications to Inflammation, Cancer, and Mental Health. Frontiers in Immunology. 2020;11. Accessed February 18, 2024. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00906
46. López-Montoya P, Rivera-Paredez B, Palacios-González B, et al. Dietary Patterns Are Associated with the Gut Microbiome and Metabolic Syndrome in Mexican Postmenopausal Women. Nutrients. 2023;15(22):4704. doi:10.3390/nu15224704
47. Kountouras J, Papaefthymiou A, Polyzos SA, et al. Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension. Microorganisms. 2021;9(11):2351. doi:10.3390/mic roorganisms9112351
48. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576-585. doi:10.1038/nm.3145
49. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63. doi:10.1038/nature09922
50. Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide. mBio. 2015;6(2):10.1128/mbio.02481-14. doi:10.1128/mbio.02481-14
51. Kuerbanjiang M, Yu W, Shang T, et al. Association between dietary betaine intake and overweight or obesity. Sci Rep. 2024;14:32031. doi:10.1038/s41598-024-83646-3