Changes in the synthesis of short-chain fatty acids under the influence of various factors in healthy people and patients with type 2 diabetes mellitus

• Tatyana Yu. Demidova
• Anna S. Teplova

Abstract

Short-chain fatty acids (SCFAs) are an important link in the maintenance and normalization of some important body functions. Recently, the metabolic component of the SCFAs effects has also been actively studied; the effect on body weight, insulin resistance and glycemia is of particular interest in the context of the prevention and treatment of carbohydrate metabolism disorders. In this regard, it is relevant to study the characteristics of SCFAs’ production in patients with impaired carbohydrate metabolism, mainly with type 2 diabetes mellitus (T2DM).

The purpose of the research was to study the modern data on the synthesis peculiarities of SCFAs in healthy people and patients with impaired carbohydrate metabolism.

Material and methods. The data of domestic and foreign literature presented in PubMed, Google Scholar, ResearchGate, Elsevier, eLibrary, CyberLeninka databases, published mainly over the past 10 years, have been analyzed.

Results. According to the concept of the philometabolic nucleus, bacteria of certain species, which are of the greatest importance compared to the rest, are responsible for the synthesis of specific SCFAs. The gut microbiota (GM) has the property of plasticity – the ability to change its composition under the influence of various factors. Most studies describe the effect of GM and its metabolites on the carbohydrate metabolism, but an equally important aspect of this process is the effect of carbohydrate metabolism disorders on GM and its functional activity. In case of disorders of carbohydrate metabolism, some altered components of homeostasis negatively affect GM and its production of SCFAs. As a result, the total amount and variety of SCFAs decrease, which exacerbate the imbalance in relation to carbohydrate metabolism. There is evidence that in patients with T2DM, the concentration of butyrate, which has a positive effect on insulin resistance, body weight, fasting glycemia and postprandial glycemia, decreases. The concentration of propionate and acetate, which didn’t show such a pronounced positive effect in studies on carbohydrate metabolism, on the contrary, increases.

Conclusion. The production of SCFAs by GM representatives depends on many factors, such as nutrition, physical activity, medication intake and the presence of chronic diseases. Numerous studies have confirmed the difference in the characteristics of the production of SCFAs in patients with T2DM and healthy people. The study of the peculiarities of GM metabolism in patients with T2DM is a tool in understanding the basics of therapy and lifestyle correction in both patients with T2DM and healthy people in order to prevent disorders of carbohydrate metabolism.

Keywords:short-chain fatty acids; gut microbiota; diabetes mellitus; hypoglycemic drugs

References

1. Ardatskaya M.D. The role of low molecular weight metabolites of the intestinal microbiota in the pathogenesis, diagnosis and prevention of colorectal cancer. Eksperimental’naya i klinicheskaya gastoenterologiya [Experimental and Clinical Gastroenterology]. 2017; (3): 13–21. (in Russian)

2. Svirin V.V., Bogdanova O.V., Ardatskaya M.D. Dynamics of oral microbiocenosis in inflammatory periodontal diseases and assessment of its correction possibility. Meditsinskiy alfavit [Medical Alphabet]. 2018; 2 (8): 14–20. (in Russian)

3. Leonov G.E., Varaeva Yu.R., Livantsova E.N., Starodubova A.V. The oral microbiome in the context of systemic disease. Voprosy pitaniia [Problems of Nutrition]. 2023; 92 (4): 6–19. DOI: https://doi.org/10.33029/0042-8833-2023-92-4-6-19 (in Russian)

4. Treneva E., Bulgakova S., Romanchuk P., Zakharova N., Sirotko I. The brain and microbiota: neuroendocrine and geriatric aspects. Byulleten’ nauki i praktiki [Bulletin of Science and Practice]. 2019; 5 (9): 26–52. DOI: https://doi.org/10.33619/2414-2948/46/03 (in Russian)

5. Zol’nikova O.Yu., Potskhverashvili N.D., Kokina N.I., Trukhmanov A.S., Ivashkin V.T. Intestinal short-chain fatty acids in patients with bronchial asthma. Rossiyskiy zhurnal gastroenterologii, gepatologii, koloproktologii [Russian Journal of Gastroenterology, Hepatology, Coloproctology]. 2019; 29 (2): 53–9. DOI: https://doi.org/10.22416/1382-4376-2019-29-2-53-59 (in Russian)

6. Nogal A., Asnicar F., Vijay A., Kouraki A., Visconti A., Louca P., et al. Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation. Gut Microbes. 2023; 15 (1): 2240050. DOI: https://doi.org/10.1080/19490976.2023.2240050

7. Anachad O., Taouil A., Taha W., Bennis F., Chegdani F. The implication of short-chain fatty acids in obesity and diabetes. Microbiol Insights. 2023; 16: 11786361231162720. DOI: https://doi.org/10.1177/11786361231162720

8. Sheveleva S.A., Kuvaeva I.B., Efimochkina N.R., Markova Yu.M., Prosyannikov M.Yu. Gut microbiome: from the reference of the norm to pathology. Voprosy pitaniia [Problems of Nutrition]. 2020; 89 (4): 35–51. DOI: https://doi.org/10.24411/0042-8833-2020-10040 (in Russian)

9. Ardatskaya M.D. Excessive bacterial growth syndrome in small intestine up-to-date diagnostics methods and approaches to therapeutic correction. Meditsinskiy sovet [Medical Council]. 2016; (14): 88–95. DOI: https://doi.org/10.21518/2079-701X-2016-14-88-95 (in Russian)

10. Arumugam M., Raes J., Pelletier E., Le Paslier D., Yamada T., Mende D.R., et al. Enterotypes of the human gut microbiome. Nature. 2011; 473 (7346): 174–80. DOI: https://doi.org/10.1038/nature09944

11. Becattini S., Sorbara M.T., Kim S.G., Littmann E.L., Dong Q., Walsh G., et al. Rapid transcriptional and metabolic adaptation of intestinal microbes to host immune activation. Cell Host Microbe. 2021; 29 (3): 378–93.e5. DOI: https://doi.org/10.1016/j.chom.2021.01.003

12. Liu Y., Wang Y., Ni Y., Cheung C.K., Lam K.S., Wang Y., et al. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metab. 2020; 31 (1): 77–91.e5. DOI: https://doi.org/10.1016/j.cmet.2019.11.001

13. Park J., Bushita H., Nakano A., Hara A., Ueno H.M., Ozato N., et al. Ramen consumption and gut microbiota diversity in Japanese women: cross-sectional data from the NEXIS cohort study. Microorganisms. 2023; 11 (8): 1892. DOI: https://doi.org/10.3390/microorganisms11081892

14. Almanza-Aguilera E., Cano A., Gil-Lespinard M., Burguera N., Zamora-Ros R., Agudo A., et al. Mediterranean diet and olive oil, microbiota, and obesity-related cancers. From mechanisms to prevention. Semin Cancer Biol. 2023; 95: 103–19. DOI: https://doi.org/10.1016/j.semcancer.2023.08.001

15. Zhang L., Liu Y., Wang X., Zhang X. Physical exercise and diet: regulation of gut microbiota to prevent and treat metabolic disorders to maintain health. Nutrients. 2023: 15 (6): 1539. DOI: https://doi.org/10.3390/nu15061539

16. Bica I.C., Pietroșel V.A., Salmen T., Diaconu C.T., Fierbinteanu Braticevici C., Stoica R.A., et al. The effects of cardioprotective antidiabetic therapy on microbiota in patients with type 2 diabetes mellitus – a systematic review. Int J Mol Sci. 2023; 24 (8): 7184. DOI: https://doi.org/10.3390/ijms24087184

17. Bragina T.V., Sheveleva S.A., Elizarova E.V., Rykova S.M., Tutelyan V.A. The structure of blood gut microbiota markers in athletes and their relationship with the diet. Voprosy pitaniia [Problems of Nutrition]. 2022; 91 (4): 35–46. DOI: https://doi.org/10.33029/0042-8833-2022-91-4-35-46 (in Russian)

18. Barton W., Penney N.C., Cronin O., Garcia-Perez I., Molloy M.G., Holmes E., et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut. 2018; 67: 625–33. DOI: https://doi.org/10.1136/gutjnl-2016-313627

19. Choi J.J., Eum S.Y., Rampersaud E., Daunert S., Abreu M.T., Toborek M. Exercise attenuates PCB-induced changes in the mouse gut microbiome. Environ Health Perspect. 2013; 121 (6): 725–30. DOI: https://doi.org/10.1289/ehp.1306534

20. Dalton A., Mermier C., Zuhl M. Exercise influence on the microbiome-gut-brain axis. Gut Microbes. 2019; 10 (5): 555–68. DOI: https://doi.org/10.1080/19490976.2018.1562268

21. Harbison J.E., Thomson R.L., Wentworth J.M., Louise J., Roth-Schulze A., Battersby R.J., et al. Associations between diet, the gut microbiome and short chain fatty acids in youth with islet autoimmunity and type 1 diabetes. Pediatr Diabetes. 2021; 22 (3): 425–33. DOI: https://doi.org/10.1111/pedi.13178

22. Nagpal R., Neth B.J., Wang S., Craft S., Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. EBioMedicine. 2019; 47: 529–42. DOI: https://doi.org/10.1016/j.ebiom.2019.08.032

23. Procházková N., Venlet N., Hansen M.L., Lieberoth C.B., Dragsted L.O., Bahl M.I., et al. Effects of a wholegrain-rich diet on markers of colonic fermentation and bowel function and their associations with the gut microbiome: a randomised controlled cross-over trial. Front Nutr. 2023; 10: 1187165. DOI: https://doi.org/10.3389/fnut.2023.1187165

24. Tan J., Ribeiro R., Barker C., Daien C., De Abreu Silveira E., Holmes A., et al. Functional profiling of gut microbial and immune responses toward different types of dietary fiber: a step toward personalized dietary interventions. Gut Microbes. 2023; 15 (2): 2274127. DOI: https://doi.org/10.1080/19490976.2023.2274127

25. Devarakonda S., Superdock D., Ren J., Johnson L., Loinard-Gonz Lez A., Poole A. Gut microbial features and dietary fiber intake predict gut microbiota response to resistant starch supplementation. medRxiv. [Preprint]. 2023: 23287665. DOI: https://doi.org/10.1101/2023.03.24.23287665

26. Egshatyan L.V., Kushkhanashkhova D.A., Ermilova E.S., Askerkhanov R.G. Gut microbiota in obese patients and after bariatric surgery. Endokrinnaya khirurgiya [Endocrine Surgery]. 2019; 13 (1): 5–16. DOI: https://doi.org/https://doi.org/10.14341/serg10112 (in Russian)

27. Kettle H., Donnelly R., Flint H.J., Marion G. pH feedback and phenotypic diversity within bacterial functional groups of the human gut. J Theor Biol. 2014; 342: 62–9. DOI: https://doi.org/10.1016/j.jtbi.2013.10.015

28. Furet J.P., Kong L.C., Tap J., Poitou C., Basdevant A., Bouillot J., et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010; 59 (12): 3049–57. DOI: https://doi.org/10.2337/db10-0253

29. Schwartz S.S., Epstein S., Corkey B., Grant S., Gavin J., Aguilar R. The time is right for a new classification system for diabetes: rationale and implications of the β-cell – centric classification schema. Diabetes Care. 2016; 39 (2): 179–86. DOI: https://doi.org/10.2337/dc15-1585

30. Ramirez J., Guarner F., Bustos Fernandez L., Maruy A., Sdepanian V.L., Cohen H. Antibiotics as major disruptors of gut microbiota. Front Cell Infect Microbiol. 2020; 10: 572912. DOI: https://doi.org/10.3389/fcimb.2020.572912

31. Liu W., Luo Z., Zhou J., Sun B. Gut microbiota and antidiabetic drugs: perspectives of personalized treatment in type 2 diabetes mellitus. Front Cell Infect Microbiol. 2022; 12: 853771. DOI: https://doi.org/10.3389/fcimb.2022.853771

32. Creely S.J., McTernan P.G., Kusminski C.M., Fisher F.M., Da Silva N.F., Khanolkar M., et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007; 292 (3): E740–7. DOI: https://doi.org/10.1152/ajpendo.00302.2006

33. Zhao L., Zhang F., Ding X., Wu G., Lam Y.Y., Wang X., et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018; 359: 1151–6. DOI: https://doi.org/10.1126/science.aao5774

34. Demidova T.Y., Lobanova K.G., Oynotkinova O.S. Gut microbiota is a factor of risk for obesity and type 2 diabetes. Terapevticheskiy arkhiv [Therapeutic Archive]. 2020; 92 (10): 97–104. DOI: https://doi.org/10.26442/00403660.2020.10.000778 (in Russian)

35. Hamer H.M., Jonkers D., Venema K., Vanhoutvin S., Troost F.J., Brumme R.J. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008; 27 (2): 104–19. DOI: https://doi.org/10.1111/j.1365-2036.2007.03562.x

36. Chassaing B., Raja S.M., Lewis J.D., Srinivasan S., Gewirtz A.T. Colonic microbiota encroachment correlates with dysglycemia in humans. Cell Mol Gastroenterol Hepatol. 2017; 4 (2): 205–21. DOI: https://doi.org/10.1016/j.jcmgh.2017.04.001

37. Yadav H., Lee J.H., Lloyd J., Walter P., Rane S.G. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem. 2013; 288 (35): 25 088–97. DOI: https://doi.org/10.1074/jbc.M113.452516

38. Schwiertz A., Taras D., Schäfer K., Beijer S., Bos N.A., Donus C., et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring). 2010; 18 (1): 190–5. DOI: https://doi.org/10.1038/oby.2009.167

39. Arora T., Tremaroli V. Therapeutic potential of butyrate for treatment of type 2 diabetes. Front Endocrinol (Lausanne). 2021; 12: 761834. DOI: https://doi.org/10.3389/fendo.2021.761834

40. Reitmeier S., Kiessling S., Clavel T., List M., Almeida E.L., Ghosh T.S., et al. Arrhythmic gut microbiome signatures predict risk of type 2 diabetes. Cell Host Microbe. 2020; 28 (2): 258–72.e6. DOI: https://doi.org/10.1016/j.chom.2020.06.004

41. Beloglazov V.A., Yatskov I.A., Kumel’sky E.D., Polovinkina V.V. Metabolic endotoxemia: possible causes and consequences. Ozhirenie i metabolism [Obesity and Metabolism]. 2021; 18 (3): 320–6. DOI: https://doi.org/10.14341/omet12750 (in Russian)

42. Cani P.D., Amar J., Iglesias M.A., Poggi M., Knau C., Bastelica D., et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56 (7): 1761–72. DOI: https://doi.org/10.2337/db06-1491

43. Forslund K., Hildebrand F., Nielsen T., Falony G., Chatelier E., Sunagawa S., et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015; 528: 262–6. DOI: https://doi.org/10.1038/nature15766

44. Zhang M., Yang X.J. Effects of a high fat diet on intestinal microbiota and gastrointestinal diseases. World J Gastroenterol. 2016; 22 (40): 8905–9. DOI: https://doi.org/10.3748/wjg.v22.i40.8905

45. Zhang X., Zhao Y., Xu J., Xue Z., Zhang M., Pang X., et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015; 5: 14405. DOI: https://doi.org/10.1038/srep14405

46. De la Cuesta-Zuluaga J., Mueller N.T., Corrales-Agudelo V., Velasquez-Mejía E.P., Carmona J.A., Abad J.M., et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017; 40 (1): 54–62. DOI: https://doi.org/10.2337/dc16-1324

47. Shin N.R., Lee J.C., Lee H.Y., Kim M.S., Whon T.W., Lee M.S., et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014; 63 (5): 727–35. DOI: https://doi.org/10.1136/gutjnl-2012-303839

48. Wu H., Esteve E., Tremaroli V., Khan M.T., Caesar R., Manneras-Holm L., et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017; 23 (7): 850–8. DOI: https://doi.org/10.1038/nm.4345

49. Bonora E., Cigolini M., Bosello O., Zancanaro C., Capretti L., Zavaroni I., et al. Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects. Curr Med Res Opin. 1984; 9 (1): 47–51. DOI: https://doi.org/10.1185/03007998409109558

50. Louis P., Flint H.J. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017; 19 (1): 29–41. DOI: https://doi.org/10.1111/1462-2920.13589

51. Zhu L. B., Zhang Y. C., Huang H. H., Lin J. Prospects for clinical applications of butyrate-producing bacteria. World J Clin Pediatr. 2021; 10 (5): 84–92. DOI: https://doi.org/10.5409/wjcp.v10.i5.84

52. Wang L., Li P., Tang Z., Yan X., Feng B. Structural modulation of the gut microbiota and the relationship with body weight: compared evaluation of liraglutide and saxagliptin treatment. Sci Rep. 2016; 6: 33251. DOI: https://doi.org/10.1038/srep33251

53. Zhang Q., Xiao X., Li M., Yu M., Ping F., Zheng J., et al. Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats. PLoS One. 2017; 12 (10): e0184735 DOI: https://doi.org/10.1371/journal.pone.0184735

54. Yan X., Feng B., Li P., Tang Z., Wang L. Microflora disturbance during progression of glucose intolerance and effect of sitagliptin: an animal study. J Diabetes Res. 2016; 2016: 2093171. DOI: https://doi.org/10.1155/2016/2093171

55. Deng L., Yang Y., Xu G. Empagliflozin ameliorates type 2 diabetes mellitus-related diabetic nephropathy via altering the gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids. 2022; 1867 (12): 159234. DOI: https://doi.org/10.1016/j.bbalip.2022.159234

56. Hata S., Okamura T., Kobayashi A., Bamba R., Miyoshi T., Nakajima H., et al. Gut microbiota changes by an SGLT2 inhibitor, luseogliflozin, alters metabolites compared with those in a low carbohydrate diet in db/db mice. Nutrients. 2022; 14 (17): 3531. DOI: https://doi.org/10.3390/nu14173531

57. Lehmann A., Hornby P.J. Intestinal SGLT1 in metabolic health and disease. Am J Physiol Gastrointest Liver Physiol. 2016; 310 (11): G887–98. DOI: https://doi.org/10.1152/ajpgi.00068.2016

58. Wang L., Liang C., Song X., Jia X., Wang X., Zhang Y., et al. Canagliflozin alters the gut, oral, and ocular surface microbiota of patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2023; 14: 1256292. DOI: https://doi.org/10.3389/fendo.2023.1256292

59. Huo T., Xiong Z., Lu X., Cai S. Metabonomic study of biochemical changes in urinary of type 2 diabetes mellitus patients after the treatment of sulfonylurea antidiabetic drugs based on ultra-performance liquid chromatography/mass spectrometry. Biomed Chromatogr. 2015; 29 (1): 115–22. DOI: https://doi.org/10.1002/bmc.3247

60. Bai J., Zhu Y., Dong Y. Response of gut microbiota and inflammatory status to bitter melon (Momordica charantia L.) in high fat diet induced obese rats. J Ethnopharmacol. 2016; 194: 717–26. DOI: https://doi.org/10.1016/j.jep.2016.10.043

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)