Published Apr 30, 2022

Kenji Fukushima  


The gut microbiota is highly capable of biotransformation, exposing the host to a wide variety of physiologically active compounds. These metabolites participate in signaling between the gastrointestinal tract and the central nervous system and may regulate physiological and pathological processes in the central nervous system. This bidirectional communication can take place in a variety of ways, including binding to receptors in the host brain, stimulating the vagus nerve in the gut, modifying central neurotransmission, and influencing neuroinflam- mation. The purpose of this article is to discuss the mechanism of action of microbial metabolites such as short-chain fatty acids, bile acids, and neurotransmitters in the gut-brain axis and to propose new strategies for treating related neurological illnesses from a gut microbiota regulation perspective.




Gut Microbiota, Metabolites, Gut-Brain Axis, Central Nervous System, Neuromodulation

1. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J 2017; 474(11):1823-1836. DOI: https://doi.org/10.1042/BCJ20160510

2. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 2015; 28(2):203-209.

3. Dicks LMT, Hurn D, Hermanus D. Gut bacteria and neuropsychiatric disorders. Microorganisms 2021; 9(12):2583. DOI: https://doi.org/10.3390/microorganisms9122583

4. Clapp M, Aurora N, Herrera L, Bhatia M, Wilen E, Wakefield S. Gut microbiota's effect on mental health: The gut-brain axis. Clin Pract 2017; 7(4):987. DOI: https://doi.org/10.4081/cp.2017.987

5. Rios-Covian D, González S, Nogacka AM, Arboleya S, Salazar N, Gueimonde M, de Los Reyes-Gavilán CG. An overview on fecal branched short-chain fatty acids along human life and as related with body mass index: Associated dietary and anthropometric factors. Front Microbiol 2020; 11:973. DOI: https://doi.org/10.3389/fmicb.2020.00973

6. Hills RD Jr, Pontefract BA, Mishcon HR, Black CA, Sutton SC, Theberge CR. Gut Microbiome: Profound Implications for Diet and Disease. Nutrients 2019; 11(7):1613. DOI: https://doi.org/10.3390/nu11071613

7. Tian T, Zhao Y, Yang Y, Wang T, Jin S, Guo J, Liu Z. The protective role of short-chain fatty acids acting as signal molecules in chemotherapy- or radiation-induced intestinal inflammation. Am J Cancer Res 2020; 10(11):3508-3531.

8. Caspani G, Kennedy S, Foster JA, Swann J. Gut microbial metabolites in depression: understanding the biochemical mechanisms. Microb Cell 2019; 6(10):454-481. DOI: https://doi.org/10.15698/mic2019.10.693

9. Averina OV, Zorkina YA, Yunes RA, Kovtun AS, Ushakova VM, Morozova AY, Kostyuk GP, Danilenko VN, Chekhonin VP. Bacterial metabolites of human gut microbiota correlating with depression. Int J Mol Sci 2020; 21(23):9234. DOI: https://doi.org/10.3390/ijms21239234

10. Alagiakrishnan K, Halverson T. Microbial therapeutics in neurocognitive and psychiatric disorders. J Clin Med Res 2021; 13(9):439-459. DOI: https://doi.org/10.14740/jocmr4575

11. Zhu G, Zhao J, Zhang H, Chen W, Wang G. Administration of Bifidobacterium breve improves the brain function of Aβ1-42-treated mice via the modulation of the gut microbiome. Nutrients 2021; 13(5):1602. DOI: https://doi.org/10.3390/nu13051602

12. Metzdorf J, Tönges L. Short-chain fatty acids in the context of Parkinson's disease. Neural Regen Res 2021; 16(10):2015-2016. DOI: https://doi.org/10.4103/1673-5374.308089

13. Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother 2018; 18(1):83-90. DOI: https://doi.org/10.1080/14737175.2018.1400909

14. Sadler R, Cramer JV, Heindl S, Kostidis S, Betz D, Zuurbier KR, Northoff BH, Heijink M, Goldberg MP, Plautz EJ, Roth S, Malik R, Dichgans M, Holdt LM, Benakis C, Giera M, Stowe AM, Liesz A. Short-chain fatty acids improve poststroke recovery via immunological mechanisms. J Neurosci 2020; 40(5):1162-1173. DOI: https://doi.org/10.1523/JNEUROSCI.1359-19.2019

15. Block RC, Dorsey ER, Beck CA, Brenna JT, Shoulson I. Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol 2010; 4(1):17-23. DOI: https://doi.org/10.1016/j.jacl.2009.11.003

16. Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 2019; 10:277. DOI: https://doi.org/10.3389/fimmu.2019.00277. Erratum in: Front Immunol 2019; 10:1486.

17. Sivaprakasam S, Prasad PD, Singh N. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther 2016; 164:144-151. DOI: https://doi.org/10.1016/j.pharmthera.2016.04.007

18. Wang Y, Wang Z, Wang Y, Li F, Jia J, Song X, Qin S, Wang R, Jin F, Kitazato K, Wang Y. The gut-microglia connection: Implications for central nervous system diseases. Front Immunol 2018; 9:2325. DOI: https://doi.org/10.3389/fimmu.2018.02325

19. Wu Y, Wang CZ, Wan JY, Yao H, Yuan CS. Dissecting the interplay mechanism between epigenetics and gut microbiota: Health maintenance and disease prevention. Int J Mol Sci 2021; 22(13):6933. DOI: https://doi.org/10.3390/ijms22136933

20. Silva YP, Bernardi A, Frozza RL. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol (Lausanne) 2020; 11:25. DOI: https://doi.org/10.3389/fendo.2020.00025

21. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012; 61(2):364-371. DOI: https://doi.org/10.2337/db11-1019

22. Larraufie P, Martin-Gallausiaux C, Lapaque N, Dore J, Gribble FM, Reimann F, Blottiere HM. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci Rep 2018; 8(1):74. DOI: https://doi.org/10.1038/s41598-017-18259-0

23. Byrne CS, Chambers ES, Morrison DJ, Frost G. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int J Obes (Lond) 2015; 39(9):1331-1338. DOI: https://doi.org/10.1038/ijo.2015.84

24. van Son J, Koekkoek LL, La Fleur SE, Serlie MJ, Nieuwdorp M. The role of the gut microbiota in the gut-brain axis in obesity: Mechanisms and future implications. Int J Mol Sci 2021; 22(6):2993. DOI: https://doi.org/10.3390/ijms22062993

25. Yu KB, Hsiao EY. Roles for the gut microbiota in regulating neuronal feeding circuits. J Clin Invest 2021; 131(10):e143772. DOI: https://doi.org/10.1172/JCI143772

26. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, Anastasovska J, Ghourab S, Hankir M, Zhang S, Carling D, Swann JR, Gibson G, Viardot A, Morrison D, Louise Thomas E, Bell JD. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 2014; 5:3611. DOI: https://doi.org/10.1038/ncomms4611

27. Rutsch A, Kantsjö JB, Ronchi F. The gut-brain axis: How microbiota and host inflammasome influence brain physiology and pathology. Front Immunol 2020; 11:604179. DOI: https://doi.org/10.3389/fimmu.2020.604179

28. Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 2009; 139(9):1619-1625. DOI: https://doi.org/10.3945/jn.109.104638

29. Yue X, Wen S, Long-Kun D, Man Y, Chang S, Min Z, Shuang-Yu L, Xin Q, Jie M, Liang W. Three important short-chain fatty acids (SCFAs) attenuate the inflammatory response induced by 5-FU and maintain the integrity of intestinal mucosal tight junction. BMC Immunol 2022; 23(1):19. DOI: https://doi.org/10.1186/s12865-022-00495-3

30. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 2016; 7(1):22-39. DOI: https://doi.org/10.1080/19490976.2015.1127483. Erratum in: Gut Microbes 2016;7(3):262.

31. Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol 2017; 101(1):47-64. DOI: https://doi.org/10.1007/s00253-016-8006-6

32. Vítek L, Haluzík M. The role of bile acids in metabolic regulation. J Endocrinol 2016; 228(3):R85-R96. DOI: https://doi.org/10.1530/JOE-15-0469

33. Taoka H, Yokoyama Y, Morimoto K, Kitamura N, Tanigaki T, Takashina Y, Tsubota K, Watanabe M. Role of bile acids in the regulation of the metabolic pathways. World J Diabetes 2016; 7(13):260-270. DOI: https://doi.org/10.4239/wjd.v7.i13.260

34. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009; 89(1):147-191. DOI: https://doi.org/10.1152/physrev.00010.2008
35. Nie YF, Hu J, Yan XH. Cross-talk between bile acids and intestinal microbiota in host metabolism and health. J Zhejiang Univ Sci B 2015; 16(6):436-446. DOI: https://doi.org/10.1631/jzus.B1400327

36. Vasile F, Dossi E, Rouach N. Human astrocytes: Structure and functions in the healthy brain. Brain Struct Funct 2017; 222(5):2017-2029. DOI: https://doi.org/10.1007/s00429-017-1383-5

37. Mertens KL, Kalsbeek A, Soeters MR, Eggink HM. Bile acid signaling pathways from the enterohepatic circulation to the central nervous system. Front Neurosci 2017; 11:617. DOI: https://doi.org/10.3389/fnins.2017.00617

38. Huang F, Wang T, Lan Y, Yang L, Pan W, Zhu Y, Lv B, Wei Y, Shi H, Wu H, Zhang B, Wang J, Duan X, Hu Z, Wu X. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior. Front Behav Neurosci 2015; 9:70. DOI: https://doi.org/10.3389/fnbeh.2015.00070

39. Mulak A. Bile acids as key modulators of the brain-gut-microbiota axis in Alzheimer’s disease. J Alzheimers Dis 2021; 84(2):461-477. DOI: https://doi.org/10.3233/JAD-210608

40. Palmela I, Correia L, Silva RF, Sasaki H, Kim KS, Brites D, Brito MA. Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study. Front Neurosci 2015; 9:80. DOI: https://doi.org/10.3389/fnins.2015.00080

41. Joo SS, Kang HC, Won TJ, Lee DI. Ursodeoxycholic acid inhibits pro-inflammatory repertoires, IL-1 beta and nitric oxide in rat microglia. Arch Pharm Res 2003; 26(12):1067-1073. DOI: https://doi.org/10.1007/BF02994760

42. Mertens KL, Kalsbeek A, Soeters MR, Eggink HM. Bile acid signaling pathways from the enterohepatic circulation to the central nervous system. Front Neurosci 2017; 11:617. DOI: https://doi.org/10.3389/fnins.2017.00617

43. Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptors in the brain: Controlling food intake and body weight. J Clin Invest 2014; 124(10):4223-4226. DOI: https://doi.org/10.1172/JCI78371

44. Chen P, Li C, Haskell-Luevano C, Cone RD, Smith MS. Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology 1999; 140(6):2645-2650. DOI: https://doi.org/10.1210/endo.140.6.6829

45. Mittal R, Debs LH, Patel AP, Nguyen D, Patel K, O'Connor G, Grati M, Mittal J, Yan D, Eshraghi AA, Deo SK, Daunert S, Liu XZ. Neurotransmitters: The critical modulators regulating gut-brain axis. J Cell Physiol 2017; 232(9):2359-2372. DOI: https://doi.org/10.1002/jcp.25518

46. Barrett E, Ross RP, O'Toole PW, Fitzgerald GF, Stanton C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012; 113(2):411-417. DOI: https://doi.org/10.1111/j.1365-2672.2012.05344.x. Erratum in: J Appl Microbiol 2014; 116(5):1384-1386.

47. Yunes RA, Poluektova EU, Vasileva EV, Odorskaya MV, Marsova MV, Kovalev GI, Danilenko VN. A multi-strain potential probiotic formulation of GABA-producing Lactobacillus plantarum 90sk and Bifidobacterium adolescentis 150 with antidepressant effects. Probiotics Antimicrob Proteins 2020; 12(3):973-979. DOI: https://doi.org/10.1007/s12602-019-09601-1

48. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015; 161(2):264-276. DOI: https://doi.org/10.1016/j.cell.2015.02.047. Erratum in: Cell 2015; 163:258.

49. Stephenson M, Rowatt E. The production of acetylcholine by a strain of Lactobacillus plantarum. J Gen Microbiol 1947; 1(3):279-298. DOI: https://doi.org/10.1099/00221287-1-3-279

50. Galland L. The gut microbiome and the brain. J Med Food 2014; 17(12):1261-1272. DOI: https://doi.org/10.1089/jmf.2014.7000

51. Xiao L, Liu Q, Luo M, Xiong L. Gut microbiota-derived metabolites in irritable bowel syndrome. Front Cell Infect Microbiol 2021; 11:729346. DOI: https://doi.org/10.3389/fcimb.2021.729346

52. van Kessel SP, Frye AK, El-Gendy AO, Castejon M, Keshavarzian A, van Dijk G, El Aidy S. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson's disease. Nat Commun 2019; 10(1):310. DOI: https://doi.org/10.1038/s41467-019-08294-y

53. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 2011; 108(38):16050-16055. DOI: https://doi.org/10.1073/pnas.1102999108

54. Chen Y, Xu J, Chen Y. Regulation of neurotransmitters by the gut microbiota and effects on cognition in neurological disorders. Nutrients 2021; 13(6):2099. DOI: https://doi.org/10.3390/nu13062099

55. Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res 2018; 1693(Pt B):128-133. DOI: https://doi.org/10.1016/j.brainres.2018.03.015

56. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998. 12, Choline. Available at: https://www.ncbi.nlm.nih.gov/books/NBK114308/

57. Cho CE, Aardema NDJ, Bunnell ML, Larson DP, Aguilar SS, Bergeson JR, Malysheva OV, Caudill MA, Lefevre M. Effect of choline forms and gut microbiota composition on trimethylamine-N-oxide response in healthy men. Nutrients 2020; 12(8):2220. DOI: https://doi.org/10.3390/nu12082220

58. Arias N, Arboleya S, Allison J, Kaliszewska A, Higarza SG, Gueimonde M, Arias JL. The relationship between choline bioavailability from diet, intestinal microbiota composition, and its modulation of human diseases. Nutrients 2020; 12(8):2340. DOI: https://doi.org/10.3390/nu12082340

59. 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):e02481. DOI: https://doi.org/10.1128/mBio.02481-14

60. Agagunduz D, Yılmaz B, Şahin TÖ, Güneşliol BE, Ayten Ş, Russo P, Spano G, Rocha JM, Bartkiene E, Özogul F. Dairy lactic acid bacteria and their potential function in dietetics: The food-gut-health axis. Foods 2021; 10(12):3099. DOI: https://doi.org/10.3390/foods10123099

61. Wang Q, Hu Y, Wan J, Dong B, Sun J. Lactate: A novel signaling molecule in synaptic plasticity and drug addiction. Bioessays 2019; 41(8):e1900008. DOI: https://doi.org/10.1002/bies.201900008

62. Descalzi G, Gao V, Steinman MQ, Suzuki A, Alberini CM. Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons. Commun Biol 2019; 2:247. DOI: https://doi.org/10.1038/s42003-019-0495-2

63. Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 2014; 24(10):2784-2795. DOI: https://doi.org/10.1093/cercor/bht136

64. Rooney K, Trayhurn P. Lactate and the GPR81 receptor in metabolic regulation: Implications for adipose tissue function and fatty acid utilisation by muscle during exercise. Br J Nutr 2011; 106(9):1310-1316. DOI: https://doi.org/10.1017/S0007114511004673

65. Ranganathan P, Shanmugam A, Swafford D, Suryawanshi A, Bhattacharjee P, Hussein MS, Koni PA, Prasad PD, Kurago ZB, Thangaraju M, Ganapathy V, Manicassamy S. GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. J Immunol 2018; 200(5):1781-1789. DOI: https://doi.org/10.4049/jimmunol.1700604

66. Luczynski P, McVey Neufeld KA, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a Bubble: Using Germ-Free Animals to Assess the Influence of the Gut Microbiota on Brain and Behavior. Int J Neuropsychopharmacol 2016; 19(8):pyw020. DOI: https://doi.org/10.1093/ijnp/pyw020

67. Morowitz MJ, Carlisle EM, Alverdy JC. Contributions of intestinal bacteria to nutrition and metabolism in the critically ill. Surg Clin North Am 2011; 91(4):771-785, viii. DOI: https://doi.org/10.1016/j.suc.2011.05.001

68. Kennedy DO. B vitamins and the brain: Mechanisms, dose and efficacy--A review. Nutrients 2016; 8(2):68. DOI: https://doi.org/10.3390/nu8020068

69. Jatoi S, Hafeez A, Riaz SU, Ali A, Ghauri MI, Zehra M. Low vitamin B12 levels: An underestimated cause of minimal cognitive impairment and dementia. Cureus 2020; 12(2):e6976. DOI: https://doi.org/10.7759/cureus.6976

70. Health Quality Ontario. Vitamin B12 and cognitive function: An evidence-based analysis. Ont Health Technol Assess Ser 2013; 13(23):1-45.
How to Cite
Fukushima, K. (2022). Metabolites from the Gut Microbiota and the Role in the Gut-Brain Axis. Science Insights, 40(5), 507–513. https://doi.org/10.15354/si.22.re037