The short-chain fatty acids and their role in the microbiota – gut – brain axis

  • Anastasiya S. Lyulya Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus
  • Sergei V. Fedorovich Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus

Abstract

Disruption of the microbiota – gut – brain axis may contribute to the pathogenesis of various diseases of the central nervous system, such as Alzheimer’s disease, Parkinson’s disease, depression, autism spectrum disorders and etc. There are several way of communication between the gut and the brain. One of them is the synthesis of bacterial metabolites, which cause a directly influence brain cells. Key metabolites with such properties include short-chain fatty acids. They is synthesised by the microbiome primarily from dietary fiber. The main short-chain fatty acids in the microbiota – gut – brain axis are propionic and butyric acids. In general, it is believed that propionic acid has a mainly neurotoxic effect, and butyric acid is neuroprotective. But at the same time, such a division is rather conditional. Both compounds are able to penetrate the blood-brain barrier. Their concentration in cerebrospinal fluid and blood plasma, according to most studies, varies in the range of 2–20 µmol/L, but in some pathologies it can rise up to 5 mmol/L. The action of short-chain fatty acids on the cells in nervous system is mediated generally by specific G-protein coupled receptors and epigenetic mechanisms. However, it cannot be ruled out that other potential signaling pathways are involved in the action of short-chain fatty acids on neurons. Deciphering the mechanisms of neuron regulation by propionic and butyric acids provides possibility to identify new pharmacological targets for the treatment of various brain diseases.

Author Biographies

Anastasiya S. Lyulya, Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus

postgraduate student at the department of biochemistry, faculty of biology

 

Sergei V. Fedorovich, Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus

PhD (biology), docent; associate professor at the department of biochemistry, faculty of biology

 

References

  1. Chernevskaya ЕA, Beloborodova NV. Mikrobiota kishechnika pri kriticheskikh sostoyaniyakh (obzor) = Gut microbiome in critical illness (review). General Reanimatology. 2018;14(5):96–119. Russian, English. DOI: 10.15360/1813-9779-2018-5-96-119.
  2. Kandsperger S, Brunner R, Rupprecht R, Baghai TC. Depressive Störungen in der Adoleszenz: aktuelle Studienlage zur Mikrobiota-Darm-Hirn-Achse. Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie. 2023;51(6):419–428. DOI: 10.1024/1422-4917/a000917.
  3. Derrien M, Collado MC, Ben-Amor K, Salminen S, de Vos WM. The mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Applied and Environmental Microbiology. 2008;74(5):1646–1648. DOI: 10.1128/AEM.01226-07.
  4. Barki N, Bolognini D, Börjesson U, Jenkins L, Riddell J, Hughes D, et al. Chemogenetics defines a short-chain fatty acid receptor gut – brain axis. eLife. 2022;11:e73777. DOI: 10.7554/eLife.73777.
  5. Fock E, Parnova R. Mechanisms of blood – brain barrier protection by microbiota-derived short-chain fatty acids. Cells. 2023;12(4):657. DOI: 10.3390/cells12040657.
  6. Gorlova EA. Microbiota and intellect. University Therapeutic Journal. 2021;3(2):39–47. Russian.
  7. Kim Y-K, Shin C. The microbiota – gut – brain axis in neuropsychiatric disorders: pathophysiological mechanisms and novel treatments. Current Neuropharmacology. 2018;16(5):559–573. DOI: 10.2174/1570159X15666170915141036.
  8. Ney L-M, Wipplinger M, Grossmann M, Engert N, Wegner VD, Mosig AS. Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections. Open Biology. 2023;13(3):230014. DOI: 10.1098/rsob.230014.
  9. Del Colle A, Israelyan N, Gross Margolis K. Novel aspects of enteric serotonergic signaling in health and brain – gut disease. Gastrointestinal and Liver Physiology. 2020;318(1):G130–G143. DOI: 10.1152/ajpgi.00173.2019.
  10. Reigstad CS, Salmonson CE, Rainey JF 3rd, Szurszewski JH, Linden DR, Sonnenburg JL, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. The FASEB Journal. 2015;29(4):1395–1403. DOI: 10.1096/fj.14-259598.
  11. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264–276. DOI: 10.1016/j.cell.2015.02.047.
  12. Chen T, Long W, Zhang C, Liu S, Zhao L, Hamaker BR. Fiber-utilizing capacity varies in Prevotella-versus Bacteroides-dominated gut microbiota. Scientific Reports. 2017;7:2594. DOI: 10.1038/s41598-017-02995-4.
  13. Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de los Reyes-Gavilán CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Frontiers in Microbiology. 2016;7:185. DOI: 10.3389/fmicb.2016.00185.
  14. Venegas DP, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Frontiers in Immunology. 2019;10:277. DOI: 10.3389/fimmu.2019.00277.
  15. Blaak EE, Canfora EE, Theis S, Frost G, Groen AK, Mithieux G, et al. Short chain fatty acids in human gut and metabolic health. Beneficial Microbes. 2020;11(5):411–455. DOI: 10.3920/BM2020.0057.
  16. Chevalier AC, Rosenberger TA. Increasing acetyl-CoA metabolism attenuates injury and alters spinal cord lipid content in mice subjected to experimental autoimmune encephalomyelitis. Journal of Neurochemistry. 2017;141(5):721–737. DOI: 10.1111/jnc.14032.
  17. Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiology Letters. 2009;294(1):1–8. DOI: 10.1111/j.1574-6968.2009.01514.x.
  18. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environmental Microbiology. 2017;19(1):29–41. DOI: 10.1111/1462-2920.13589.
  19. Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. mBio. 2014;5(2):e00889-14. DOI: 10.1128/mBio.00889-14.
  20. Champ MMJ. Physiological aspects of resistant starch and in vivo measurements. Journal of AOAC International. 2004;87(3):749–755. PMID: 15287675.
  21. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota – gut – brain communication. Nature Reviews Gastroenterology and Hepatology. 2019;16(8):461–478. DOI: 10.1038/s41575-019-0157-3.
  22. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud D-J, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Journal of Lipid Research. 2013;54(9):2325–2340. DOI: 10.1194/jlr.R036012.
  23. Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987;28(10):1221–1227. DOI: 10.1136/gut.28.10.1221.
  24. Duncan SH, Barcenilla A, Stewart CS, Pryde SE, Flint HJ. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Applied and Environmental Microbiology. 2002;68(10):5186–5190. DOI: 10.1128/AEM.68.10.5186-5190.2002.
  25. Duncan SH, Holtrop G, Lobley GE, Calder AG, Stewart CS, Flint HJ. Contribution of acetate to butyrate formation by human faecal bacteria. British Journal of Nutrition. 2004;91(6):915–923. DOI: 10.1079/BJN20041150.
  26. Miller TL, Wolin MJ. Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Applied and Environmental Microbiology. 1996;62(5):1589–1592. DOI: 10.1128/aem.62.5.1589-1592.1996.
  27. Buey B, Forcén A, Grasa L, Layunta E, Mesonero JE, Latorre E. Gut microbiota-derived short-chain fatty acids: novel regulators of intestinal serotonin transporter. Life. 2023;13(5):1085. DOI: 10.3390/life13051085.
  28. Killingsworth J, Sawmiller D, Shytle RD. Propionate and Alzheimer’s disease. Frontiers in Aging Neuroscience. 2020;12:580001. DOI: 10.3389/fnagi.2020.580001.
  29. O’Riordan KJ, Collins MK, Moloney GM, Knox EG, Aburto MR, Fülling C, et al. Short chain fatty acids: microbial metabolites for gut – brain axis signaling. Molecular and Cellular Endocrinology. 2022;546:111572. DOI: 10.1016/j.mce.2022.111572.
  30. Alruways MW. Impact of the exercise on the gut microbiota and short-chain fatty acids (SCFAs) production. Progress in Nutrition. 2023;25(1):e2023010. DOI: 10.23751/pn.v25i1.13614.
  31. Silva YP, Bernardi A, Frozza RL. The role of short-chain fatty acids from gut microbiota in gut – brain communication. Frontiers in Endocrinology. 2020;11:25. DOI: 10.3389/fendo.2020.00025.
  32. Mirzaei R, Bouzari B, Hosseini-Fard SR, Mazaheri M, Ahmadyousefi Y, Abdi M, et al. Role of microbiota-derived short-chain fatty acids in nervous system disorders. Biomedicine and Pharmacotherapy. 2021;139:111661. DOI: 10.1016/j.biopha.2021.111661.
  33. Sun J, Ling Z, Wang F, Chen W, Li H, Jin J, et al. Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. Neuroscience Letters. 2016;613:30–35. DOI: 10.1016/j.neulet.2015.12.047.
  34. Haijes HA, Jans JJM, Tas SY, Verhoeven-Duif NM, van Hasselt PM. Pathophysiology of propionic and methylmalonic acidemias. Part 1, Complications. Journal of Inherited Metabolic Disease. 2019;42(5):730–744. DOI: 10.1002/jimd.12129.
  35. Scholl-Bürgi S, Sass JO, Zschocke J, Karall D. Amino acid metabolism in patients with propionic acidaemia. Journal of Inherited Metabolic Disease. 2012;35(1):65–70. DOI: 10.1007/s10545-010-9245-9.
  36. Bourassa MW, Alim I, Bultman SJ, Ratan RR. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health? Neuroscience Letters. 2016;625:56–63. DOI: 10.1016/j.neulet.2016.02.009.
  37. Grüter T, Mohamad N, Rilke N, Blusch A, Sgodzai M, Demir S, et al. Propionate exerts neuroprotective and neuroregenerative effects in the peripheral nervous system. PNAS. 2023;120(4):e2216941120. DOI: 10.1073/pnas.2216941120.
  38. Yatskevich EV, Jawad M, Fedorovich SV. Influence of propionic and butyric acids on lipid peroxidation in rat brain and liver homogenates. Experimental Biology and Biotechnology. 2023;1:26–32. Russian.
  39. Serger E, Luengo-Gutierrez L, Chadwick JS, Kong G, Zhou L, Crawford G, et al. The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature. 2022;607(7919):585–592. DOI: 10.1038/s41586-022-04884-x.
  40. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, et al. The gut microbiota influences blood – brain barrier permeability in mice. Science Translational Medicine. 2014;6(263):263ra158. DOI: 10.1126/scitranslmed.3009759.
  41. Dinan TG, Cryan JF. Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. The Journal of Physiology. 2017;595(2):489–503. DOI: 10.1113/JP273106.
  42. Hoyles L, Snelling T, Umlai U-K, Nicholson JK, Carding SR, Glen RC, et al. Microbiome – host systems interactions: protective effects of propionate upon the blood – brain barrier. Microbiome. 2018;6:55. DOI: 10.1186/s40168-018-0439-y.
  43. Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 2017;1863(2):585–597. DOI: 10.1016/j.bbadis.2016.11.005.
  44. Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2018;1865(5):721–733. DOI: 10.1016/j.bbamcr.2018.02.010.
  45. Bachmann C, Colombo J-P, Berüter J. Short chain fatty acids in plasma and brain: quantitative determination by gas chromatography. Clinica Chimica Acta. 1979;92(2):153–159. DOI: 10.1016/0009-8981(79)90109-8.
  46. Halestrap AP, Wilson MC. The monocarboxylate transporter family – role and regulation. IUBMB Life. 2012;64(2):109–119. DOI: 10.1002/iub.572.
  47. Guo C, Huo Y-J, Li Y, Han Y, Zhou D. Gut – brain axis: focus on gut metabolites short-chain fatty acids. World Journal of Clinical Cases. 2022;10(6):1754–1763. DOI: 10.12998/wjcc.v10.i6.1754.
  48. Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, et al. GPR109a is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Research. 2009;69(7):2826–2832. DOI: 10.1158/0008-5472.can-08-4466.
  49. Priyadarshini M, Kotlo KU, Dudeja PK, Layden BT. Role of short chain fatty acid receptors in intestinal physiology and pathophysiology. Comprehensive Physiology. 2018;8(3):1091–1115. DOI: 10.1002/cphy.c170050.
  50. Erny D, Jaitin D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nature Neuroscience. 2015;18(7):965–977. DOI: 10.1038/nn.4030.
  51. Zubareva OE, Melik-Kasumov TB. The gut – brain axis and peroxisome proliferator-activated receptors in the regulation of epileptogenesis. Zhurnal evolyutsionnoi biokhimii i fiziologii. 2021;57(4):273–288. Russian. DOI: 10.31857/s0044452921040070.
  52. Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science. 2010;330(6004):622–627. DOI: 10.1126/science.1190614.
  53. Gupta R, Ambasta RK, Kumar P. Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders. Life Sciences. 2020;243:117278. DOI: 10.1016/j.lfs.2020.117278.
  54. González-Bosch C, Boorman E, Zunszain PA, Mann GE. Short-chain fatty acids as modulators of redox signaling in health and disease. Redox Biology. 2021;47:102165. DOI: 10.1016/j.redox.2021.102165.
  55. Zefirov AL, Mukhametzyanov RD, Zakharov AV, Mukhutdinova KA, Odnoshivkina UG, Petrov AM. Intracellular acidification suppresses synaptic vesicle mobilization in the motor nerve terminals. Acta Naturae. 2020;12(4):105–113. DOI: 10.32607/actanaturae.11054.
  56. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. The microbiota – gut – brain axis. Physiological Reviews. 2019;99(4):1877–2013. DOI: 10.1152/physrev.00018.2018.
Published
2024-03-05
Keywords: microbiota – gut – brain axis, short-chain fatty acids, bacterial metabolites, propionic acid, butyric acid, brain
Supporting Agencies This work was supported by Belarusian State University rector’s grant (S. V. Fedorovich).
How to Cite
Lyulya, A. S., & Fedorovich, S. V. (2024). The short-chain fatty acids and their role in the microbiota – gut – brain axis. Experimental Biology and Biotechnology, 1, 77-85. Retrieved from https://journals.bsu.by/index.php/biology/article/view/5679