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From “Leaky Gut” to Impaired Glia-Neuron Communication in Depression

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Major Depressive Disorder

Abstract

In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD). Psychological stress and various inflammatory comorbidities contribute to such immune activation. Still, this is not uncommon that patients with depression do not have defined inflammatory comorbidities, and alternative mechanisms of immune activation need to take place. The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. There is a broad range of reciprocal interactions between the GI tract, intestinal microbiota, increased intestinal permeability, activation of immune-inflammatory response, and the CNS that has crucial implications in brain function and mental health. This intercommunication takes place within the microbiota-gut-immune-glia (MGIG) axis, and glial cells are the main orchestrator of this communication. A broad range of factors, including psychological stress, inflammation, dysbiosis, may compromise the permeability of this barrier. This leads to excessive bacterial translocation and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. This chapter summarizes the role of increased intestinal permeability in MDD and mechanisms of how the “leaky gut” may contribute to immune-inflammatory response in this disorder.

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References

  1. Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35(4):298–306

    Article  CAS  PubMed  Google Scholar 

  2. Maes M, Smith R, Simon S (1995) The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology 20(2):111–116

    Article  CAS  PubMed  Google Scholar 

  3. Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61(5–6):519–525

    Article  CAS  PubMed  Google Scholar 

  4. Maes M (2008) The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 29(3):287–291

    CAS  PubMed  Google Scholar 

  5. Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression. Neuropharmacology 62(1):63–77

    Article  CAS  PubMed  Google Scholar 

  6. Maes M, Kubera M, Leunis JC (2008) The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett 29(1):117–124

    PubMed  Google Scholar 

  7. Maes M, Kubera M, Leunis JC, Berk M (2012) Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 141(1):55–62

    Article  CAS  PubMed  Google Scholar 

  8. Rial D, Lemos C, Pinheiro H, Duarte JM, Gonçalves FQ, Real JI et al (2016) Depression as a glial-based synaptic dysfunction. Front Cell Neurosci 9

    Google Scholar 

  9. Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Prog Neuro-Psychopharmacol Biol Psychiatry 19(1):11–38

    Article  CAS  Google Scholar 

  10. Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):676–692

    Article  CAS  Google Scholar 

  11. Liu T, Zhong S, Liao X, Chen J, He T, Lai S et al (2015) A meta-analysis of oxidative stress markers in depression. PLoS One 10(10):e0138904

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Maes M, Landucci Bonifacio K, Morelli NR, Vargas HO, Barbosa DS, Carvalho AF et al (2018) Major differences in neurooxidative and neuronitrosative stress pathways between major depressive disorder and Types I and II bipolar disorder. Mol Neurobiol 56:1–16

    Google Scholar 

  13. Maes M, Moraes JB, Congio A, Bonifacio KL, Barbosa DS, Vargas HO et al (2019) Development of a novel staging model for affective disorders using partial least squares bootstrapping: effects of lipid-associated antioxidant defenses and neuro-oxidative stress. Mol Neurobiol

    Google Scholar 

  14. Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127(5):344–354

    Article  CAS  PubMed  Google Scholar 

  15. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98(1–2):143–151

    Article  CAS  PubMed  Google Scholar 

  16. Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R (2011) The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):702–721

    Article  CAS  Google Scholar 

  17. Myint AM, Schwarz MJ, Muller N. The role of the kynurenine metabolism in major depression. Journal of neural transmission (Vienna, Austria : 1996). 2012;119(2):245–51

    Google Scholar 

  18. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein H-G, Sarnyai Z et al (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation 8(1):94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shields GS, Slavich GM (2017) Lifetime stress exposure and health: a review of contemporary assessment methods and biological mechanisms. Soc Personal Psychol Compass 11(8):e12335

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D et al (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A 100(4):1920–1925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Munhoz CD, Lepsch LB, Kawamoto EM, Malta MB, Lima LS, Werneck Avellar MC et al (2006) Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-κB in the frontal cortex and Hippocampus via glucocorticoid secretion. J Neurosci 26(14):3813–3820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garate I, Garcia-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML et al (2013) Stress-induced neuroinflammation: role of the toll-like receptor-4 pathway. Biol Psychiatry 73(1):32–43

    Article  CAS  PubMed  Google Scholar 

  23. Bailey MT, Engler H, Powell ND, Padgett DA, Sheridan JF (2007) Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway. Am J Physiol Regul Integr Comp Physiol 293(3):R1180–R1R90

    Article  CAS  PubMed  Google Scholar 

  24. Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN et al (2005) Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135(4):1295–1307

    Article  CAS  PubMed  Google Scholar 

  25. Rudzki L, Maes M (2020) The microbiota-gut-immune-glia (MGIG) Axis in major depression. Mol Neurobiol 57(10):4269–4295

    Article  CAS  PubMed  Google Scholar 

  26. Vaure CL, Liu Y (2014) A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol 5

    Google Scholar 

  27. Wang L, Wu J, Guo X, Huang X, Huang Q (2017) RAGE plays a role in LPS-induced NF-κB activation and endothelial Hyperpermeability. Sensors 17(4):722

    Article  CAS  PubMed Central  Google Scholar 

  28. Soderholm JD, Perdue MH (2001) Stress and gastrointestinal tract. II. Stress and intestinal barrier function. Am J Physiol Gastrointest Liver Physiol 280(1):G7–g13

    Article  CAS  PubMed  Google Scholar 

  29. Ferrier L (2008) Significance of increased human colonic permeability in response to corticotrophin-releasing hormone (CRH). Gut 57(1):7–9

    Article  CAS  PubMed  Google Scholar 

  30. Lambert GP (2009) Stress-induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci 87(14 Suppl):E101–E108

    Article  CAS  PubMed  Google Scholar 

  31. Keita AV, Soderholm JD (2010) The intestinal barrier and its regulation by neuroimmune factors. Neurogastroenterol Motil 22(7):718–733

    Article  CAS  PubMed  Google Scholar 

  32. Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E et al (2014) Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 63(8):1293–1299

    Article  CAS  PubMed  Google Scholar 

  33. De Punder K, Pruimboom L (2015) Stress induces Endotoxemia and low-grade inflammation by increasing barrier permeability. Front Immunol 6

    Google Scholar 

  34. Zhang L, Song J, Bai T, Qian W, Hou X-H (2017) Stress induces more serious barrier dysfunction in follicle-associated epithelium than villus epithelium involving mast cells and protease-activated receptor-2. Sci Rep 7(1):4950

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Lange S, Delbro DS (1995) Adrenoceptor-mediated modulation of Evans blue dye permeation of rat small intestine. Dig Dis Sci 40(12):2623–2629

    Article  CAS  PubMed  Google Scholar 

  36. Schäper J, Wagner A, Enigk F, Brell B, Mousa SA, Habazettl H et al (2013) Regional sympathetic blockade attenuates activation of intestinal macrophages and reduces Gut barrier failure. Anesthesiology 118(1):134–142

    Article  PubMed  CAS  Google Scholar 

  37. Beaurepaire C, Smyth D, McKay DM (2009) Interferon-gamma regulation of intestinal epithelial permeability. J Interf Cytokine Res 29(3):133–144

    Article  CAS  Google Scholar 

  38. Schmitz H, Fromm M, Bentzel CJ, Scholz P, Detjen K, Mankertz J et al (1999) Tumor necrosis factor-alpha (TNFalpha) regulates the epithelial barrier in the human intestinal cell line HT-29/B6. J Cell Sci 112(Pt 1):137–146

    Article  CAS  PubMed  Google Scholar 

  39. Ye D, Ma I, Ma TY (2006) Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol 290(3):G496–G504

    Article  CAS  PubMed  Google Scholar 

  40. Al-Sadi RM, Ma TY (2007) IL-1beta causes an increase in intestinal epithelial tight junction permeability. J Immunol (Baltimore, Md: 1950) 178(7):4641–4649

    Article  CAS  Google Scholar 

  41. Chavez AM, Menconi MJ, Hodin RA, Fink MP (1999) Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide. Crit Care Med 27(10):2246–2251

    Article  CAS  PubMed  Google Scholar 

  42. Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA et al (2004) TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol 286(3):G367–G376

    Article  CAS  PubMed  Google Scholar 

  43. Bjarnason I, Peters TJ, Wise RJ (1984) The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet (London, England) 1(8370):179–182

    Article  CAS  Google Scholar 

  44. Bode C, Bode JC (2003) Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol 17(4):575–592

    Article  CAS  PubMed  Google Scholar 

  45. Leclercq S, Cani PD, Neyrinck AM, Starkel P, Jamar F, Mikolajczak M et al (2012) Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun 26(6):911–918

    Article  CAS  PubMed  Google Scholar 

  46. Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Starkel P et al (2014) Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A 111(42):E4485–E4493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Moreira APB, Texeira TFS, Ferreira AB, Do Carmo Gouveia Peluzio M, De Cássia Gonçalves Alfenas R (2012) Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br J Nutr 108(5):801–809

    Article  CAS  PubMed  Google Scholar 

  48. Teixeira TF, Collado MC, Ferreira CL, Bressan J, Peluzio MC (2012) Potential mechanisms for the emerging link between obesity and increased intestinal permeability. Nut Res (New York, NY) 32(9):637–647

    Article  CAS  Google Scholar 

  49. Pan P, Song Y, Du X, Bai L, Hua X, Xiao Y et al (2019) Intestinal barrier dysfunction following traumatic brain injury. Neurol Sci 40(6):1105–1110

    Article  PubMed  Google Scholar 

  50. Lerner A, Matthias T (2015) Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmun Rev 14(6):479–489

    Article  CAS  PubMed  Google Scholar 

  51. Csáki KF (2011) Synthetic surfactant food additives can cause intestinal barrier dysfunction. Med Hypotheses 76(5):676–681

    Article  PubMed  CAS  Google Scholar 

  52. Gillois K, Lévêque M, Théodorou V, Robert H, Mercier-Bonin M (2018) Mucus: an underestimated gut target for environmental pollutants and food additives. Microorganisms 6(2):53

    Article  PubMed Central  CAS  Google Scholar 

  53. Samsel A, Seneff S (2013) Glyphosate, pathways to modern diseases II: celiac sprue and gluten intolerance. Interdiscip Toxicol 6(4):159–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Joly Condette C, Khorsi-Cauet H, Morlière P, Zabijak L, Reygner J, Bach V et al (2014) Increased gut permeability and bacterial translocation after chronic chlorpyrifos exposure in rats. PLoS ONE 9(7):e102217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Defois C, Ratel J, Garrait G, Denis S, Le Goff O, Talvas J, et al. Food Chemicals Disrupt Human Gut Microbiota Activity And Impact Intestinal Homeostasis As Revealed By In Vitro Systems. Scientific reports. 2018;8(1)

    Google Scholar 

  56. Lambert GP (2008) Intestinal barrier dysfunction, endotoxemia, and gastrointestinal symptoms: the ‘canary in the coal mine’ during exercise-heat stress? Med Sport Sci 53:61–73

    Article  PubMed  Google Scholar 

  57. Pals KL, Chang RT, Ryan AJ, Gisolfi CV. Effect of running intensity on intestinal permeability. Journal of applied physiology (Bethesda, Md : 1985). 1997;82(2):571–6

    Google Scholar 

  58. Lambert GP, Gisolfi CV, Berg DJ, Moseley PL, Oberley LW, Kregel KC (2002) Selected contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress. J Appl Physiol (Bethesda, Md: 1985) 92(4):1750–1761; discussion 49

    Article  CAS  Google Scholar 

  59. Yamaguchi N, Sugita R, Miki A, Takemura N, Kawabata J, Watanabe J et al (2006) Gastrointestinal Candida colonisation promotes sensitisation against food antigens by affecting the mucosal barrier in mice. Gut 55(7):954–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Severance EG, Kannan G, Gressitt KL, Dickerson FB, Pletnikov MV, Yolken RH (2012) Antibodies to food antigens: translational research in psychiatric disorders. Neurol Psychiatry Brain Res 18(2):87–88

    Article  Google Scholar 

  61. van Ampting MT, Schonewille AJ, Vink C, Brummer RJ, van der Meer R, Bovee-Oudenhoven IM (2010) Damage to the intestinal epithelial barrier by antibiotic pretreatment of salmonella-infected rats is lessened by dietary calcium or tannic acid. J Nutr 140(12):2167–2172

    Article  PubMed  CAS  Google Scholar 

  62. Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC, Gopinath S et al (2013) Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502(7469):96–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tulstrup MV-L, Christensen EG, Carvalho V, Linninge C, Ahrné S, Højberg O et al (2015) Antibiotic treatment affects intestinal permeability and gut microbial composition in Wistar rats dependent on antibiotic class. PLoS One 10(12):e0144854

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Becattini S, Taur Y, Pamer EG (2016) Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med 22(6):458–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bjarnason I, Williams P, Smethurst P, Peters TJ, Levi AJ (1986) Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 27(11):1292–1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Smetanka RD, Lambert GP, Murray R, Eddy D, Horn M, Gisolfi CV (1999) Intestinal permeability in runners in the 1996 Chicago marathon. Int J Sport Nutr 9(4):426–433

    Article  CAS  PubMed  Google Scholar 

  67. Fukui H (2016) Increased intestinal permeability and decreased barrier function: does it really influence the risk of inflammation? Inflamm Intest Dis 1(3):135–145

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG (2001) The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48(2):206–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linlokken A, Wilson R et al (2014) Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil 26(8):1155–1162

    Article  CAS  PubMed  Google Scholar 

  70. Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y et al (2015) Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 48:186–194

    Article  PubMed  Google Scholar 

  71. Aizawa E, Tsuji H, Asahara T, Takahashi T, Teraishi T, Yoshida S et al (2016) Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder. J Affect Disord 202:254–257

    Article  PubMed  Google Scholar 

  72. Lin P, Ding B, Feng C, Yin S, Zhang T, Qi X et al (2017) Prevotella and Klebsiella proportions in fecal microbial communities are potential characteristic parameters for patients with major depressive disorder. J Affect Disord 207:300–304

    Article  PubMed  Google Scholar 

  73. Cheung SG, Goldenthal AR, Uhlemann AC, Mann JJ, Miller JM, Sublette ME (2019) Systematic review of gut microbiota and major depression. Front Psych 10:34

    Article  Google Scholar 

  74. Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR (2016) Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 4(1):30

    Article  PubMed  PubMed Central  Google Scholar 

  75. Nguyen TT, Kosciolek T, Eyler LT, Knight R, Jeste DV (2018) Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. J Psychiatr Res 99:50–61

    Article  PubMed  PubMed Central  Google Scholar 

  76. Simeonova D, Stoyanov D, Leunis JC, Carvalho AF, Kubera M, Murdjeva M et al (2019) Increased serum immunoglobulin responses to gut commensal gram-negative Bacteria in unipolar major depression and bipolar disorder type 1, especially when Melancholia is present. Neurotox Res 37:338–348

    Article  PubMed  CAS  Google Scholar 

  77. Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism--comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11:22

    Article  PubMed  PubMed Central  Google Scholar 

  78. De Angelis M, Francavilla R, Piccolo M, De Giacomo A, Gobbetti M (2015) Autism spectrum disorders and intestinal microbiota. Gut Microbes 6(3):207–213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K et al (2015) Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav 138:179–187

    Article  CAS  PubMed  Google Scholar 

  80. Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J et al (2017) New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5(1):24

    Article  PubMed  PubMed Central  Google Scholar 

  81. Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I et al (2011) Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One 6(9):e24585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M (2011) Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 25(3):397–407

    Article  CAS  PubMed  Google Scholar 

  83. Galley JD, Bailey MT (2014) Impact of stressor exposure on the interplay between commensal microbiota and host inflammation. Gut Microbes 5(3):390–396

    Article  PubMed  PubMed Central  Google Scholar 

  84. Maltz RM, Keirsey J, Kim SC, Mackos AR, Gharaibeh RZ, Moore CC et al (2018) Prolonged restraint stressor exposure in outbred CD-1 mice impacts microbiota, colonic inflammation, and short chain fatty acids. PLoS One 13(5):e0196961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Stevens BR, Goel R, Seungbum K, Richards EM, Holbert RC, Pepine CJ et al (2018) Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut 67(8):1555.2–1555.7

    Article  CAS  Google Scholar 

  86. Calarge CA, Devaraj S, Shulman RJ (2019) Gut permeability and depressive symptom severity in unmedicated adolescents. J Affect Disord 246:586–594

    Article  PubMed  Google Scholar 

  87. Ohlsson L, Gustafsson A, Lavant E, Suneson K, Brundin L, Westrin A et al (2019) Leaky gut biomarkers in depression and suicidal behavior. Acta Psychiatrica Scandinavica 139(2):185–193

    Article  CAS  PubMed  Google Scholar 

  88. Severance EG, Alaedini A, Yang S, Halling M, Gressitt KL, Stallings CR et al (2012) Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res 138(1):48–53

    Article  PubMed  PubMed Central  Google Scholar 

  89. Severance EG, Gressitt KL, Stallings CR, Origoni AE, Khushalani S, Leweke FM et al (2013) Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res 148(1–3):130–137

    Article  PubMed  PubMed Central  Google Scholar 

  90. Maes M, Sirivichayakul S, Kanchanatawan B, Vodjani A (2019) Breakdown of the Paracellular tight and Adherens junctions in the gut and blood brain barrier and damage to the vascular barrier in patients with deficit schizophrenia. Neurotox Res 36(2):306–322

    Article  CAS  PubMed  Google Scholar 

  91. Maes M, Leunis JC (2008) Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett 29(6):902–910

    PubMed  Google Scholar 

  92. Maes M, Mihaylova I, Leunis JC (2007) Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord 99(1–3):237–240

    Article  CAS  PubMed  Google Scholar 

  93. D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M et al (1996) Abnormal intestinal permeability in children with autism. Acta Paediatrica (Oslo, Norway: 1992) 85(9):1076–1079

    Article  Google Scholar 

  94. de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P et al (2010) Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr 51(4):418–424

    Article  PubMed  Google Scholar 

  95. Fasano A, Hill I (2017) Serum Zonulin, gut permeability, and the pathogenesis of autism Spectrum disorders: cause, effect, or an epiphenomenon? J Pediatr 188:15–17

    Article  CAS  PubMed  Google Scholar 

  96. Fasano A (2012) Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol 42(1):71–78

    Article  CAS  PubMed  Google Scholar 

  97. Liu Z, Li N, Neu J (2005) Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatrica (Oslo, Norway: 1992) 94(4):386–393

    Article  CAS  Google Scholar 

  98. Addolorato G, Marsigli L, Capristo E, Caputo F, Dall’Aglio C, Baudanza P (1998) Anxiety and depression: a common feature of health care seeking patients with irritable bowel syndrome and food allergy. Hepato-Gastroenterology 45(23):1559–1564

    CAS  PubMed  Google Scholar 

  99. Jayashree B, Bibin YS, Prabhu D, Shanthirani CS, Gokulakrishnan K, Lakshmi BS et al (2014) Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol Cell Biochem 388(1–2):203–210

    Article  CAS  PubMed  Google Scholar 

  100. Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58(9):1094–1103

    Article  PubMed  Google Scholar 

  101. Wang Q, Jie W, Liu JH, Yang JM, Gao TM (2017) An astroglial basis of major depressive disorder? An overview. Glia 65(8):1227–1250

    Article  PubMed  Google Scholar 

  102. Cotter DR, Pariante CM, Everall IP (2001) Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 55(5):585–595

    Article  CAS  PubMed  Google Scholar 

  103. Torres-Platas SG, Hercher C, Davoli MA, Maussion G, Labonté B, Turecki G et al (2011) Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology 36(13):2650–2658

    Article  PubMed  PubMed Central  Google Scholar 

  104. Mayhew J, Beart PM, Walker FR (2015) Astrocyte and microglial control of Glutamatergic Signalling: a primer on understanding the disruptive role of chronic stress. J Neuroendocrinol 27(6):498–506

    Article  CAS  PubMed  Google Scholar 

  105. Li N, Zhang X, Dong H, Zhang S, Sun J, Qian Y (2016) Lithium ameliorates LPS-induced astrocytes activation partly via inhibition of toll-like receptor 4 expression. Cell Physiol Biochem 38(2):714–725

    Article  CAS  PubMed  Google Scholar 

  106. Liu GJ, Nagarajah R, Banati RB, Bennett MR (2009) Glutamate induces directed chemotaxis of microglia. Eur J Neurosci 29(6):1108–1118

    Article  PubMed  Google Scholar 

  107. Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38(10):637–658

    Article  CAS  PubMed  Google Scholar 

  108. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N (2014) Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun 42:50–59

    Article  CAS  PubMed  Google Scholar 

  109. Ramirez K, Shea DT, McKim DB, Reader BF, Sheridan JF (2015) Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun 46:212–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR (2012) A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 26(3):469–479

    Article  CAS  PubMed  Google Scholar 

  111. Dhami KS, Churchward MA, Baker GB, Todd KG (2013) Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult. Mol Cell Neurosci 56:365–374

    Article  CAS  PubMed  Google Scholar 

  112. Wohleb ES (2016) Neuron–microglia interactions in mental health disorders: “for better, and for worse”. Front Immunol 7

    Google Scholar 

  113. Sokolov BP (2007) Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies? Int J Neuropsychopharmacol 10(04):547

    Article  CAS  PubMed  Google Scholar 

  114. Tham MW, Woon PS, Sum MY, Lee T-S, Sim K (2011) White matter abnormalities in major depression: evidence from post-mortem, neuroimaging and genetic studies. J Affect Disord 132(1–2):26–36

    Article  PubMed  Google Scholar 

  115. Sacchet MD, Gotlib IH (2017) Myelination of the brain in major depressive disorder: an in vivo quantitative magnetic resonance imaging study. Sci Rep 7(1):2200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Sturgeon C, Fasano A (2016) Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barr 4(4):e1251384

    Article  CAS  Google Scholar 

  117. Kéri S, Szabó C, Kelemen O (2014) Expression of Toll-Like Receptors in peripheral blood mononuclear cells and response to cognitive-behavioral therapy in major depressive disorder. Brain Behav Immun 40:235–243

    Article  PubMed  CAS  Google Scholar 

  118. Rudzki L, Frank M, Szulc A, Gałęcka M, Szachta P, Barwinek D (2012) Od jelit do depresji – rola zaburzeń ciągłości bariery jelitowej i następcza aktywacja układu immunologicznego w zapalnej hipotezie depresji. Neuropsychiatria i Neuropsychologia/Neuropsychiatry and Neuropsychology 7(2):76–84

    Google Scholar 

  119. Rudzki L, Pawlak D, Pawlak K, Waszkiewicz N, Malus A, Konarzewska B et al (2017) Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry 17(1):268

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Tao R, Fu Z, Xiao L (2019) Chronic food antigen-specific IgG-mediated hypersensitivity reaction as a risk factor for adolescent depressive disorder. Genomics Proteomics Bioinformatics 17:183–189

    Article  PubMed  PubMed Central  Google Scholar 

  121. Beutier H, Gillis CM, Iannascoli B, Godon O, England P, Sibilano R et al (2017) IgG subclasses determine pathways of anaphylaxis in mice. J Aller Clin Immunol 139(1):269–280.e7

    Article  CAS  Google Scholar 

  122. Karakula-Juchnowicz H, Gałęcka M, Rog J, Bartnicka A, Łukaszewicz Z, Krukow P et al (2018) The food-specific serum IgG reactivity in major depressive disorder patients, irritable bowel syndrome patients and healthy controls. Nutrients 10(5):548

    Article  PubMed Central  CAS  Google Scholar 

  123. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58(5):445–452

    Article  CAS  PubMed  Google Scholar 

  124. Grigoleit JS, Kullmann JS, Wolf OT, Hammes F, Wegner A, Jablonowski S et al (2011) Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PLoS One 6(12):e28330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sandiego CM, Gallezot J-D, Pittman B, Nabulsi N, Lim K, Lin S-F et al (2015) Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci U S A 112(40):12468–12473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Furube E, Kawai S, Inagaki H, Takagi S, Miyata S (2018) Brain region-dependent heterogeneity and dose-dependent difference in transient microglia population increase during lipopolysaccharide-induced inflammation. Sci Rep 8(1):2203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Wang Y, Ni J, Zhai L, Gao C, Xie L, Zhao L et al (2019) Inhibition of activated astrocyte ameliorates lipopolysaccharide- induced depressive-like behaviors. J Affect Disord 242:52–59

    Article  CAS  PubMed  Google Scholar 

  128. Rosenblat JD, McIntyre RS (2018) Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. J Affect Disord 227:219–225

    Article  CAS  PubMed  Google Scholar 

  129. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT et al (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5(1):15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Pang Y, Cai Z, Rhodes PG (2003) Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 140(2):205–214

    Article  CAS  PubMed  Google Scholar 

  131. Jacob A, Hensley LK, Safratowich BD, Quigg RJ, Alexander JJ (2007) The role of the complement cascade in endotoxin-induced septic encephalopathy. Lab Investig 87(12):1186–1194

    Article  CAS  PubMed  Google Scholar 

  132. Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R et al (2014) Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci 34(25):8546–8556

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Capuron L, Miller AH (2011) Immune system to brain signaling: Neuropsychopharmacological implications. Pharmacol Ther 130(2):226–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in Response to tumor necrosis factor signaling during peripheral organ inflammation. J Neurosci 29(7):2089–2102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Thomson CA, McColl A, Graham GJ, Cavanagh J (2020) Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes. J Neuroinflammation 17(1):94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chakravarty S (2005) Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during Endotoxemia, independent of systemic cytokines. J Neurosci 25(7):1788–1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hung YY, Kang HY, Huang KW, Huang TL (2014) Association between toll-like receptors expression and major depressive disorder. Psychiatry Res 220(1–2):283–286

    Article  CAS  PubMed  Google Scholar 

  138. Pandey GN, Rizavi HS, Ren X, Bhaumik R, Dwivedi Y (2014) Toll-like receptors in the depressed and suicide brain. J Psychiatr Res 53:62–68

    Article  PubMed  PubMed Central  Google Scholar 

  139. Lin FY, Chen YH, Tasi JS, Chen JW, Yang TL, Wang HJ, et al. Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Smooth Muscle Cells via NADPH Oxidase Activation and Mitogen-Activated Protein Kinase Signaling Pathways. 2006;26(12):2630–7

    Google Scholar 

  140. Wang P, Han X, Mo B, Huang G, Wang C (2017) LPS enhances TLR4 expression and IFNgamma production via the TLR4/IRAK/NFkappaB signaling pathway in rat pulmonary arterial smooth muscle cells. Mol Med Rep 16(3):3111–3116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gárate I, García-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR et al (2011) Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflamm (8, 1):151

    Google Scholar 

  142. Hung Y-Y, Huang K-W, Kang H-Y, Huang GY-L, Huang T-L (2015) Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder. Psychopharmacology 233:1707–1714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72(4):411–412

    Article  CAS  PubMed  Google Scholar 

  144. Schwarcz R, Whetsell WO, Jr., Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science (New York, NY). 1983;219(4582):316–8

    Google Scholar 

  145. Tavares RG, Tasca CI, Santos CE, Alves LB, Porciuncula LO, Emanuelli T et al (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40(7):621–627

    Article  CAS  PubMed  Google Scholar 

  146. Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1(8):609–620

    Article  CAS  PubMed  Google Scholar 

  147. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13(7):465–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Stone TW, Darlington LG (2013) The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol 169(6):1211–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Forrest CM, Mackay GM, Oxford L, Millar K, Darlington LG, Higgins MJ et al (2011) Kynurenine metabolism predicts cognitive function in patients following cardiac bypass and thoracic surgery. J Neurochem 119(1):136–152

    Article  CAS  PubMed  Google Scholar 

  150. Tan L, Yu JT, Tan L (2012) The kynurenine pathway in neurodegenerative diseases: mechanistic and therapeutic considerations. J Neurol Sci 323(1–2):1–8

    Article  CAS  PubMed  Google Scholar 

  151. Parrott JM, Redus L, O’Connor JC (2016) Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge. J Neuroinflammation 13(1):124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Rodrigues FTS, de Souza MRM, Lima CNC, da Silva FER, Costa D, Dos Santos CC et al (2018) Major depression model induced by repeated and intermittent lipopolysaccharide administration: long-lasting behavioral, neuroimmune and neuroprogressive alterations. J Psychiatr Res 107:57–67

    Article  PubMed  Google Scholar 

  153. Zang X, Zheng X, Hou Y, Hu M, Wang H, Bao X et al (2018) Regulation of proinflammatory monocyte activation by the kynurenine–AhR axis underlies immunometabolic control of depressive behavior in mice. FASEB J 32(4):1944–1956

    Article  CAS  PubMed  Google Scholar 

  154. Kawasaki H, Chang HW, Tseng HC, Hsu SC, Yang SJ, Hung CH et al (2014) A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor. Allergy 69(4):445–452

    Article  CAS  PubMed  Google Scholar 

  155. Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10(6):538–544

    Article  CAS  PubMed  Google Scholar 

  156. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G et al (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15(4):393–403

    Article  CAS  PubMed  Google Scholar 

  157. Erhardt S, Lim CK, Linderholm KR, Janelidze S, Lindqvist D, Samuelsson M et al (2013) Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology 38(5):743–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA et al (2011) Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun 25(6):1272–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Bradley KA, Case JA, Khan O, Ricart T, Hanna A, Alonso CM et al (2015) The role of the kynurenine pathway in suicidality in adolescent major depressive disorder. Psychiatry Res 227(2–3):206–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Anacker C, Zunszain PA, Carvalho LA, Pariante CM (2011) The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36(3):415–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Quan N, Avitsur R, Stark JL, He L, Lai W, Dhabhar F et al (2003) Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice. J Neuroimmunol 137(1):51–58

    Article  CAS  PubMed  Google Scholar 

  162. Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS et al (2012) Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A 109(16):5995–5999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Boivin MA, Ye D, Kennedy JC, Al-Sadi R, Shepela C, Ma TY (2006) Mechanism of glucocorticoid regulation of the intestinal tight junction barrier. Am J Physiol Gastrointest Liver Physiol 292(2):G590–G5G8

    Article  PubMed  CAS  Google Scholar 

  164. Fischer A, Gluth M, Weege F, Pape UF, Wiedenmann B, Baumgart DC et al (2014) Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1. Am J Physiol 306(3):G218–GG28

    CAS  Google Scholar 

  165. Aranda CJ, Arredondo-Amador M, Ocón B, Lavín JL, Aransay AM, Martínez-Augustin O et al (2019) Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function. FASEB J 33(12):14067–14082

    Article  CAS  PubMed  Google Scholar 

  166. Haim YO, Unger ND, Souroujon MC, Mittelman M, Neumann D (2014) Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone. Sci Rep 4:4323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Fernández-Bertolín L, Mullol J, Fuentes-Prado M, Roca-Ferrer J, Alobid I, Picado C et al (2015) Effect of lipopolysaccharide on glucocorticoid receptor function in control nasal mucosa fibroblasts and in fibroblasts from patients with chronic Rhinosinusitis with nasal polyps and asthma. PLoS One 10(5):e0125443

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Molina ML, Guerrero J, Cidlowski JA, Gatica H, Goecke A (2017) LPS regulates the expression of glucocorticoid receptor α and β isoforms and induces a selective glucocorticoid resistance in vitro. J Inflamm (Lond) 14:22

    Article  CAS  Google Scholar 

  169. Esposito P, Gheorghe D, Kandere K, Pang X, Connolly R, Jacobson S et al (2001) Acute stress increases permeability of the blood–brain-barrier through activation of brain mast cells. Brain Res 888(1):117–127

    Article  CAS  PubMed  Google Scholar 

  170. Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY (2001) Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis. J Med Microbiol 50(9):812–821

    Article  CAS  PubMed  Google Scholar 

  171. Yang GY, Gong C, Qin Z, Liu XH, Lorris BA (1999) Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice. Brain Res Mol Brain Res 69(1):135–143

    Article  CAS  PubMed  Google Scholar 

  172. Wang W, Lv S, Zhou Y, Fu J, Li C, Liu P (2011) Tumor necrosis factor-alpha affects blood-brain barrier permeability in acetaminophen-induced acute liver failure. Eur J Gastroenterol Hepatol 23(7):552–558

    Article  CAS  PubMed  Google Scholar 

  173. Wong D, Dorovini-Zis K, Vincent SR (2004) Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. Exp Neurol 190(2):446–455

    Article  CAS  PubMed  Google Scholar 

  174. Enciu AM, Gherghiceanu M, Popescu BO (2013) Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Oxidative Med Cell Longev 2013:297512

    Article  Google Scholar 

  175. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M et al (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6(263):263ra158–263ra158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Hoyles L, Snelling T, Umlai U-K, Nicholson JK, Carding SR, Glen RC et al (2018) Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier. Microbiome 6(1):55

    Article  PubMed  PubMed Central  Google Scholar 

  177. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Varatharaj A, Galea I (2017) The blood-brain barrier in systemic inflammation. Brain Behav Immun 60:1–12

    Article  CAS  PubMed  Google Scholar 

  179. Morris G, Fernandes BS, Puri BK, Walker AJ, Carvalho AF, Berk M (2018) Leaky brain in neurological and psychiatric disorders: drivers and consequences. Aust N Z J Psychiatry 52(10):924–948

    Article  PubMed  Google Scholar 

  180. Vargas-Caraveo A, Sayd A, Maus SR, Caso JR, Madrigal JLM, García-Bueno B et al (2017) Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Sci Rep 7(1):13113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Zhan X, Stamova B, Jin LW, DeCarli C, Phinney B, Sharp FR (2016) Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology 87(22):2324–2332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhao Y, Jaber V, Lukiw WJ (2017) Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD Hippocampus. Front Cell Infect Microbiol 7:318

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Kamintsky L, Cairns KA, Veksler R, Bowen C, Beyea SD, Friedman A et al (2019) Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression. NeuroImage: Clinical 102049

    Google Scholar 

  184. Vreugdenhil ACE, Snoek AMP, Van ‘T Veer C, J-WM G, Buurman WA (2001) LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction. J Clin Investig 107(2):225–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Yao Z, Mates JM, Cheplowitz AM, Hammer LP, Maiseyeu A, Phillips GS et al (2016) Blood-Borne Lipopolysaccharide Is rapidly eliminated by Liver Sinusoidal Endothelial cells via high-density lipoprotein. J Immunol 197(6):2390–2399

    Article  CAS  PubMed  Google Scholar 

  186. Sumenkova DV, Polyakov LM, Panin LE (2013) Apolipoprotein A-I as a Carrier of Lipopolysaccharide into Rat Hepatocytes. Bull Exp Biol Med 155(6):738–740

    Article  CAS  PubMed  Google Scholar 

  187. Maes M, Smith R, Christophe A, Vandoolaeghe E, Gastel AV, Neels H et al (1997) Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers. Acta Psychiatr Scand 95(3):212–221

    Article  CAS  PubMed  Google Scholar 

  188. Huang T-L, Wu S-C, Chiang Y-S, Chen J-F (2003) Correlation between serum lipid, lipoprotein concentrations and anxious state, depressive state or major depressive disorder. Psychiatry Res 118(2):147–153

    Article  CAS  PubMed  Google Scholar 

  189. van Reedt Dortland AK, Giltay EJ, van Veen T, van Pelt J, Zitman FG, Penninx BW (2010) Associations between serum lipids and major depressive disorder: results from the Netherlands study of depression and anxiety (NESDA). J Clin Psychiatry 71(6):729–736

    Article  PubMed  CAS  Google Scholar 

  190. Lehto SM, Hintikka J, Niskanen L, Tolmunen T, Koivumaa-Honkanen H, Honkalampi K et al (2008) Low HDL cholesterol associates with major depression in a sample with a 7-year history of depressive symptoms. Prog Neuro-Psychopharmacol Biol Psychiatry 32(6):1557–1561

    Article  CAS  Google Scholar 

  191. Lehto SM, Niskanen L, Tolmunen T, Hintikka J, Viinamäki H, Heiskanen T et al (2010) Low serum HDL-cholesterol levels are associated with long symptom duration in patients with major depressive disorder. Psychiatry Clin Neurosci 64(3):279–283

    Article  CAS  PubMed  Google Scholar 

  192. Benros ME, Waltoft BL, Nordentoft M, Krogh J, Mortensen PB (2012) Autoimmunity and infections as risk factors for depression and other severe mental illnesses. Neurol Psychiatry Brain Res 18(2):40–41

    Article  Google Scholar 

  193. Benros ME, Waltoft BL, Nordentoft M, Østergaard SD, Eaton WW, Krogh J et al (2013) Autoimmune diseases and severe infections as risk factors for mood disorders. JAMA Psychiat 70(8):812

    Article  Google Scholar 

  194. Fasano A (2020) All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research 9:69

    Article  CAS  Google Scholar 

  195. Fasano A, Shea-Donohue T (2005) Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2(9):416–422

    Article  CAS  PubMed  Google Scholar 

  196. Opazo MC, Ortega-Rocha EM, Coronado-Arrázola I, Bonifaz LC, Boudin H, Neunlist M et al (2018) Intestinal microbiota influences non-intestinal related autoimmune diseases. Front Microbiol 9

    Google Scholar 

  197. Vojdani A, Kharrazian D, Mukherjee P (2013) The prevalence of antibodies against wheat and milk proteins in blood donors and their contribution to neuroimmune reactivities. Nutrients 6(1):15–36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Guggenmos J, Schubart AS, Ogg S, Andersson M, Olsson T, Mather IH et al (2004) Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein Butyrophilin in multiple sclerosis. J Immunol 172(1):661–668

    Article  CAS  PubMed  Google Scholar 

  199. Vojdani A, O’Bryan T, Green JA, McCandless J, Woeller KN, Vojdani E et al (2004) Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci 7(3):151–161

    Article  CAS  PubMed  Google Scholar 

  200. Stefferl A, Schubart A, Storch M, Amini A, Mather I, Lassmann H et al (2000) Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to Myelin Oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. J Immunol 165(5):2859–2865

    Article  CAS  PubMed  Google Scholar 

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Rudzki, L., Maes, M. (2021). From “Leaky Gut” to Impaired Glia-Neuron Communication in Depression. In: Kim, YK. (eds) Major Depressive Disorder. Advances in Experimental Medicine and Biology, vol 1305. Springer, Singapore. https://doi.org/10.1007/978-981-33-6044-0_9

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