1932

Abstract

The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Dysbiosis of the gut microbiome and dysregulated neuroimmune responses are common comorbidities of neurodevelopmental, neuropsychiatric, and neurological disorders, highlighting the importance of the gut microbiome–neuroimmune axis as a regulator of central nervous system homeostasis. In this review, we discuss recent evidence supporting a role for the gut microbiome in regulating the neuroimmune landscape in health and disease.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-101320-014237
2022-04-26
2024-12-14
Loading full text...

Full text loading...

/deliver/fulltext/immunol/40/1/annurev-immunol-101320-014237.html?itemId=/content/journals/10.1146/annurev-immunol-101320-014237&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Thion MS, Ginhoux F, Garel S 2018. Microglia and early brain development: an intimate journey. Science 362:185–89
    [Google Scholar]
  2. 2. 
    Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. 2018. Microglia in neurodegeneration. Nat. Neurosci. 21:1359–69
    [Google Scholar]
  3. 3. 
    Wolf SA, Boddeke HW, Kettenmann H. 2017. Microglia in physiology and disease. Annu. Rev. Physiol. 79:619–43
    [Google Scholar]
  4. 4. 
    Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O et al. 2015. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18:965–77
    [Google Scholar]
  5. 5. 
    Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A et al. 2016. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:aad8670
    [Google Scholar]
  6. 6. 
    Thion MS, Low D, Silvin A, Chen J, Grisel P et al. 2018. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172:500–16.e16
    [Google Scholar]
  7. 7. 
    Castillo-Ruiz A, Mosley M, George AJ, Mussaji LF, Fullerton EF et al. 2018. The microbiota influences cell death and microglial colonization in the perinatal mouse brain. Brain Behav. Immun. 67:218–29
    [Google Scholar]
  8. 8. 
    Luck B, Engevik MA, Ganesh BP, Lackey EP, Lin T et al. 2020. Bifidobacteria shape host neural circuits during postnatal development by promoting synapse formation and microglial function. Sci. Rep. 10:7737
    [Google Scholar]
  9. 9. 
    Lu J, Lu L, Yu Y, Baranowski J, Claud EC. 2020. Maternal administration of probiotics promotes brain development and protects offspring's brain from postnatal inflammatory insults in C57/BL6J mice. Sci. Rep. 10:8178
    [Google Scholar]
  10. 10. 
    Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J et al. 2019. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J. Exp. Med. 216:1542–60
    [Google Scholar]
  11. 11. 
    Chu C, Murdock MH, Jing D, Won TH, Chung H et al. 2019. The microbiota regulate neuronal function and fear extinction learning. Nature 574:543–48
    [Google Scholar]
  12. 12. 
    Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B et al. 2011. Normal gut microbiota modulates brain development and behavior. PNAS 108:3047–52
    [Google Scholar]
  13. 13. 
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR et al. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705
    [Google Scholar]
  14. 14. 
    Stephan AH, Barres BA, Stevens B. 2012. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35:369–89
    [Google Scholar]
  15. 15. 
    Fonseca MI, Chu SH, Hernandez MX, Fang MJ, Modarresi L et al. 2017. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J. Neuroinflamm. 14:48
    [Google Scholar]
  16. 16. 
    Pronovost GN, Hsiao EY. 2019. Perinatal interactions between the microbiome, immunity, and neurodevelopment. Immunity 50:18–36
    [Google Scholar]
  17. 17. 
    Yoshiya K, Lapchak PH, Thai TH, Kannan L, Rani P et al. 2011. Depletion of gut commensal bacteria attenuates intestinal ischemia/reperfusion injury. Am. J. Physiol. Gastrointest. Liver Physiol. 301:G1020–30
    [Google Scholar]
  18. 18. 
    Meisel JS, Sfyroera G, Bartow-McKenney C, Gimblet C, Bugayev J et al. 2018. Commensal microbiota modulate gene expression in the skin. Microbiome 6:20
    [Google Scholar]
  19. 19. 
    Shi Q, Chowdhury S, Ma R, Le KX, Hong S et al. 2017. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. 9:eaaf6295
    [Google Scholar]
  20. 20. 
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S et al. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–16
    [Google Scholar]
  21. 21. 
    Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW et al. 2016. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165:921–35
    [Google Scholar]
  22. 22. 
    Veerhuis R, Nielsen HM, Tenner AJ. 2011. Complement in the brain. Mol. Immunol. 48:1592–603
    [Google Scholar]
  23. 23. 
    Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S et al. 2015. Complement C3-deficient mice fail to display age-related hippocampal decline. J. Neurosci. 35:13029–42
    [Google Scholar]
  24. 24. 
    Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA 2008. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J. Neurosci. 28:6333–41
    [Google Scholar]
  25. 25. 
    Zysset-Burri DC, Keller I, Berger LE, Largiader CR, Wittwer M et al. 2020. Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration. NPJ Genom. Med. 5:34
    [Google Scholar]
  26. 26. 
    Feng W, Ao H, Peng C. 2018. Gut microbiota, short-chain fatty acids, and herbal medicines. Front. Pharmacol. 9:1354
    [Google Scholar]
  27. 27. 
    Pasciuto E, Burton OT, Roca CP, Lagou V, Rajan WD et al. 2020. Microglia require CD4 T cells to complete the fetal-to-adult transition. Cell 182:625–40.e24
    [Google Scholar]
  28. 28. 
    Sanmarco LM, Wheeler MA, Gutiérrez-Vázquez C, Polonio CM, Linnerbauer M et al. 2021. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature 590:473–79
    [Google Scholar]
  29. 29. 
    Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N et al. 2020. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature 587:472–76
    [Google Scholar]
  30. 30. 
    Alves de Lima K, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF et al. 2020. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat. Immunol. 21:1421–29
    [Google Scholar]
  31. 31. 
    Eltokhi A, Janmaat IE, Genedi M, Haarman BCM, Sommer IEC. 2020. Dysregulation of synaptic pruning as a possible link between intestinal microbiota dysbiosis and neuropsychiatric disorders. J. Neurosci. Res. 98:1335–69
    [Google Scholar]
  32. 32. 
    Wenzel TJ, Gates EJ, Ranger AL, Klegeris A. 2020. Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Mol. Cell Neurosci. 105:103493
    [Google Scholar]
  33. 33. 
    Shukla S, Tekwani BL. 2020. Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation. Front. Pharmacol. 11:537
    [Google Scholar]
  34. 34. 
    Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I et al. 2019. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50:432–45.e7
    [Google Scholar]
  35. 35. 
    Wang P, Zhang Y, Gong Y, Yang R, Chen Z et al. 2018. Sodium butyrate triggers a functional elongation of microglial process via Akt-small RhoGTPase activation and HDACs inhibition. Neurobiol. Dis. 111:12–25
    [Google Scholar]
  36. 36. 
    Dalile B, Van Oudenhove L, Vervliet B, Verbeke K 2019. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat. Rev. Gastroenterol. Hepatol. 16:461–78
    [Google Scholar]
  37. 37. 
    Soliman ML, Rosenberger TA. 2011. Acetate supplementation increases brain histone acetylation and inhibits histone deacetylase activity and expression. Mol. Cell Biochem. 352:173–80
    [Google Scholar]
  38. 38. 
    Soliman ML, Puig KL, Combs CK, Rosenberger TA. 2012. Acetate reduces microglia inflammatory signaling in vitro. J. Neurochem. 123:555–67
    [Google Scholar]
  39. 39. 
    Brissette CA, Houdek HM, Floden AM, Rosenberger TA. 2012. Acetate supplementation reduces microglia activation and brain interleukin-1β levels in a rat model of Lyme neuroborreliosis. J. Neuroinflamm. 9:249
    [Google Scholar]
  40. 40. 
    Soliman ML, Smith MD, Houdek HM, Rosenberger TA. 2012. Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation. J. Neuroinflamm. 9:51
    [Google Scholar]
  41. 41. 
    Franco R, Fernandez-Suarez D. 2015. Alternatively activated microglia and macrophages in the central nervous system. Prog. Neurobiol. 131:65–86
    [Google Scholar]
  42. 42. 
    Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG et al. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167:1469–80.e12
    [Google Scholar]
  43. 43. 
    Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD et al. 2018. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: gut microbiota, glial reaction and TLR4/TNF-alpha signaling pathway. Brain Behav. Immun. 70:48–60
    [Google Scholar]
  44. 44. 
    Qiao CM, Sun MF, Jia XB, Li Y, Zhang BP et al. 2020. Sodium butyrate exacerbates Parkinson's disease by aggravating neuroinflammation and colonic inflammation in MPTP-induced mice model. Neurochem. Res. 45:2128–42
    [Google Scholar]
  45. 45. 
    Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H et al. 2016. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat. Disord. 32:66–72
    [Google Scholar]
  46. 46. 
    Sun J, Li H, Jin Y, Yu J, Mao S et al. 2021. Probiotic Clostridium butyricum ameliorated motor deficits in a mouse model of Parkinson's disease via gut microbiota-GLP-1 pathway. Brain Behav. Immun. 91:703–15
    [Google Scholar]
  47. 47. 
    Srivastav S, Neupane S, Bhurtel S, Katila N, Maharjan S et al. 2019. Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity. J. Nutr. Biochem. 69:73–86
    [Google Scholar]
  48. 48. 
    Hou YF, Shan C, Zhuang SY, Zhuang QQ, Ghosh A et al. 2021. Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease. Microbiome 9:34
    [Google Scholar]
  49. 49. 
    Jiang Y, Li K, Li X, Xu L, Yang Z. 2021. Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice. Chem. Biol. Interact. 341:109452
    [Google Scholar]
  50. 50. 
    Sun J, Xu J, Yang B, Chen K, Kong Y et al. 2020. Effect of Clostridium butyricum against microglia-mediated neuroinflammation in Alzheimer's disease via regulating gut microbiota and metabolites butyrate. Mol. Nutr. Food Res. 64:e1900636
    [Google Scholar]
  51. 51. 
    Colombo AV, Sadler RK, Llovera G, Singh V, Roth S et al. 2021. Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. eLife 10:e59826
    [Google Scholar]
  52. 52. 
    Hanke ML, Kielian T. 2011. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin. Sci. 121:367–87
    [Google Scholar]
  53. 53. 
    Okun E, Griffioen KJ, Mattson MP. 2011. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34:269–81
    [Google Scholar]
  54. 54. 
    Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. 2018. Role of microglia TLRs in neurodegeneration. Front. Cell Neurosci. 12:329
    [Google Scholar]
  55. 55. 
    Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell 124:783–801
    [Google Scholar]
  56. 56. 
    Qiu C, Yuan Z, He Z, Chen H, Liao Y et al. 2021. Lipopolysaccharide preparation derived from Porphyromonas gingivalis induces a weaker immuno-inflammatory response in BV-2 microglial cells than Escherichia coli by differentially activating TLR2/4-mediated NF-κB/STAT3 signaling pathways. Front. Cell Infect. Microbiol. 11:606986
    [Google Scholar]
  57. 57. 
    Eder K, Vizler C, Kusz E, Karcagi I, Glavinas H et al. 2009. The role of lipopolysaccharide moieties in macrophage response to Escherichia coli. Biochem. Biophys. Res. Commun. 389:46–51
    [Google Scholar]
  58. 58. 
    Lin HY, Huang CC, Chang KF. 2009. Lipopolysaccharide preconditioning reduces neuroinflammation against hypoxic ischemia and provides long-term outcome of neuroprotection in neonatal rat. Pediatr. Res. 66:254–59
    [Google Scholar]
  59. 59. 
    Vartanian KB, Stevens SL, Marsh BJ, Williams-Karnesky R, Lessov NS, Stenzel-Poore MP. 2011. LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury. J. Neuroinflamm. 8:140
    [Google Scholar]
  60. 60. 
    Garcia-Bonilla L, Brea D, Benakis C, Lane DA, Murphy M et al. 2018. Endogenous protection from ischemic brain injury by preconditioned monocytes. J. Neurosci. 38:6722–36
    [Google Scholar]
  61. 61. 
    Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R et al. 2012. Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J. Neurosci. 32:11706–15
    [Google Scholar]
  62. 62. 
    Mizobuchi H, Yamamoto K, Tsutsui S, Yamashita M, Nakata Y et al. 2020. A unique hybrid characteristic having both pro- and anti-inflammatory phenotype transformed by repetitive low-dose lipopolysaccharide in C8-B4 microglia. Sci. Rep. 10:8945
    [Google Scholar]
  63. 63. 
    Mizobuchi H, Yamamoto K, Yamashita M, Inagawa H, Kohchi C, Soma GI. 2020. A novel anti-inflammatory phenotype transformed by repetitive low-dose lipopolysaccharide in primary peritoneal tissue-resident macrophages. Anticancer Res 40:4457–64
    [Google Scholar]
  64. 64. 
    Halder SK, Matsunaga H, Ishii KJ, Akira S, Miyake K, Ueda H 2013. Retinal cell type-specific prevention of ischemia-induced damages by LPS-TLR4 signaling through microglia. J. Neurochem. 126:243–60
    [Google Scholar]
  65. 65. 
    Schaafsma W, Zhang X, van Zomeren KC, Jacobs S, Georgieva PB et al. 2015. Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing. Brain Behav. Immun. 48:205–21
    [Google Scholar]
  66. 66. 
    Lagier JC, Million M, Hugon P, Armougom F, Raoult D. 2012. Human gut microbiota: repertoire and variations. Front. Cell Infect. Microbiol. 2:136
    [Google Scholar]
  67. 67. 
    Salguero MV, Al-Obaide MAI, Singh R, Siepmann T, Vasylyeva TL. 2019. Dysbiosis of Gram-negative gut microbiota and the associated serum lipopolysaccharide exacerbates inflammation in type 2 diabetic patients with chronic kidney disease. Exp. Ther. Med. 18:3461–69
    [Google Scholar]
  68. 68. 
    Jacobson AN, Choudhury BP, Fischbach MA. 2018. The biosynthesis of lipooligosaccharide from Bacteroides thetaiotaomicron. mBio 9:e02289–17
    [Google Scholar]
  69. 69. 
    Yoshida N, Yamashita T, Kishino S, Watanabe H, Sasaki K et al. 2020. A possible beneficial effect of Bacteroides on faecal lipopolysaccharide activity and cardiovascular diseases. Sci. Rep. 10:13009
    [Google Scholar]
  70. 70. 
    Steimle A, Michaelis L, Di Lorenzo F, Kliem T, Munzner T et al. 2019. Weak agonistic LPS restores intestinal immune homeostasis. Mol. Ther. 27:1974–91
    [Google Scholar]
  71. 71. 
    Zhao Y, Lukiw WJ. 2018. Bacteroidetes neurotoxins and inflammatory neurodegeneration. Mol. Neurobiol. 55:9100–7
    [Google Scholar]
  72. 72. 
    Fields CT, Chassaing B, Castillo-Ruiz A, Osan R, Gewirtz AT, de Vries GJ. 2018. Effects of gut-derived endotoxin on anxiety-like and repetitive behaviors in male and female mice. Biol. Sex. Differ. 9:7
    [Google Scholar]
  73. 73. 
    Pittman DW, Dong G, Brantly AM, He L, Nelson TS et al. 2020. Behavioral and neurophysiological taste responses to sweet and salt are diminished in a model of subclinical intestinal inflammation. Sci. Rep. 10:17611
    [Google Scholar]
  74. 74. 
    Kobayashi Y, Inagawa H, Kohchi C, Okazaki K, Zhang R et al. 2017. Lipopolysaccharides derived from Pantoea agglomerans can promote the phagocytic activity of amyloid β in mouse microglial cells. Anticancer Res 37:3917–20
    [Google Scholar]
  75. 75. 
    Kobayashi Y, Inagawa H, Kohchi C, Okazaki K, Zhang R, Soma G. 2016. Effect of lipopolysaccharide derived from Pantoea agglomerans on the phagocytic activity of amyloid β by primary murine microglial cells. Anticancer Res 36:3693–98
    [Google Scholar]
  76. 76. 
    Brown DG, Soto R, Yandamuri S, Stone C, Dickey L et al. 2019. The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling. eLife 8:e47117
    [Google Scholar]
  77. 77. 
    Brown GC. 2019. The endotoxin hypothesis of neurodegeneration. J. Neuroinflamm. 16:180
    [Google Scholar]
  78. 78. 
    Zhang R, Miller RG, Gascon R, Champion S, Katz J et al. 2009. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J. Neuroimmunol. 206:121–24
    [Google Scholar]
  79. 79. 
    Zhao Y, Cong L, Lukiw WJ. 2017. Lipopolysaccharide (LPS) accumulates in neocortical neurons of Alzheimer's disease (AD) brain and impairs transcription in human neuronal-glial primary co-cultures. Front. Aging Neurosci. 9:407
    [Google Scholar]
  80. 80. 
    Emanuele E, Orsi P, Boso M, Broglia D, Brondino N et al. 2010. Low-grade endotoxemia in patients with severe autism. Neurosci. Lett. 471:162–65
    [Google Scholar]
  81. 81. 
    Fuke N, Nagata N, Suganuma H, Ota T. 2019. Regulation of gut microbiota and metabolic endotoxemia with dietary factors. Nutrients 11:2277
    [Google Scholar]
  82. 82. 
    Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K et al. 2015. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. PNAS 112:12468–73
    [Google Scholar]
  83. 83. 
    Agus A, Planchais J, Sokol H. 2018. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23:716–24
    [Google Scholar]
  84. 84. 
    Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA et al. 2009. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. PNAS 106:3698–703
    [Google Scholar]
  85. 85. 
    Gutierrez-Vazquez C, Quintana FJ. 2018. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48:19–33
    [Google Scholar]
  86. 86. 
    Rothhammer V, Quintana FJ. 2019. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19:184–97
    [Google Scholar]
  87. 87. 
    Tanaka M, Fujikawa M, Oguro A, Itoh K, Vogel CFA, Ishihara Y. 2021. Involvement of the microglial aryl hydrocarbon receptor in neuroinflammation and vasogenic edema after ischemic stroke. Cells 10:718
    [Google Scholar]
  88. 88. 
    Matsumoto K, Kinoshita K, Yoshimizu A, Kurauchi Y, Hisatsune A et al. 2020. Laquinimod and 3,3′-diindolylemethane alleviate neuropathological events and neurological deficits in a mouse model of intracerebral hemorrhage. J. Neuroimmunol. 342:577195
    [Google Scholar]
  89. 89. 
    Lee YH, Lin CH, Hsu PC, Sun YY, Huang YJ et al. 2015. Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia. Glia 63:1138–54
    [Google Scholar]
  90. 90. 
    Huang Y, He J, Liang H, Hu K, Jiang S et al. 2018. Aryl hydrocarbon receptor regulates apoptosis and inflammation in a murine model of experimental autoimmune uveitis. Front. Immunol. 9:1713
    [Google Scholar]
  91. 91. 
    Kim SY, Yang HJ, Chang YS, Kim JW, Brooks M et al. 2014. Deletion of aryl hydrocarbon receptor AHR in mice leads to subretinal accumulation of microglia and RPE atrophy. Investig. Ophthalmol. Vis. Sci. 55:6031–40
    [Google Scholar]
  92. 92. 
    Shen PX, Li X, Deng SY, Zhao L, Zhang YY et al. 2021. Urolithin A ameliorates experimental autoimmune encephalomyelitis by targeting aryl hydrocarbon receptor. EBioMedicine 64:103227
    [Google Scholar]
  93. 93. 
    Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC et al. 2018. Microglial control of astrocytes in response to microbial metabolites. Nature 557:724–28
    [Google Scholar]
  94. 94. 
    Chen WC, Chang LH, Huang SS, Huang YJ, Chih CL et al. 2019. Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain. J. Neuroinflamm. 16:187
    [Google Scholar]
  95. 95. 
    Adesso S, Magnus T, Cuzzocrea S, Campolo M, Rissiek B et al. 2017. Indoxyl sulfate affects glial function increasing oxidative stress and neuroinflammation in chronic kidney disease: interaction between astrocytes and microglia. Front. Pharmacol. 8:370
    [Google Scholar]
  96. 96. 
    Adesso S, Paterniti I, Cuzzocrea S, Fujioka M, Autore G et al. 2018. AST-120 reduces neuroinflammation induced by indoxyl sulfate in glial cells. J. Clin. Med. 7:365
    [Google Scholar]
  97. 97. 
    Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE et al. 2016. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22:586–97
    [Google Scholar]
  98. 98. 
    Han RT, Kim RD, Molofsky AV, Liddelow SA. 2021. Astrocyte-immune cell interactions in physiology and pathology. Immunity 54:211–24
    [Google Scholar]
  99. 99. 
    Vainchtein ID, Chin G, Cho FS, Kelley KW, Miller JG et al. 2018. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359:1269–73
    [Google Scholar]
  100. 100. 
    Bialas AR, Stevens B. 2013. TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16:1773–82
    [Google Scholar]
  101. 101. 
    Vainchtein ID, Molofsky AV. 2020. Astrocytes and microglia: in sickness and in health. Trends Neurosci 43:144–54
    [Google Scholar]
  102. 102. 
    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–87
    [Google Scholar]
  103. 103. 
    Garcez ML, Tan VX, Heng B, Guillemin GJ. 2020. Sodium butyrate and indole-3-propionic acid prevent the increase of cytokines and kynurenine levels in LPS-induced human primary astrocytes. Int. J. Tryptophan Res. 13: https://doi.org/10.1177/1178646920978404
    [Crossref] [Google Scholar]
  104. 104. 
    Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E et al. 2016. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. PNAS 113:E6145–52
    [Google Scholar]
  105. 105. 
    Rothhammer V, Kenison JE, Li Z, Tjon E, Takenaka MC et al. 2021. Aryl hydrocarbon receptor activation in astrocytes by laquinimod ameliorates autoimmune inflammation in the CNS. Neurol. Neuroimmunol. Neuroinflamm. 8:e946
    [Google Scholar]
  106. 106. 
    Sag D, Ayyildiz ZO, Gunalp S, Wingender G 2019. The role of TRAIL/DRs in the modulation of immune cells and responses. Cancers 11:1469
    [Google Scholar]
  107. 107. 
    Ding X, Yan Y, Li X, Li K, Ciric B et al. 2015. Silencing IFN-gamma binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity. J. Immunol. 194:4251–64
    [Google Scholar]
  108. 108. 
    Alves de Lima K, Rustenhoven J, Kipnis J 2020. Meningeal immunity and its function in maintenance of the central nervous system in health and disease. Annu. Rev. Immunol. 38:597–620
    [Google Scholar]
  109. 109. 
    Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR et al. 2019. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22:1021–35
    [Google Scholar]
  110. 110. 
    Rustenhoven J, Drieu A, Mamuladze T, de Lima KA, Dykstra T et al. 2021. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184:1000–16.e27
    [Google Scholar]
  111. 111. 
    Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A et al. 2010. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207:1067–80
    [Google Scholar]
  112. 112. 
    Benakis C, Brea D, Caballero S, Faraco G, Moore J et al. 2016. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat. Med. 22:516–23
    [Google Scholar]
  113. 113. 
    Hapfelmeier S, Lawson MA, Slack E, Kirundi JK, Stoel M et al. 2010. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328:1705–9
    [Google Scholar]
  114. 114. 
    Rojas OL, Probstel AK, Porfilio EA, Wang AA, Charabati M et al. 2019. Recirculating intestinal IgA-producing cells regulate neuroinflammation via IL-10. Cell 176:610–24.e18
    [Google Scholar]
  115. 115. 
    Hawkins BT, Davis TP. 2005. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57:173–85
    [Google Scholar]
  116. 116. 
    Abbott NJ, Ronnback L, Hansson E 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7:41–53
    [Google Scholar]
  117. 117. 
    Banjara M, Ghosh C. 2017. Sterile neuroinflammation and strategies for therapeutic intervention. Int. J. Inflamm. 2017:8385961
    [Google Scholar]
  118. 118. 
    Hiippala K, Jouhten H, Ronkainen A, Hartikainen A, Kainulainen V et al. 2018. The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation. Nutrients 10:988
    [Google Scholar]
  119. 119. 
    Kayama H, Okumura R, Takeda K. 2020. Interaction between the microbiota, epithelia, and immune cells in the intestine. Annu. Rev. Immunol. 38:23–48
    [Google Scholar]
  120. 120. 
    Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A et al. 2014. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6:263ra158
    [Google Scholar]
  121. 121. 
    Sun N, Hu H, Wang F, Li L, Zhu W et al. 2021. Antibiotic-induced microbiome depletion in adult mice disrupts blood-brain barrier and facilitates brain infiltration of monocytes after bone-marrow transplantation. Brain Behav. Immun. 92:102–14
    [Google Scholar]
  122. 122. 
    Wu Q, Zhang Y, Zhang Y, Xia C, Lai Q et al. 2020. Potential effects of antibiotic-induced gut microbiome alteration on blood-brain barrier permeability compromise in rhesus monkeys. Ann. N. Y. Acad. Sci. 1470:14–24
    [Google Scholar]
  123. 123. 
    Leclercq S, Mian FM, Stanisz AM, Bindels LB, Cambier E et al. 2017. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat. Commun. 8:15062
    [Google Scholar]
  124. 124. 
    Hoyles L, Snelling T, Umlai UK, Nicholson JK, Carding SR et al. 2018. Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier. Microbiome 6:55
    [Google Scholar]
  125. 125. 
    Li K, Wei S, Hu L, Yin X, Mai Y et al. 2020. Protection of fecal microbiota transplantation in a mouse model of multiple sclerosis. Mediators Inflamm 2020:2058272
    [Google Scholar]
  126. 126. 
    Nelson JW, Phillips SC, Ganesh BP, Petrosino JF, Durgan DJ, Bryan RM. 2021. The gut microbiome contributes to blood-brain barrier disruption in spontaneously hypertensive stroke prone rats. FASEB J 35:e21201
    [Google Scholar]
  127. 127. 
    Li H, Sun J, Du J, Wang F, Fang R et al. 2018. Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis. Neurogastroenterol. Motil. 30:e13260
    [Google Scholar]
  128. 128. 
    Li H, Sun J, Wang F, Ding G, Chen W et al. 2016. Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice. Brain Res 1642:70–78
    [Google Scholar]
  129. 129. 
    Yang X, Yu D, Xue L, Li H, Du J 2020. Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice. Acta Pharm. Sin. B 10:475–87
    [Google Scholar]
  130. 130. 
    Yu W, Gao D, Wang Z, Jin W, Peng X et al. 2019. Probiotics alleviate cognitive dysfunction associated with neuroinflammation in cardiac surgery. Am. J. Transl. Res. 11:7614–26
    [Google Scholar]
  131. 131. 
    Korin B, Ben-Shaanan TL, Schiller M, Dubovik T, Azulay-Debby H et al. 2017. High-dimensional, single-cell characterization of the brain's immune compartment. Nat. Neurosci. 20:1300–9
    [Google Scholar]
  132. 132. 
    Prinz M, Priller J. 2017. The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 20:136–44
    [Google Scholar]
  133. 133. 
    Engelhardt B, Vajkoczy P, Weller RO. 2017. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18:123–31
    [Google Scholar]
  134. 134. 
    Golomb SM, Guldner IH, Zhao A, Wang Q, Palakurthi B et al. 2020. Multi-modal single-cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis. Cell Rep 33:108438
    [Google Scholar]
  135. 135. 
    Erdo F, Denes L, de Lange E. 2017. Age-associated physiological and pathological changes at the blood-brain barrier: a review. J. Cereb. Blood Flow Metab. 37:4–24
    [Google Scholar]
  136. 136. 
    Mohle L, Mattei D, Heimesaat MM, Bereswill S, Fischer A et al. 2016. Ly6Chi monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep 15:1945–56
    [Google Scholar]
  137. 137. 
    Celorrio M, Abellanas MA, Rhodes J, Goodwin V, Moritz J et al. 2021. Gut microbial dysbiosis after traumatic brain injury modulates the immune response and impairs neurogenesis. Acta Neuropathol. Commun. 9:40
    [Google Scholar]
  138. 138. 
    D'Mello C, Ronaghan N, Zaheer R, Dicay M, Le T et al. 2015. Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain. J. Neurosci. 35:10821–30
    [Google Scholar]
  139. 139. 
    Fox EJ. 2004. Immunopathology of multiple sclerosis. Neurology 63:S3–7
    [Google Scholar]
  140. 140. 
    Mirza A, Forbes JD, Zhu F, Bernstein CN, Van Domselaar G et al. 2020. The multiple sclerosis gut microbiota: a systematic review. Mult. Scler. Relat. Disord. 37:101427
    [Google Scholar]
  141. 141. 
    Berer K, Gerdes LA, Cekanaviciute E, Jia X, Xiao L et al. 2017. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. PNAS 114:10719–24
    [Google Scholar]
  142. 142. 
    Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S et al. 2017. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. PNAS 114:10713–18
    [Google Scholar]
  143. 143. 
    Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ et al. 2017. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci. Adv. 3:e1700492
    [Google Scholar]
  144. 144. 
    Balasa R, Barcutean L, Balasa A, Motataianu A, Roman-Filip C, Manu D. 2020. The action of TH17 cells on blood brain barrier in multiple sclerosis and experimental autoimmune encephalomyelitis. Hum. Immunol. 81:237–43
    [Google Scholar]
  145. 145. 
    Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M et al. 2011. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479:538–41
    [Google Scholar]
  146. 146. 
    Miyauchi E, Kim SW, Suda W, Kawasumi M, Onawa S et al. 2020. Gut microorganisms act together to exacerbate inflammation in spinal cords. Nature 585:102–6
    [Google Scholar]
  147. 147. 
    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM et al. 2009. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J. Immunol. 183:6041–50
    [Google Scholar]
  148. 148. 
    Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. 2011. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. PNAS 108:Suppl. 14615–22
    [Google Scholar]
  149. 149. 
    Seifert HA, Benedek G, Nguyen H, Gerstner G, Zhang Y et al. 2018. Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells. Metab. Brain Dis. 33:1599–607
    [Google Scholar]
  150. 150. 
    Godel C, Kunkel B, Kashani A, Lassmann H, Arumugam M, Krishnamoorthy G 2020. Perturbation of gut microbiota decreases susceptibility but does not modulate ongoing autoimmune neurological disease. J. Neuroinflamm. 17:79
    [Google Scholar]
  151. 151. 
    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–98
    [Google Scholar]
  152. 152. 
    Ivanov II, de Llanos Frutos R, Manel N, Yoshinaga K, Rifkin DB et al. 2008. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–49
    [Google Scholar]
  153. 153. 
    Goto Y, Panea C, Nakato G, Cebula A, Lee C et al. 2014. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40:594–607
    [Google Scholar]
  154. 154. 
    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S et al. 2010. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J. Immunol. 185:4101–8
    [Google Scholar]
  155. 155. 
    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. 2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–18
    [Google Scholar]
  156. 156. 
    Ochoa-Reparaz J, Mielcarz DW, Wang Y, Begum-Haque S, Dasgupta S et al. 2010. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol 3:487–95
    [Google Scholar]
  157. 157. 
    Wang Y, Begum-Haque S, Telesford KM, Ochoa-Reparaz J, Christy M et al. 2014. A commensal bacterial product elicits and modulates migratory capacity of CD39+ CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes 5:552–61
    [Google Scholar]
  158. 158. 
    Wang Y, Telesford KM, Ochoa-Reparaz J, Haque-Begum S, Christy M et al. 2014. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat. Commun. 5:4432
    [Google Scholar]
  159. 159. 
    Shahi SK, Freedman SN, Murra AC, Zarei K, Sompallae R et al. 2019. Prevotella histicola, a human gut commensal, is as potent as COPAXONE® in an animal model of multiple sclerosis. Front. Immunol. 10:462
    [Google Scholar]
  160. 160. 
    Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E et al. 2017. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep 20:1269–77
    [Google Scholar]
  161. 161. 
    Liu S, Rezende RM, Moreira TG, Tankou SK, Cox LM et al. 2019. Oral administration of miR-30d from feces of MS patients suppresses MS-like symptoms in mice by expanding Akkermansia muciniphila. Cell Host Microbe 26:779–94.e8
    [Google Scholar]
  162. 162. 
    Zhang T, Li Q, Cheng L, Buch H, Zhang F. 2019. Akkermansia muciniphila is a promising probiotic. Microb. Biotechnol. 12:1109–25
    [Google Scholar]
  163. 163. 
    Kuczma MP, Szurek EA, Cebula A, Chassaing B, Jung YJ et al. 2020. Commensal epitopes drive differentiation of colonic Tregs. Sci. Adv. 6:eaaz3186
    [Google Scholar]
  164. 164. 
    Trend S, Leffler J, Jones AP, Cha L, Gorman S et al. 2021. Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis. Sci. Rep. 11:5244
    [Google Scholar]
  165. 165. 
    Saresella M, Marventano I, Barone M, La Rosa F, Piancone F et al. 2020. Alterations in circulating fatty acid are associated with gut microbiota dysbiosis and inflammation in multiple sclerosis. Front. Immunol. 11:1390
    [Google Scholar]
  166. 166. 
    Olsson A, Gustavsen S, Nguyen TD, Nyman M, Langkilde AR et al. 2021. Serum short-chain fatty acids and associations with inflammation in newly diagnosed patients with multiple sclerosis and healthy controls. Front. Immunol. 12:661493
    [Google Scholar]
  167. 167. 
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–41
    [Google Scholar]
  168. 168. 
    Calvo-Barreiro L, Eixarch H, Cornejo T, Costa C, Castillo M et al. 2021. Selected Clostridia strains from the human microbiota and their metabolite, butyrate, improve experimental autoimmune encephalomyelitis. Neurotherapeutics 18:92037
    [Google Scholar]
  169. 169. 
    Chen H, Ma X, Liu Y, Ma L, Chen Z et al. 2019. Gut microbiota interventions with Clostridium butyricum and norfloxacin modulate immune response in experimental autoimmune encephalomyelitis mice. Front. Immunol. 10:1662
    [Google Scholar]
  170. 170. 
    Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J et al. 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–55
    [Google Scholar]
  171. 171. 
    Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–50
    [Google Scholar]
  172. 172. 
    Park J, Kim M, Kang SG, Jannasch AH, Cooper B et al. 2015. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 8:80–93
    [Google Scholar]
  173. 173. 
    Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI et al. 2020. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell 180:1067–80.e16
    [Google Scholar]
/content/journals/10.1146/annurev-immunol-101320-014237
Loading
/content/journals/10.1146/annurev-immunol-101320-014237
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error