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Organ-specific protection mediated by cooperation between vascular and epithelial barriers

Key Points

  • The classical concept of immune privilege as an exclusion of immune cells has been extended to include sites of immune tolerance induction, such as the intestine.

  • Barriers can be grouped into three main categories: first, protective barriers consisting of tightly regulated endothelial layers, such as the blood–brain barrier and the inner blood–retinal barrier; second, more permissive endothelial layers, such as the gut–vascular barrier; and third, immunomodulatory selective epithelial gateways, such as the blood–cerebrospinal fluid barrier, intestinal epithelial barrier and outer blood–retinal barrier.

  • The intestinal microbiota can influence the functionality of not only proximal intestinal barriers but also other vascular barriers that are present at distant sites, such as the brain, eye and testis.

  • Disruption of intestinal barriers and leakage of bacteria and/or bacterial metabolites can lead to the failure of other barriers at distant sites and the development of various neurological, metabolic and intestinal disorders.

Abstract

Immune privilege is a complex process that protects organs from immune-mediated attack and damage. It is accomplished by a series of cellular barriers that both control immune cell entry and promote the development of tolerogenic immune cells. In this Review, we describe the vascular endothelial and epithelial barriers in organs that are commonly considered to be immune privileged, such as the brain and the eye. We compare these classical barriers with barriers in the intestine, which share features with barriers of immune-privileged organs, such as the capacity to induce tolerance and to protect from external insults. We suggest that when intestinal barriers break down, disruption of other barriers at distant sites can ensue, and this may underlie the development of various neurological, metabolic and intestinal disorders.

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Figure 1: Cellular components of brain barriers.
Figure 2: The blood–retinal barrier.
Figure 3: The intestinal barriers.
Figure 4: Impact of the microbiota on physiological barrier functions.
Figure 5: Effect of dysbiosis and barrier failure on disease onset.

References

  1. 1

    Medawar, P. B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 129, 58–69 (1948).

    Google Scholar 

  2. 2

    Iweala, O. I. & Nagler, C. R. Immune privilege in the gut: the establishment and maintenance of non-responsiveness to dietary antigens and commensal flora. Immunol. Rev. 213, 82–100 (2006).

    PubMed  Google Scholar 

  3. 3

    Chistiakov, D. A., Bobryshev, Y. V., Kozarov, E., Sobenin, I. A. & Orekhov, A. N. Intestinal mucosal tolerance and impact of gut microbiota to mucosal tolerance. Front. Microbiol. 6, 781 (2015).

    Google Scholar 

  4. 4

    Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Spadoni, I. et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 350, 830–834 (2015). This study demonstrates the existence of the GVB and shows that endothelial cells control the passage of antigens into the bloodstream and prohibit entry of the microbiota.

    CAS  PubMed  Google Scholar 

  6. 6

    Forrester, J. V., Xu, H., Lambe, T. & Cornall, R. Immune privilege or privileged immunity? Mucosal Immunol. 1, 372–381 (2008).

    CAS  PubMed  Google Scholar 

  7. 7

    Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    CAS  PubMed  Google Scholar 

  8. 8

    Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D. & Ploix, C. C. CNS immune privilege: Hiding in plain sight. Immunol. Rev. 213, 48–65 (2006).

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Louveau, A., Harris, T. H. & Kipnis, J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36, 569–577 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Shechter, R., London, A. & Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13, 206–218 (2013). This article summarizes literature on barriers at immune-privileged sites.

    CAS  PubMed  Google Scholar 

  11. 11

    Goto, Y. & Kiyono, H. Epithelial barrier: an interface for the cross-communication between gut flora and immune system. Immunol. Rev. 245, 147–163 (2012).

    CAS  PubMed  Google Scholar 

  12. 12

    Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).

    CAS  PubMed  Google Scholar 

  13. 13

    Stappenbeck, T. S., Hooper, L. V. & Gordon, J. I. Developmental regulation of intestinal angiogene sis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002).

    CAS  PubMed  Google Scholar 

  14. 14

    Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012).

    CAS  PubMed  Google Scholar 

  15. 15

    Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

    CAS  PubMed  Google Scholar 

  16. 16

    Braniste, V. et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158 (2014). This study demonstrates that the intestinal microbiota can shape BBB properties. It shows that mice lacking a normal intestinal microbiota have increased BBB permeability compared with pathogen-free mice and that recolonization of germ-free adult mice restores BBB functionality.

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Sharon, G., Sampson, T. R., Geschwind, D. H. & Mazmanian, S. K. The central nervous system and the gut microbiome. Cell 167, 915–932 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Amaral, F. A. et al. Commensal microbiota is fundamental for the development of inflammatory pain. Proc. Natl Acad. Sci. USA 105, 2193–2197 (2008).

    CAS  PubMed  Google Scholar 

  19. 19

    Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011). This study provides evidence that microbial colonization regulates signalling mechanisms, neurotransmitter turnover and synaptic-related protein production to affect motor control and anxiety behaviour.

    PubMed  Google Scholar 

  20. 20

    Al-Asmakh, M. et al. The gut microbiota and developmental programming of the testis in mice. PLoS ONE 9, e103809 (2014).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Andriessen, E. M. et al. Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization. EMBO Mol. Med. 8, e201606531 (2016).

    Google Scholar 

  22. 22

    Engelhardt, B. & Ransohoff, R. M. Capture, crawl, cross: The T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579–589 (2012).

    CAS  PubMed  Google Scholar 

  23. 23

    Nicholas, M. K., Antel, J. P., Stefansson, K. & Arnason, B. G. Rejection of fetal neocortical neural transplants by H-2 incompatible mice. J. Immunol. 139, 2275–2283 (1987).

    CAS  PubMed  Google Scholar 

  24. 24

    Mason, D. W. et al. The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents. Neuroscience 19, 685–694 (1986).

    CAS  PubMed  Google Scholar 

  25. 25

    Obermeier, B., Daneman, R. & Ransohoff, R. M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584–1596 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Alvarez, J. I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).

    CAS  PubMed  Google Scholar 

  27. 27

    Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).

    CAS  PubMed  Google Scholar 

  28. 28

    Owens, T., Bechmann, I. & Engelhardt, B. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol. 67, 1113–1121 (2008).

    PubMed  Google Scholar 

  29. 29

    Hickey, W. F. & Kimura, H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239, 290–292 (1988).

    CAS  PubMed  Google Scholar 

  30. 30

    Williams, K., Alvarez, X. & Lackner, A. A. Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 36, 156–164 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Harris, M. G. et al. Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci. Rep. 4, 4422 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Stewart, P. A. & Wiley, M. J. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev. Biol. 84, 183–192 (1981).

    CAS  PubMed  Google Scholar 

  33. 33

    Janzer, R. C. & Raff, M. C. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325, 253–257 (1987).

    CAS  PubMed  Google Scholar 

  34. 34

    Stenman, J. M. et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008).

    CAS  PubMed  Google Scholar 

  35. 35

    Raab, S. et al. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb. Haemost. 91, 595–605 (2004).

    CAS  PubMed  Google Scholar 

  36. 36

    Daneman, R. et al. Wnt/ß-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl Acad. Sci. USA 106, 641–646 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Liebner, S. et al. Wnt/ß-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409–417 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kuhnert, F. et al. Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330, 985–989 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Anderson, K. D. et al. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc. Natl Acad. Sci. USA 108, 2807–2812 (2011).

    CAS  PubMed  Google Scholar 

  40. 40

    Cullen, M. et al. GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc. Natl Acad. Sci. USA 108, 5759–5764 (2011).

    CAS  PubMed  Google Scholar 

  41. 41

    Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).

    CAS  PubMed  Google Scholar 

  44. 44

    Bell, R. D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010). The studies in references 42–44 demonstrate a clear role for pericytes in different phases of BBB development and during ageing.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Lee, S.-W. et al. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat. Med. 9, 900–906 (2003).

    CAS  PubMed  Google Scholar 

  46. 46

    Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Methia, N. et al. ApoE deficiency compromises the blood brain barrier especially after injury. Mol. Med. 7, 810–815 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Hafezi-Moghadam, A., Thomas, K. L. & Wagner, D. D. ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. AJP Cell Physiol. 292, C1256–C1262 (2006).

    Google Scholar 

  49. 49

    Mizee, M. R. et al. Retinoic acid induces blood-brain barrier development. J. Neurosci. 33, 1660–1671 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Liddelow, S. A. Development of the choroid plexus and blood-CSF barrier. Front. Neurosci. 9, 32 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Lun, M. P., Monuki, E. S. & Lehtinen, M. K. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat. Rev. Neurosci. 16, 445–457 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Johansson, P. A. The choroid plexuses and their impact on developmental neurogenesis. Front. Neurosci. 8, 340 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. 53

    Steinemann, A., Galm, I., Chip, S., Nitsch, C. & Maly, I. P. Claudin-1, -2 and -3 are selectively expressed in the epithelia of the choroid plexus of the mouse from early development and into adulthood while claudin-5 is restricted to endothelial cells. Front. Neuroanat. 10, 16 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    Kratzer, I. et al. Complexity and developmental changes in the expression pattern of claudins at the blood-CSF barrier. Histochem. Cell Biol. 138, 861–879 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Wolburg, H., Wolburg-Buchholz, K., Liebner, S. & Engelhardt, B. Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci. Lett. 307, 77–80 (2001).

    CAS  PubMed  Google Scholar 

  56. 56

    Lun, M. P., Monuki, E. S. & Lehtinen, M. K. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat Rev Neurosci. 16, 445–457 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Caspi, R. R. Ocular autoimmunity: the price of privilege? Immunol. Rev. 213, 23–35 (2006).

    PubMed  Google Scholar 

  58. 58

    Zhou, L. et al. The Schlemm's canal is a VEGF-C/VEGFR-3–responsive lymphatic-like vessel. Mol. Vis. 12, 639–643 (2014).

    Google Scholar 

  59. 59

    Kaur, C., Foulds, W. S. & Ling, E. A. Blood–retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog. Retin. Eye Res. 27, 622–647 (2008).

    CAS  PubMed  Google Scholar 

  60. 60

    Kim, J. H., Kim, J. H., Yu, Y. S., Kim, D. H. & Kim, K. W. Recruitment of pericytes and astrocytes is closely related to the formation of tight junction in developing retinal vessels. J. Neurosci. Res. 87, 653–659 (2009).

    CAS  PubMed  Google Scholar 

  61. 61

    Yao, H. et al. The development of blood-retinal barrier during the interaction of astrocytes with vascular wall cells. Neural Regen. Res. 9, 1047–1054 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Tout, S., Chan-Ling, T., Holländer, H. & Stone, J. The role of müller cells in the formation of the blood-retinal barrier. Neuroscience 55, 291–301 (1993).

    CAS  PubMed  Google Scholar 

  63. 63

    Shen, W. et al. Conditional muller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J. Neurosci. 32, 15715–15727 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Chow, B. W. & Gu, C. Gradual suppression of transcytosis governs functional blood-retinal barrier formation. Neuron 93, 1325–1333.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Ogura, S. et al. Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown. JCI Insight 2, e90905 (2017).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Simò, R., Villarroel, M., Corraliza, L., Hernàndez, C. & Garcia-Ramìrez, M. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier — implications for the pathogenesis of diabetic retinopathy. BioMed Res. 2010, 1–15 (2010).

    Google Scholar 

  67. 67

    Rizzolo, L. J. Barrier properties of cultured retinal pigment epithelium. Exp. Eye Res. 126, 16–26 (2014).

    CAS  PubMed  Google Scholar 

  68. 68

    Sugita, S., Futagami, Y., Smith, S. B., Naggar, H. & Mochizuki, M. Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp. Eye Res. 83, 1459–1471 (2006).

    CAS  PubMed  Google Scholar 

  69. 69

    Fang, Y., Yu, S., Ellis, J. S., Sharav, T. & Braley-mullen, H. Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis. J. Leukoc. Biol. 87, 1019–1028 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Sohn, J. H., Kaplan, H. J., Suk, H. J., Bora, P. S. & Bora, N. S. Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Investig. Ophthalmol. Vis. Sci. 41, 3492–3502 (2000).

    CAS  Google Scholar 

  71. 71

    Taylor, A. A review of the influence of aqueous humor on immunity. Ocul. Immunol. Inflamm. 11, 231–241 (2003).

    CAS  PubMed  Google Scholar 

  72. 72

    Cousins, S. W., McCabe, M. M., Danielpour, D. & Streilein, J. W. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Investig. Ophthalmol. Vis. Sci. 32, 2201–2211 (1991).

    CAS  Google Scholar 

  73. 73

    Wilbanks, G. A. & Streilein, J. W. Characterization of suppressor cells in anterior chamber-associated immune deviation (ACAID) induced by soluble antigen. Evidence of two functionally and phenotypically distinct T-suppressor cell populations. Immunology 71, 383–389 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Niederkorn, J. Y. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat. Immunol. 7, 354–359 (2006). An exhaustive review of the processes contributing to the immune-privileged status of the eye.

    CAS  PubMed  Google Scholar 

  75. 75

    Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006).

    CAS  PubMed  Google Scholar 

  76. 76

    Mowat, A. M. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–341 (2003).

    CAS  PubMed  Google Scholar 

  77. 77

    Pelaseyed, T. et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8–20 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Daneman, R. & Rescigno, M. The gut immune barrier and the blood-brain barrier: are they so different? Immunity 31, 722–735 (2009).

    CAS  PubMed  Google Scholar 

  79. 79

    Spadoni, I., Pietrelli, A., Pesole, G. & Rescigno, M. Gene expression profile of endothelial cells during perturbation of the gut vascular barrier. Gut Microbes 7, 1–9 (2016).

    Google Scholar 

  80. 80

    Bush, T. G. et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93, 189–201 (1998).

    CAS  PubMed  Google Scholar 

  81. 81

    Cornet, A. et al. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease? Proc. Natl Acad. Sci. USA 98, 13306–13311 (2001).

    CAS  PubMed  Google Scholar 

  82. 82

    Savidge, T. C. et al. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 132, 1344–1358 (2007).

    CAS  PubMed  Google Scholar 

  83. 83

    Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Mazzini, E., Massimiliano, L., Penna, G. & Rescigno, M. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 40, 248–261 (2014).

    CAS  PubMed  Google Scholar 

  85. 85

    Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Schulz, O. et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 206, 3101–3114 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Iliev, I. D., Mileti, E., Matteoli, G., Chieppa, M. & Rescigno, M. Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. 2, 340–350 (2009).

    CAS  PubMed  Google Scholar 

  90. 90

    Iliev, I. D. et al. Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut 58, 1481–1489 (2009).

    CAS  PubMed  Google Scholar 

  91. 91

    Goubier, A. et al. Plasmacytoid dendritic cells mediate oral tolerance. Immunity 29, 464–475 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Balmer, M. L. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl. Med. 6, 237ra66 (2014). This study demonstrates that the liver acts as a vascular firewall that impedes intestinal bacteria from entering the bloodstream during intestinal pathology, spreading systemically and activating non-mucosal immune responses.

    PubMed  Google Scholar 

  93. 93

    Macpherson, A. J. & Smith, K. Mesenteric lymph nodes at the center of immune anatomy. J. Exp. Med. 203, 497–500 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Sonobe, Y. et al. Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase C-dependent manner. J. Biol. Chem. 284, 31834–31842 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Barkalow, F. J., Goodman, M. J., Gerritsen, M. E. & Mayadas, T. N. Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion. Blood 88, 4585–4593 (1996).

    CAS  PubMed  Google Scholar 

  96. 96

    McCandless, E. E., Wang, Q., Woerner, B. M., Harper, J. M. & Klein, R. S. CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J. Immunol. 177, 8053–8064 (2006).

    CAS  PubMed  Google Scholar 

  97. 97

    Kivisakk, P. et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl Acad. Sci. USA 100, 8389–8394 (2003).

    PubMed  Google Scholar 

  98. 98

    Taylor, A. W. & Streilein, J. W. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation 3, 112–118 (1996).

    CAS  PubMed  Google Scholar 

  99. 99

    Pentreath, V. W., Rees, K., Owolabi, O. A., Philip, K. A. & Doua, F. The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients. Trans. R. Soc. Trop. Med. Hyg. 84, 795–799 (1990).

    CAS  PubMed  Google Scholar 

  100. 100

    Tarkowski, E., Liljeroth, A. M., Nilsson, A., Minthon, L. & Blennow, K. Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 12, 314–317 (2001).

    CAS  PubMed  Google Scholar 

  101. 101

    Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-ß and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Matteoli, G. et al. Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut 59, 595–604 (2010).

    CAS  PubMed  Google Scholar 

  103. 103

    Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275 (2006).

    CAS  PubMed  Google Scholar 

  104. 104

    Antoniol, C. & Stankoff, B. Immunological markers for PML prediction in MS patients treated with natalizumab. Front. Immunol. 6, 668 (2015).

    Google Scholar 

  105. 105

    Tsilingiri, K. & Rescigno, M. Postbiotics: what else? Benef. Microbes 4, 101–107 (2013).

    CAS  PubMed  Google Scholar 

  106. 106

    Kelly, J. R. et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front. Cell. Neurosci. 9, 392 (2015).

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Acharya, N. K. et al. Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib. J. Alzheimers Dis. 35, 179–198 (2013).

    CAS  PubMed  Google Scholar 

  108. 108

    Acharya, N. K. et al. Retinal pathology is associated with increased blood-retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib. Diabetes Vasc. Dis. Res. 14, 200–213 (2017).

    CAS  Google Scholar 

  109. 109

    Ibrahim, S. H., Voigt, R. G., Katusic, S. K., Weaver, A. L. & Barbaresi, W. J. Incidence of gastrointestinal symptoms in children with autism: a population-based study. Pediatrics 124, 680–686 (2009).

    PubMed  PubMed Central  Google Scholar 

  110. 110

    Klukowski, M., Wasilewska, J. & Lebensztejn, D. Sleep and gastrointestinal disturbances in autism spectrum disorder in children. Dev. Period Med. 19, 157–161 (2015).

    PubMed  Google Scholar 

  111. 111

    Chaidez, V., Hansen, R. L. & Hertz-Picciotto, I. Gastrointestinal problems in children with autism, developmental delays or typical development. J. Autism Dev. Disord. 44, 1117–1127 (2014).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Horvath, K. & Perman, J. Autistic disorder and gastrointestinal disease. Curr. Opin. Pediatr. 14, 583–587 (2002).

    PubMed  Google Scholar 

  113. 113

    Kushak, R. I. et al. Evaluation of intestinal function in children with autism and gastrointestinal symptoms. J. Pediatr. Gastroenterol. Nutr. 62, 687–691 (2016).

    PubMed  Google Scholar 

  114. 114

    de Magistris, L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J. Pediatr. Gastroenterol. Nutr. 51, 418–424 (2010).

    PubMed  Google Scholar 

  115. 115

    Fiorentino, M. et al. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol. Autism 7, 49 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Nitta, T. et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J. Cell. Biol. 161, 653–660 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Bruce-Keller, A. J. et al. Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol. Psychiatry 77, 607–615 (2015).

    PubMed  Google Scholar 

  118. 118

    Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011). This work demonstrates that intestinal bacteria influence inflammatory immune responses in the CNS, favouring EAE development.

    CAS  PubMed  Google Scholar 

  120. 120

    Devos, D. et al. Colonic inflammation in Parkinson's disease. Neurobiol. Dis. 50, 42–48 (2013).

    CAS  PubMed  Google Scholar 

  121. 121

    Shannon, K. M. et al. α-Synuclein in colonic submucosa in early untreated Parkinson's disease. Mov. Disord. 27, 709–715 (2012).

    PubMed  Google Scholar 

  122. 122

    Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).

    PubMed  Google Scholar 

  123. 123

    Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of parkinson's disease. Cell 167, 1469–1480 (2016). This study shows the functional role of the intestinal microbiota in promoting α -synuclein-mediated brain pathology and motor deficits in a mouse model of Parkinson disease. Interestingly, transplantation of faecal microorganisms from patients with Parkinson disease into mice is shown to be sufficient to impair motor functions.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Mariadason, J. M., Barkla, D. H. & Gibson, P. R. Effect of short-chain fatty acids on paracellular permeability in Caco-2 intestinal epithelium model. Am. J. Physiol. 272, G705–G712 (1997).

    CAS  PubMed  Google Scholar 

  126. 126

    Tărlungeanu, D. C. et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell 167, 1481–1494 (2016).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Bosi, E. et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824–2827 (2006).

    CAS  PubMed  Google Scholar 

  128. 128

    Sapone, A. et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55, 1443–1449 (2006).

    CAS  PubMed  Google Scholar 

  129. 129

    Daft, J. G. & Lorenz, R. G. Role of the gastrointestinal ecosystem in the development of type 1 diabetes. Pediatr. Diabetes 16, 407–418 (2015).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    Schuppan, D. & Hahn, E. G. Celiac disease and its link to type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 14 (Suppl. 1), 597–605 (2001).

    PubMed  Google Scholar 

  131. 131

    Ménard, S., Cerf-Bensussan, N. & Heyman, M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 3, 247–259 (2010).

    PubMed  Google Scholar 

  132. 132

    De Goffau, M. C. et al. Fecal microbiota composition differs between children with b-cell autoimmunity and those without. Diabetes 62, 1238–1244 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Mariño, E. et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat. Immunol. 18, 552–562 (2017).

    PubMed  Google Scholar 

  134. 134

    Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    CAS  PubMed  Google Scholar 

  135. 135

    Mosier, M. A., Lopez, K. H., Noorbaksh, K. R. & Charles, M. A. Early retinal and renal abnormalities in diabetes. J. Diabetes Compl. 11, 218–224 (1997).

    CAS  Google Scholar 

  136. 136

    Gordin, D. et al. Pre-eclampsia and pregnancy-induced hypertension are associated with severe diabetic retinopathy in type 1 diabetes later in life. Acta Diabetol. 50, 781–787 (2013).

    CAS  PubMed  Google Scholar 

  137. 137

    Slyepchenko, A. et al. Intestinal dysbiosis, gut hyperpermeability and bacterial translocation: missing links between depression, obesity and type 2 diabetes? Curr. Pharm. Des. 22, 6087–6106 (2016).

    CAS  PubMed  Google Scholar 

  138. 138

    Slyepchenko, A. et al. Gut microbiota, bacterial translocation, and interactions with diet: pathophysiological links between major depressive disorder and non-communicable medical comorbidities. Psychother Psychosom. 8686, 31–4631 (2017).

    Google Scholar 

  139. 139

    Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15, 382–392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Duboc, H. et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62, 531–539 (2013). This work shows that IBD-associated dysbiosis leads to modifications in the bile acid pool and consequently amplifies chronic inflammation processes.

    CAS  PubMed  Google Scholar 

  141. 141

    Chiodini, R. J., Dowd, S. E., Galandiuk, S., Davis, B. & Glassing, A. The predominant site of bacterial translocation across the intestinal mucosal barrier occurs at the advancing disease margin in Crohn's disease. Microbiol 162, 1608–1619 (2016).

    CAS  Google Scholar 

  142. 142

    Ott, C. & Scholmerich, J. Extraintestinal manifestations and complications in IBD. Nat. Rev. Gastroenterol. Hepatol. 10, 585–595 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work is supported by the European Council of Research (Consolidator grant HomeoGUT, 615735), the Italian Association for Cancer Research (AIRC) and the Italian Ministry of Health (Ricerca finalizzata). G.F. is supported by the Italian Ministry of Health (grant GR-2013-02359806) and by Fondazione Cariplo (grant 2016–0472).

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I.S. and M.R. wrote the article and reviewed and edited the manuscript before submission. G.F. contributed to researching data for the article and reviewed and edited the manuscript before submission.

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Correspondence to Maria Rescigno.

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The authors declare no competing financial interests.

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Glossary

Inflammatory bowel diseases

(IBDs). Chronic disorders of the intestine characterized by severe inflammation and mucosal tissue destruction. There are two main forms: Crohn's disease, which is a granulomatous segmental inflammation affecting any part of the intestine, and ulcerative colitis, which is a mucosal inflammation involving the rectum and extending for a variable distance along the colon.

Meninges

Vascularized tissue membranes that envelop superficial central nervous system areas and enclose the parenchyma. The meninges are composed of three layers: the dura mater (outermost, beneath the skull), the arachnoid mater and the pia mater (the innermost layer, which is proximal to the parenchyma).

Astrocyte

A type of glial cell that is found in the vertebrate brain and is named for its characteristic star-like shape. Astrocytes provide both mechanical and metabolic support for neurons, thereby regulating the environment in which neurons function.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Pericytes

Cells that are embedded in the vascular basement membrane of microvessels. They make close contact with endothelial cells, and this interaction is essential for the maintenance of vessel function, as well as for the regulation of angiogenesis and vascular remodelling.

Fenestrated capillaries

A non-continuous vascular bed characterized by the presence of pore-like subcellular structures, or fenestrae, that are responsible for transcellular exchange of molecules. Fenestrated endothelia are located in the intestine, pancreas, endocrine glands, glomeruli of the kidney and liver sinusoids.

Müller cells

The major type of glial cell that is found in the retina. These cells contribute to retinal homeostasis and function and regulate the tightness of the blood–retinal barrier.

Diabetic retinopathy

A condition affecting people with diabetes that causes progressive damage to the retina, the light-sensitive tissue at the back of the eye.

Aqueous humour

The clear immunosuppressive and anti-inflammatory fluid that fills the anterior chamber of the eye.

Anterior chamber-associated immune deviation

(ACAID). A form of eye-derived tolerance in which T helper 1 (TH1)- and TH2-mediated immunity is suppressed but non-inflammatory adaptive immune effectors are present.

Lamina propria

The layer of mucosal tissue directly under the mucosal epithelial cell surface in which effector cells for mucosal immunity reside.

Goblet cells

Mucus-producing cells found in the epithelial-cell lining of the intestine and lungs.

Paneth cells

Specialized enterocytes that are present at the base of the crypts in the intestinal epithelium and that produce antimicrobial proteins and peptides, including phospholipase A2 and defensins.

Pyramidal neurons

Type of nerve cells with a pyramidal-shaped cell body (soma) and two distinct dendrite trees (the longer apical and the shorter basal trees). They are present in most mammalian forebrain structures (cerebral cortex, hippocampus and amygdala), and they are associated with advanced cognitive functions.

Dysbiosis

A condition in which the balance of the bacterial communities that constitute the intestinal microbiota is altered. Dysbiosis may be a predisposition factor for several diseases.

Lewy pathology

A pathology characterized by the presence of abnormal α-synuclein aggregates (bodies) in the residual neurons of the substantia nigra and in the enteric nervous system. Lewy bodies are the histological hallmark of Parkinson disease.

Microglia

Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are thought to be the major brain-resident macrophages.

Autophagy

A specialized process involving the degradative delivery of a portion of the cytoplasm or of damaged organelles to the lysosome. Internalized pathogens can also be eliminated by this pathway.

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Spadoni, I., Fornasa, G. & Rescigno, M. Organ-specific protection mediated by cooperation between vascular and epithelial barriers. Nat Rev Immunol 17, 761–773 (2017). https://doi.org/10.1038/nri.2017.100

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