Микробный метаболом кишечника: современные данные и перспективы практического применения
Ключевые слова:
микробный метаболом кишечника, короткоцепочечные жирные кислоты, ароматические аминокислоты, биомаркеры метаболических нарушений, метаболическое дактилоскопирование, синбиотики
Аннотация
Исследования последнего десятилетия показали непосредственное участие кишечного микробиома и его метаболитов в регуляции жизненно важных процессов в организме человека. Обнаружено непосредственное воздействие микробного метаболома на центральный (конструктивный и энергетический) метаболизм человека, углеводный и липидный обмен. Наиболее изученными составляющими микробного метаболома являются короткоцепочечные жирные кислоты и продукты метаболизма ароматических аминокислот, синтез которых осуществляется как строгими анаэробами, так и факультативно-анаэробными обитателями кишечника человека. Показано, что кишечный микробный метаболом непосредственно вовлечен в синтез вторичных жирных кислот. Он также является участником нейроэндокринных взаимодействий. Полученные данные делают необходимым пересмотреть подходы к профилактике, а также схемы диагностики ряда патологий, в основе которых лежат метаболические нарушения. Ведется поиск микробных метаболитов, которые можно было бы использовать в качестве биомаркеров, позволяющих уточнять диагноз или стадии заболевания. Для этого предполагается разработка индивидуальных профилей клинически значимых микробных метаболитов человека. Результаты исследования метаболома открывают реальные перспективы для создания новых пероральных форм лекарственных препаратов, позволяющих минимизировать возможное вмешательство кишечной микрофлоры. Представляется весьма реальным создание синбиотиков, с учетом индивидуальных особенностей организма человека.
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Литература
Список литературы
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40. Rachmühl C., Lacroix C., Giorgetti A., Stoffel N.U., Zimmermann M.B., Brittenham G.M., et al. Validation of a batch cultivation protocol for fecal microbiota of Kenyan infants. BMC Microbiol. 2023;23(1):174. https://doi.org/10.1186/s12866-023-02915-9
1. Ceglarek U., Leichtle A., Brügel M., Kortz L., Brauer R., Bresler K., et al. Challenges and developments in tandem mass spectrometry based clinical metabolomics. Mol Cell Endocrinol. 2009;25;301(1-2):266-271. https://doi.org/10.1016/j.mce.2008.10.013
2. Gibbs R.A. The Human Genome Project Changed Everything. Nat Rev Genet. 2020;21(10):575-576. https://doi.org/10.1038/s41576-020-0275-3
3. Wishart D.S., Guo A., Oler E., Wang F., Anjum A., Peters H., et al. HMDB 5.0: the Human Metabolome Database for 2022. Nucleic Acids Res. 2022; 7;50(D1):D622-D631. https://doi.org/10.1093/nar/gkab1062
4. Le Gouellec A., Plazy C., Toussaint B. What clinical metabolomics will bring to the medicine of tomorrow. Front. Anal. Sci. 2023;3:1142606. https://doi.org/10.3389/frans.2023.1142606
5. Alseekh S., Aharoni A., Brotman Y., Contrepois K., D'Auria J., Ewald J., et al. Mass spectrometry-based metabolomics: a guide for annotation, quantification and best reporting practices. Nat Methods. 2021;18(7):747-756. https://doi.org/10.1038/s41592-021-01197-1
6. Cox T.O., Lundgren P., Nath K., Thaiss C.A. Metabolic control by the microbiome. Genome Med. 2022; 14(1):80. https://doi.org/10.1186/s13073-022-01092-0
7. Yan S., Wang H., Feng B., Ye L., Chen A. Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study. Front Immunol. 2024; 15:1332757. https://doi.org/10.3389/fimmu.2024.1332757
8. Jiang Y., Pang S., Liu X., Wang L., Liu Y. The Gut Microbiome Affects Atherosclerosis by Regulating Reverse Cholesterol Transport. J Cardiovasc Transl Res. 2024; Jan 17. https://doi.org/10.1007/s12265-024-10480-3 Online ahead of print.
9. Khan M.T., Nieuwdorp M., Backhed F. Microbial modulation of insulin sensitivity. Cell Metab. 2014;20(5):753-760. https://doi.org/10.1016/j.cmet.2014.07.006
10. Fluhr L., Mor U., Kolodziejczyk A.A., Dori-Bachash M., Leshem A., Itav S., et al. Gut microbiota modulates weight gain in mice after discontinued smoke exposure. Nature. 2021;600(7890):713-719. https://doi.org/10.1038/s41586-021-04194-8
11. Breton J., Tennoune N., Lucas N., Francois M., Legrand R., Jacquemot J., et al. Gut Commensal E. coli Proteins Activate Host Satiety Pathways following Nutrient-Induced Bacterial Growth. Cell Metab. 2016;23(2):324-334. https://doi.org/10.1016/j.cmet.2015.10.017
12. Becher T., Palanisamy S., Kramer D.J., Eljalby M., Marx S.J., Wibmer A.G., et al. Brown adipose tissue is associated with cardiometabolic health. Nat Med. 2021;27(1):58-65. https://doi.org/10.1038/s41591-020-1126-7
13. Agrawal L., Korkutata M., Vimal S.K., Yadav M.K., Bhattacharyya S., Shiga T. Therapeutic potential of serotonin 4 receptor for chronic depression and its associated comorbidity in the gut. Neuropharmacology. 2020;166:107969. https://doi.org/10.1016/j.neuropharm.2020.107969
14. Bhattarai Y., Williams B.B., Battaglioli E.J., Whitaker W.R., Till L., Grover M., et al. Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. Cell Host Microbe. 2018;23(6):775-785.e5. https://doi.org/10.1016/j.chom.2018.05.004
15. Agus A., Planchais J., Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe. 2018;23(6):716-724. https://doi.org/10.1016/j.chom.2018.05.003
16. Dodd D., Spitzer M.H., Van Treuren W., Merrill B.D., Hryckowian A.J., Higginbottom S.K., et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. 2017;551(7682):648-652. https://doi.org/10.1038/nature24661
17. Leitão-Gonçalves R., Carvalho-Santos Z., Francisco A.P., Fioreze G.T., Anjos M., Baltazar C., et al. Commensal bacteria and essential amino acids control food choice behavior and reproduction. PLoS Biol. 2017;15(4):e2000862. https://doi.org/10.1371/journal.pbio.2000862
18. Martinez-Guryn K., Hubert N., Frazier K., Urlass S., Musch M.W., Ojeda P., et al. Small Intestine Microbiota Regulate Host Digestive and Absorptive Adaptive Responses to Dietary Lipids. Cell Host Microbe. 2018; 23(4):458-469.e5. https://doi.org/10.1016/j.chom.2018.03.011
19. Araújo J.R., Tazi A., Burlen-Defranoux O., Vichier-Guerre S., Nigro G., Licandro H., et al. Fermentation Products of Commensal Bacteria Alter Enterocyte Lipid Metabolism. Cell Host Microbe. 2020; 27(3):358-375.e7. https://doi.org/10.1016/j.chom.2020.01.028
20. Kenny D.J., Plichta D.R., Shungin D., Koppel N., Hall A.B., Fu B., et al. Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level. Cell Host Microbe. 2020;28(2):245-257.e6. https://doi.org/10.1016/j.chom.2020.05.013
21. Du Toit, A. Reducing cholesterol levels. Nat Rev Microbiol. 2020;18(9):476. https://doi.org/10.1038/s41579-020-0410-3
22. Long S.L., Gahan C.G.M., Joyce S.A. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017;56:54-65. https://doi.org/10.1016/j.mam.2017.06.002
23. Guzior D.V., Quinn R.A. Review: microbial transformations of human bile acids. Microbiome. 2021;9(1):140. https://doi.org/10.1186/s40168-021-01101-1
24. Chun E., Lavoie S., Fonseca-Pereira D., Bae S., Michaud M., Hoveyda H.R., et al. Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity. Immunity. 2019; 51(5):871-884.e6. https://doi.org/10.1016/j.immuni.2019.09.014
25. Molinaro A., Bel Lassen P., Henricsson M., Wu H., Adriouch S., Belda E., et al. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology. Nat Commun. 2020;11(1):5881. https://doi.org/10.1038/s41467-020-19589-w
26. Virtue A.T., McCright S.J., Wright J.M., Jimenez M.T., Mowel W.K., et al. The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs. Sci Transl Med. 2019;11(496):eaav1892. https://doi.org/10.1126/scitranslmed.aav1892
27. Perry R.J., Peng L., Barry N.A., Cline G.W., Zhang D., Cardone R.L., et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature. 2016;534(7606):213-217. https://doi.org/10.1038/nature18309
28. Tirosh A., Calay E.S., Tuncman G., Claiborn K.C., Inouye K.E., Eguchi K., et al. The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans. Sci Transl Med. 2019;11(489):eaav0120. https://doi.org/10.1126/scitranslmed.aav0120
29. Subramaniam S., Fletcher C. Trimethylamine N-oxide: breathe new life. Br J Pharmacol. 2018;175(8):1344-1353. https://doi.org/10.1111/bph.13959
30. Zhang Y., Wang Y., Ke B., Du J. TMAO: How gut microbiota contributes to heart failure. Transl Res. 2021;228:109-125. https://doi.org/10.1016/j.trsl.2020.08.007
31. Gessner A., di Giuseppe R., Koch K., Fromm M.F., Lieb W., Maas R. Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort. Clin Chem Lab Med. 2020;58(5):733-740. https://doi.org/10.1515/cclm-2019-1146
32. Wang Z., Klipfell E., Bennett B.J., Koeth R., Levison B.S., Dugar B., et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63. https://doi.org/10.1038/nature09922
33. Griffin L.E., Djuric Z., Angiletta C.J., Mitchell C.M., Baugh M.E., Davy K.P., et al. A Mediterranean diet does not alter plasma trimethylamine N-oxide concentrations in healthy adults at risk for colon cancer. Food Funct. 2019;10(4):2138-2147. https://doi.org/10.1039/c9fo00333a
34. Li X., Fan Z., Cui J., Li D., Lu J., Cui X., et al. Trimethylamine N-Oxide in Heart Failure: A Meta-Analysis of Prognostic Value. Front Cardiovasc Med. 2022;9:817396. https://doi.org/10.3389/fcvm.2022.817396. eCollection 2022
35. SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021;42(25):2439-2454. https://doi.org/10.1093/eurheartj/ehab309
36. Le Gouellec A., Plazy C., Toussaint B. What clinical metabolomics will bring to the medicine of tomorrow. Front. Anal. Sci. 2023;3:1142606. https://doi.org/10.3389/frans.2023.1142606
37. Maier L., Pruteanu M., Kuhn M., Zeller G., Telzerow A., Anderson E.E., et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555(7698):623-628. https://doi.org/10.1038/nature25979
38. Javdan B., Lopez J.G., Chankhamjon P., Lee Y.J., Hull R., Wu Q., et al. Personalized Mapping of Drug Metabolism by the Human Gut Microbiome. Cell. 2020;181(7):1661-1679.e22. https://doi.org/10.1016/j.cell.2020.05.001
39. Guan H., Pu Y., Liu C., Lou T., Tan S., Kong M., et al. Comparison of Fecal Collection Methods on Variation in Gut Metagenomics and Untargeted Metabolomics. mSphere. 2021;6(5):e0063621. https://doi.org/10.1128/mSphere.00636-21
40. Rachmühl C., Lacroix C., Giorgetti A., Stoffel N.U., Zimmermann M.B., Brittenham G.M., et al. Validation of a batch cultivation protocol for fecal microbiota of Kenyan infants. BMC Microbiol. 2023;23(1):174. https://doi.org/10.1186/s12866-023-02915-9
Опубликован
2025-03-25
Как цитировать
Евдокимова Н. В., Черненькая Т. В. . . Микробный метаболом кишечника: современные данные и перспективы практического применения // Патологическая физиология и экспериментальная терапия. 2025. Т. 69. № 1. С. 102–110.
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