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Gut-Brain Connection: Microbiome, Gut Barrier, and Environmental Sensors

  • Min-Gyu Gwak (Laboratory of Microbiology, College of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University) ;
  • Sun-Young Chang (Laboratory of Microbiology, College of Pharmacy, and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University)
  • Received : 2021.06.03
  • Accepted : 2021.06.12
  • Published : 2021.06.30
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Abstract

The gut is an important organ with digestive and immune regulatory function which consistently harbors microbiome ecosystem. The gut microbiome cooperates with the host to regulate the development and function of the immune, metabolic, and nervous systems. It can influence disease processes in the gut as well as extra-intestinal organs, including the brain. The gut closely connects with the central nervous system through dynamic bidirectional communication along the gut-brain axis. The connection between gut environment and brain may affect host mood and behaviors. Disruptions in microbial communities have been implicated in several neurological disorders. A link between the gut microbiota and the brain has long been described, but recent studies have started to reveal the underlying mechanism of the impact of the gut microbiota and gut barrier integrity on the brain and behavior. Here, we summarized the gut barrier environment and the 4 main gut-brain axis pathways. We focused on the important function of gut barrier on neurological diseases such as stress responses and ischemic stroke. Finally, we described the impact of representative environmental sensors generated by gut bacteria on acute neurological disease via the gut-brain axis.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (grant numbers NRF-2020R1A2B5B01001690).

References

  1. Gribble FM, Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol 2016;78:277-299. https://doi.org/10.1146/annurev-physiol-021115-105439
  2. Kim SH, Jang YS. Recent insights into cellular crosstalk in respiratory and gastrointestinal mucosal immune systems. Immune Netw 2020;20:e44.
  3. Seo K, Seo J, Yeun J, Choi H, Kim YI, Chang SY. The role of mucosal barriers in human gut health. Arch Pharm Res 2021;44:325-341. https://doi.org/10.1007/s12272-021-01327-5
  4. Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 2018;50:1-9. https://doi.org/10.1038/s12276-018-0126-x
  5. Szakal DN, Gyorffy H, Arato A, Cseh A, Molnar K, Papp M, Dezsofi A, Veres G. Mucosal expression of claudins 2, 3 and 4 in proximal and distal part of duodenum in children with coeliac disease. Virchows Arch 2010;456:245-250. https://doi.org/10.1007/s00428-009-0879-7
  6. Davis MA, Ireton RC, Reynolds AB. A core function for p120-catenin in cadherin turnover. J Cell Biol 2003;163:525-534. https://doi.org/10.1083/jcb.200307111
  7. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009;459:262-265. https://doi.org/10.1038/nature07935
  8. Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 2013;340:1190-1194. https://doi.org/10.1126/science.1234852
  9. Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ, Pearce EL, Oltz EM, Stappenbeck TS. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 2016;165:1708-1720. https://doi.org/10.1016/j.cell.2016.05.018
  10. Lee YS, Kim TY, Kim Y, Lee SH, Kim S, Kang SW, Yang JY, Baek IJ, Sung YH, Park YY, et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host Microbe 2018;24:833-846.e6. https://doi.org/10.1016/j.chom.2018.11.002
  11. Morais LH, Schreiber HL 4th, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol 2021;19:241-255. https://doi.org/10.1038/s41579-020-00460-0
  12. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 2015;28:203-209.
  13. Ma Q, Xing C, Long W, Wang HY, Liu Q, Wang RF. Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflammation 2019;16:53.
  14. Gutierrez-Aguilar R, Woods SC. Nutrition and l and k-enteroendocrine cells. Curr Opin Endocrinol Diabetes Obes 2011;18:35-41. https://doi.org/10.1097/MED.0b013e32834190b5
  15. Spreckley E, Murphy KG. The l-cell in nutritional sensing and the regulation of appetite. Front Nutr 2015;2:23.
  16. Worthington JJ, Reimann F, Gribble FM. Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity. Mucosal Immunol 2018;11:3-20. https://doi.org/10.1038/mi.2017.73
  17. Abdel-Haq R, Schlachetzki JC, Glass CK, Mazmanian SK. Microbiome-microglia connections via the gut-brain axis. J Exp Med 2019;216:41-59. https://doi.org/10.1084/jem.20180794
  18. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015;18:965-977. https://doi.org/10.1038/nn.4030
  19. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, Korecka A, Bakocevic N, Ng LG, Kundu P, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 2014;6:263ra158.
  20. Amoo M, O'Halloran PJ, Henry J, Husien MB, Brennan P, Campbell M, Caird J, Curley GF. Permeability of the blood-brain barrier after traumatic brain injury; radiological considerations. J Neurotrauma 2021. doi: 10.1089/neu.2020.7545.
  21. El Aidy S, Dinan TG, Cryan JF. Immune modulation of the brain-gut-microbe axis. Front Microbiol 2014;5:146.
  22. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010;170:1179-1188. https://doi.org/10.1016/j.neuroscience.2010.08.005
  23. Lyte M. Microbial endocrinology and the microbiota-gut-brain axis. Adv Exp Med Biol 2014;817:3-24. https://doi.org/10.1007/978-1-4939-0897-4_1
  24. 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.
  25. Mawe GM, Hoffman JM. Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 2013;10:473-486. https://doi.org/10.1038/nrgastro.2013.105
  26. Banskota S, Ghia JE, Khan WI. Serotonin in the gut: blessing or a curse. Biochimie 2019;161:56-64. https://doi.org/10.1016/j.biochi.2018.06.008
  27. Fidalgo S, Ivanov DK, Wood SH. Serotonin: from top to bottom. Biogerontology 2013;14:21-45. https://doi.org/10.1007/s10522-012-9406-3
  28. Nozawa K, Kawabata-Shoda E, Doihara H, Kojima R, Okada H, Mochizuki S, Sano Y, Inamura K, Matsushime H, Koizumi T, et al. TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci U S A 2009;106:3408-3413. https://doi.org/10.1073/pnas.0805323106
  29. Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol 2011;11:29-33. https://doi.org/10.1016/j.coph.2011.02.004
  30. Regmi SC, Park SY, Ku SK, Kim JA. Serotonin regulates innate immune responses of colon epithelial cells through Nox2-derived reactive oxygen species. Free Radic Biol Med 2014;69:377-389. https://doi.org/10.1016/j.freeradbiomed.2014.02.003
  31. Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 2004;126:1657-1664. https://doi.org/10.1053/j.gastro.2004.03.013
  32. Docherty M. Elevated serotonin associated with collagenous colitis. Am J Gastroenterol 2010;105:1449.
  33. D'Alessio S, Tacconi C, Fiocchi C, Danese S. Advances in therapeutic interventions targeting the vascular and lymphatic endothelium in inflammatory bowel disease. Curr Opin Gastroenterol 2013;29:608-613. https://doi.org/10.1097/MOG.0b013e328365d37c
  34. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 2019;101:246-259.e6. https://doi.org/10.1016/j.neuron.2018.11.018
  35. Bravo-Ferrer I, Cuartero MI, Medina V, Ahedo-Quero D, Pena-Martinez C, Perez-Ruiz A, Fernandez-Valle ME, Hernandez-Sanchez C, Fernandez-Salguero PM, Lizasoain I, et al. Lack of the aryl hydrocarbon receptor accelerates aging in mice. FASEB J 2019;33:12644-12654. https://doi.org/10.1096/fj.201901333R
  36. Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 2017;153:448-459.e8. https://doi.org/10.1053/j.gastro.2017.05.003
  37. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451-1463. https://doi.org/10.1016/j.cell.2013.11.024
  38. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 2016;167:1469-1480.e12. https://doi.org/10.1016/j.cell.2016.11.018
  39. Chu C, Murdock MH, Jing D, Won TH, Chung H, Kressel AM, Tsaava T, Addorisio ME, Putzel GG, Zhou L, et al. The microbiota regulate neuronal function and fear extinction learning. Nature 2019;574:543-548. https://doi.org/10.1038/s41586-019-1644-y
  40. Barden N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J Psychiatry Neurosci 2004;29:185-193.
  41. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558:263-275. https://doi.org/10.1113/jphysiol.2004.063388
  42. Garcia-Rodenas CL, Bergonzelli GE, Nutten S, Schumann A, Cherbut C, Turini M, Ornstein K, Rochat F, Corthesy-Theulaz I. Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J Pediatr Gastroenterol Nutr 2006;43:16-24. https://doi.org/10.1097/01.mpg.0000226376.95623.9f
  43. O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 2009;65:263-267. https://doi.org/10.1016/j.biopsych.2008.06.026
  44. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015;9:392.
  45. Gareau MG, Silva MA, Perdue MH. Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med 2008;8:274-281. https://doi.org/10.2174/156652408784533760
  46. Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 2007;56:1522-1528. https://doi.org/10.1136/gut.2006.117176
  47. Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L, Houdeau E, Fioramonti J, Bueno L, Theodorou V. Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 2012;37:1885-1895. https://doi.org/10.1016/j.psyneuen.2012.03.024
  48. Goehler LE, Park SM, Opitz N, Lyte M, Gaykema RP. Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun 2008;22:354-366. https://doi.org/10.1016/j.bbi.2007.08.009
  49. Lyte M, Li W, Opitz N, Gaykema RP, Goehler LE. Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol Behav 2006;89:350-357. https://doi.org/10.1016/j.physbeh.2006.06.019
  50. GBD 2016 Lifetime Risk of Stroke CollaboratorsFeigin VL, Nguyen G, Cercy K, Johnson CO, Alam T, Parmar PG, Abajobir AA, Abate KH, Abd-Allah F, et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med 2018;379:2429-2437. https://doi.org/10.1056/NEJMoa1804492
  51. Singh V, Roth S, Llovera G, Sadler R, Garzetti D, Stecher B, Dichgans M, Liesz A. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci 2016;36:7428-7440. https://doi.org/10.1523/JNEUROSCI.1114-16.2016
  52. Huang YY, Li X, Li X, Sheng YY, Zhuang PW, Zhang YJ. Neuroimmune crosstalk in central nervous system injury-induced infection and pharmacological intervention. Brain Res Bull 2019;153:232-238. https://doi.org/10.1016/j.brainresbull.2019.09.003
  53. Benakis C, Poon C, Lane D, Brea D, Sita G, Moore J, Murphy M, Racchumi G, Iadecola C, Anrather J. Distinct commensal bacterial signature in the gut is associated with acute and long-term protection from ischemic stroke. Stroke 2020;51:1844-1854. https://doi.org/10.1161/STROKEAHA.120.029262
  54. Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, Sita G, Racchumi G, Ling L, Pamer EG, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med 2016;22:516-523. https://doi.org/10.1038/nm.4068
  55. Stanley D, Mason LJ, Mackin KE, Srikhanta YN, Lyras D, Prakash MD, Nurgali K, Venegas A, Hill MD, Moore RJ, et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med 2016;22:1277-1284. https://doi.org/10.1038/nm.4194
  56. Xu K, Gao X, Xia G, Chen M, Zeng N, Wang S, You C, Tian X, Di H, Tang W, et al. Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn. Gut 2021; gutjnl-2020-323263. 
  57. Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg 2018;20:378-392. https://doi.org/10.1177/1098612X17729626
  58. Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 2019;19:184-197. https://doi.org/10.1038/s41577-019-0125-8
  59. Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E, Li V, Maradana MR, Schiering C, Stockinger B. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 2018;49:353-362.e5. https://doi.org/10.1016/j.immuni.2018.07.010
  60. Lanis JM, Alexeev EE, Curtis VF, Kitzenberg DA, Kao DJ, Battista KD, Gerich ME, Glover LE, Kominsky DJ, Colgan SP. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol 2017;10:1133-1144. https://doi.org/10.1038/mi.2016.133
  61. Yu M, Wang Q, Ma Y, Li L, Yu K, Zhang Z, Chen G, Li X, Xiao W, Xu P, et al. Aryl hydrocarbon receptor activation modulates intestinal epithelial barrier function by maintaining tight junction integrity. Int J Biol Sci 2018;14:69-77. https://doi.org/10.7150/ijbs.22259
  62. Benson JM, Shepherd DM. Dietary ligands of the aryl hydrocarbon receptor induce anti-inflammatory and immunoregulatory effects on murine dendritic cells. Toxicol Sci 2011;124:327-338. https://doi.org/10.1093/toxsci/kfr249
  63. Cervantes-Barragan L, Chai JN, Tianero MD, Di Luccia B, Ahern PP, Merriman J, Cortez VS, Caparon MG, Donia MS, Gilfillan S, et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 2017;357:806-810. https://doi.org/10.1126/science.aah5825
  64. Kadowaki A, Miyake S, Saga R, Chiba A, Mochizuki H, Yamamura T. Gut environment-induced intraepithelial autoreactive CD4+ T cells suppress central nervous system autoimmunity via LAG-3. Nat Commun 2016;7:11639.
  65. Brandstatter O, Schanz O, Vorac J, Konig J, Mori T, Maruyama T, Korkowski M, Haarmann-Stemmann T, von Smolinski D, Schultze JL, et al. Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor. Sci Rep 2016;6:26091.
  66. Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, Mantovani A, Kopan R, Bradfield CA, Newberry RD, et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol 2011;13:144-151. https://doi.org/10.1038/ni.2187
  67. Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 2012;36:92-104. https://doi.org/10.1016/j.immuni.2011.11.011
  68. Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF, Artis D, Fu YX, Zhou L. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 2013;39:386-399. https://doi.org/10.1016/j.immuni.2013.08.002
  69. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016;22:586-597. https://doi.org/10.1038/nm.4106
  70. Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutierrez-Vazquez C, Hewson P, Staszewski O, et al. Microglial control of astrocytes in response to microbial metabolites. Nature 2018;557:724-728. https://doi.org/10.1038/s41586-018-0119-x
  71. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 2008;453:106-109. https://doi.org/10.1038/nature06881
  72. Chen WC, Chang LH, Huang SS, Huang YJ, Chih CL, Kuo HC, Lee YH, Lee IH. Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain. J Neuroinflammation 2019;16:187.
  73. Brouns R, Verkerk R, Aerts T, De Surgeloose D, Wauters A, Scharpe S, De Deyn PP. The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochem Res 2010;35:1315-1322. https://doi.org/10.1007/s11064-010-0187-2
  74. Di Giaimo R, Durovic T, Barquin P, Kociaj A, Lepko T, Aschenbroich S, Breunig CT, Irmler M, Cernilogar FM, Schotta G, et al. The aryl hydrocarbon receptor pathway defines the time frame for restorative neurogenesis. Cell Rep 2018;25:3241-3251.e5. https://doi.org/10.1016/j.celrep.2018.11.055
  75. Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E, Kashi R, Amit-Romach E, Caballero IS, Towfic F, Ator MA, et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 2016;113:E6145-E6152. https://doi.org/10.1073/pnas.1607843113
  76. Berg J, Mahmoudjanlou Y, Duscha A, Massa MG, Thone J, Esser C, Gold R, Haghikia A. The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor. J Neuroimmunol 2016;298:9-15. https://doi.org/10.1016/j.jneuroim.2016.06.003
  77. Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013;39:372-385. https://doi.org/10.1016/j.immuni.2013.08.003
  78. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 2019;16:461-478. https://doi.org/10.1038/s41575-019-0157-3
  79. Chen J, Vitetta L. The role of butyrate in attenuating pathobiont-induced hyperinflammation. Immune Netw 2020;20:e15.
  80. Zhao Y, Chen F, Wu W, Sun M, Bilotta AJ, Yao S, Xiao Y, Huang X, Eaves-Pyles TD, Golovko G, et al. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol 2018;11:752-762. https://doi.org/10.1038/mi.2017.118
  81. Martin-Gallausiaux C, Beguet-Crespel F, Marinelli L, Jamet A, Ledue F, Blottiere HM, Lapaque N. Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells. Sci Rep 2018;8:9742.
  82. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013;504:446-450. https://doi.org/10.1038/nature12721
  83. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 2014;111:2247-2252. https://doi.org/10.1073/pnas.1322269111
  84. Sadler R, Cramer JV, Heindl S, Kostidis S, Betz D, Zuurbier KR, Northoff BH, Heijink M, Goldberg MP, Plautz EJ, et al. Short-chain fatty acids improve poststroke recovery via immunological mechanisms. J Neurosci 2020;40:1162-1173. https://doi.org/10.1523/JNEUROSCI.1359-19.2019
  85. Lee J, d'Aigle J, Atadja L, Quaicoe V, Honarpisheh P, Ganesh BP, Hassan A, Graf J, Petrosino J, Putluri N, et al. Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice. Circ Res 2020;127:453-465. https://doi.org/10.1161/CIRCRESAHA.119.316448