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The Impact of Chronic Intestinal Inflammation on Brain Disorders: the Microbiota-Gut-Brain Axis

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Abstract

It has been shown that the gut microbiota plays a crucial role in the maintenance of intestinal homeostasis. Additionally, it has been demonstrated that dysbiosis is closely correlated with chronic intestinal inflammation, contributing to the development of chronic intestinal diseases, and also of brain pathologies, including neurodegenerative, neurodevelopmental, and psychiatric disorders. Given the paramount importance of gut microbiota for the establishment of communication between the gut and the brain, the microbiota-gut-brain axis has been increasingly explored within the scope of neurosciences. In this review article, we present an overview of key cellular signaling pathways underlying chronic intestinal inflammation and the influence of chronic intestinal inflammation and dysbiosis on brain disorders. This will include the presentation of valuable data from recent preclinical and clinical research. We will also address the importance of probiotics and prebiotics to targeting the microbiota-gut-brain axis in the context of some brain disorders, where they are seen to be promising strategies for ameliorating brain disorders.

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References

  1. Ghaisas S, Maher J, Kanthasam A (2016) Gut microbiome in health and disease: linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. Pharmacol Ther 158:52–62

    Article  CAS  PubMed  Google Scholar 

  2. Matsuoka K, Kanai T (2015) The gut microbiota and inflammatory bowel disease. Semin Immunopathol 37:47–55

    Article  CAS  PubMed  Google Scholar 

  3. Hooper LV, Macpherson AJ (2010) Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 10:159–169

    Article  CAS  PubMed  Google Scholar 

  4. Maynard CL, Elson CO, Hatton RD, Weaver CT (2012) Reciprocal interactions of the intestinal microbiota and immune system. Nature 489:231–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S (2016) Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep 6:23129–23142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hornef M, Penders J (2017) Does a prenatal bacterial microbiota exist? Mucosal Immunol 10:598–601

    Article  CAS  PubMed  Google Scholar 

  7. Xu Z, Knight R (2015) Dietary effects on human gut microbiome diversity. Br J Nutr 113(Suppl):S1–S5

    Article  CAS  PubMed  Google Scholar 

  8. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G et al (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci 107:14691–14696

    Article  PubMed  PubMed Central  Google Scholar 

  9. Albenberg LG, Wu GD (2014) Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology 146:1564–1572

    Article  CAS  PubMed  Google Scholar 

  10. Vaiserman AM, Koliada AK, Marotta F (2017) Gut microbiota: a player in aging and a target for anti-aging intervention. Ageing Res Rev 35:36–45

    Article  CAS  PubMed  Google Scholar 

  11. Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, Finlay BB (2007) Host-mediated inflammation disrupts the intestinal microbiota and promotes overgrowth of Enterobacteriaceae. Cell Host Microbe 2:119–129

    Article  CAS  PubMed  Google Scholar 

  12. Brown EM, Sadarangani M, Finlay BB (2013) The role of the immune system in governing host-microbe interactions in the intestine. Nat Immunol 14:660–667

    Article  CAS  PubMed  Google Scholar 

  13. Zeng MY, Inohara N, Nunez G (2017) Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol 10:18–26

    Article  CAS  PubMed  Google Scholar 

  14. Butto LF, Haller D (2016) Dysbiosis in intestinal inflammation: cause or consequence. Int J Med Microbiol 306:302–309

    Article  PubMed  Google Scholar 

  15. Houser MC, Tansey MG (2017) The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinsons Dis 3:3–12

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP (2015) Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 9:392–412

    PubMed  PubMed Central  Google Scholar 

  17. Moos WH, Faller DV, Harpp DN, Kanara I, Pernokas J, Powers WR, Steliou K (2016) Microbiota and neurological disorders: a gut feeling. Biores Open Access 5:137–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappaB signaling pathways. Nat Immunol 12:695–708

    Article  CAS  PubMed  Google Scholar 

  19. Wullaert A, Bonnet MC, Pasparakis M (2011) NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Res 21:146–158

    Article  CAS  PubMed  Google Scholar 

  20. Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734

    Article  CAS  PubMed  Google Scholar 

  21. Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nature reviews. Mol Cell Biol 8:49–62

    CAS  Google Scholar 

  22. Uwe S (2008) Anti-inflammatory interventions of NF-kappaB signaling: potential applications and risks. Biochem Pharmacol 75:1567–1579

    Article  CAS  PubMed  Google Scholar 

  23. Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72:1493–1505

    Article  CAS  PubMed  Google Scholar 

  24. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoffmann A, Baltimore D (2006) Circuitry of nuclear factor kappaB signaling. Immunol Rev 210:171–186

    Article  PubMed  Google Scholar 

  26. Wu S, Powell J, Mathioudakis N, Kane S, Fernadez E, Sears CL (2004) Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosin kinase-regulated nuclear factor-kB pathway. Infect Immun 72:5832–5839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Prindiville TP, Sheikh RA, Cohen SH, Tang YJ, Cantrell MC, Silva J Jr (2000) Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease. Emerg Infect Dis 6:171–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Atreya I, Atreya R, Neurath MF (2008) NF-kappa B in inflammatory bowel disease. J Intern Med 263:591–596

    Article  CAS  PubMed  Google Scholar 

  29. Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, Baeuerle PA et al (1998) Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357–369

    Article  CAS  PubMed  Google Scholar 

  30. Pasparakis M (2009) Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol 9:778–788

    Article  CAS  PubMed  Google Scholar 

  31. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mole Cell Biol 3:651–662

    Article  CAS  Google Scholar 

  33. Rane SG, Reddy EP (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19:5662–5679

    Article  CAS  PubMed  Google Scholar 

  34. Coskun M, Salem M, Pedersen J, Nielsen OH (2013) Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res 76:1–8

    Article  CAS  PubMed  Google Scholar 

  35. Rauch I, Muller M, Decker T (2013) The regulation of inflammation by interferons and their STATs. JakStat 2:e23820

    PubMed  PubMed Central  Google Scholar 

  36. Ramana CV, Chatterjee-Kishore M, Nguyen H, Stark GR (2000) Complex roles of Stat1 in regulating gene expression. Oncogene 19:2619–2627

    Article  CAS  PubMed  Google Scholar 

  37. Stempelj M, Kedinger M, Augenlicht L, Klampfer L (2007) Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate. J Biol Chem 282:9797–9804

    Article  CAS  PubMed  Google Scholar 

  38. Shuai K, Liu B (2003) Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 3:900–911

    Article  CAS  PubMed  Google Scholar 

  39. De Prati AC, Ciampa AR, Cavalieri E, Zaffini R, Darra E, Menegazzi M, Suzuki H, Mariotto S (2005) STAT1 as a new molecular target of anti-inflammatory treatment. Curr Med Chem 12:1819–1828

    Article  PubMed  Google Scholar 

  40. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL et al (2009) A human colonic commensal promotes colon tumorogenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Andujar I, Recio MC, Giner RM, Cienfuegos-Jovellanos E, Laghi S, Muguerza B, Rios JL (2011) Inhibition of ulcerative colitis in mice after oral administration of a polyphenol-enriched cocoa extract is mediated by the inhibition of STAT1 and STAT3 phosphorylation in colon cells. J Agric Food Chem 59:6474–6483

    Article  CAS  PubMed  Google Scholar 

  42. Serra D, Paixao J, Nunes C, Dinis TC, Almeida LM (2013) Cyanidin-3-glucoside suppresses cytokine-induced inflammatory response in human intestinal cells: comparison with 5-aminosalicylic acid. PLoS One 8(9):e73001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Serra D, Rufino AT, Mendes AF, Almeida LM, Dinis TC (2014) Resveratrol modulates cytokine-induced Jak/STAT activation more efficiently than 5-aminosalicylic acid: an in vitro approach. PLoS One 9(10):e109048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. ClinicalTrials.gov, U.S. https://clinicaltrials.gov/ct2/show/study/NCT02914600?term=filgotinib&rank=5. Accessed 25 July 2018

  45. Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hommes D, Blink BVD, Plasse T, Bartelsman J, Xu C, Macperson B, Tytgat G, Peppelenbosch M et al (2002) Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease. Gastroenterology 122:7–14

    Article  CAS  PubMed  Google Scholar 

  47. Broom OJ, Widjaya B, Troelsen J, Olsen J, Nielsen OH (2009) Mitogen activated protein kinases: a role in inflammatory bowel disease? Clin Exp Immunol 158:272–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Feng YJ, Li YY (2011) The role of p38 mitogen-activated protein kinase in the pathogenesis of inflammatory bowel disease. J Dig Dis 12:327–332

    Article  CAS  PubMed  Google Scholar 

  49. Roy PK, Rashid F, Bragg J, Ibdah JA (2008) Role of the JNK signal transduction pathway in inflammatory bowel disease. World J Gastroenterol 14:200–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Goh KC, Haque SJ, Williams BR (1999) p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J 18:5601–5608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang Y, Cho YY, Petersen BL, Zhu F, Dong Z (2004) Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. Carcinogenesis 25:1165–1175

    Article  CAS  PubMed  Google Scholar 

  52. Kracht M, Saklatvala J (2002) Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine 20:91–106

    Article  CAS  PubMed  Google Scholar 

  53. Saklatvala J (2004) The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol 4:372–377

    Article  CAS  PubMed  Google Scholar 

  54. Otsuka M, Kang YJ, Ren J, Jiang H, Wang Y, Omata M, Han J (2010) Distinct effects of p38α deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease. Gastroenterology 138:1255–1265

    Article  CAS  PubMed  Google Scholar 

  55. Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429:403–417

    Article  CAS  PubMed  Google Scholar 

  56. Reinecke K, Eminel S, Dierck F, Roessner W, Kersting S, Chromik AM, Gavrilova O, Laukevicience A et al (2012) The JNK inhibitor XG-102 protects against TNBS-induced colitis. PLoS One 7(3):e30985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Annese V, Rogai F, Settesoldi A, Bagnoli S (2012) PPARgamma in inflammatory bowel disease. PPAR Res 2012:620839–620848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, Chamaillard M, Desreumaux P (2006) PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut 55:1341–1349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Glass CK, Ogawa S (2006) Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6:44–55

    Article  PubMed  Google Scholar 

  60. Varga T, Czimmerer Z, Nagy L (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812:1007–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Desreumaux P, Ghosh S (2006) Review article: mode of action and delivery of 5-aminosalicylic acid - new evidence. Alim Pharmacol Ther 24(Suppl 1):2–9

    Article  CAS  Google Scholar 

  62. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D, Wahli W et al (2005) Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 201:1205–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Byndloss MX, Olsan EE, Rivera-Chávez F, Tiffany CR, Cevallos SA, Lokken KL, Torres TP, Byndloss AJ et al (2017) Microbiota-activated PPAR-γ-signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357:570–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Strowig T, Henao-Mejia J, Elinav E, Flavell R (2012) Inflammasomes in health and disease. Nature 481:278–286

    Article  CAS  PubMed  Google Scholar 

  65. Zmora N, Levy M, Pevsner-Fishcer M, Elinav E (2017) Inflammasomes and intestinal inflammation. Mucosal Immunol 10:865–883

    Article  CAS  PubMed  Google Scholar 

  66. Gagliani N, Palm NW, de Zoete MR, Flavell RA (2014) Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota. Int Immunol 26:495–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zaki MH, Lamkanfi M, Kanneganti TD (2011) The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol 32:171–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bauer C, Duewell P, Mayer C, Lehr HA, Fitzgerald KA, Dauer M, Tschopp J, Endres S et al (2010) Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59:1192–1199

    Article  CAS  PubMed  Google Scholar 

  69. Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA (2001) IL-1-converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci 98:13249–13254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Liu L, Dong Y, Ye M, Jin S, Yang J, Joosse ME, Sun Y, Zhang J et al (2017) The pathogenic role of NLRP3 inflammasome activation in inflammatory bowel diseases of both mice and humans. J Crohns Colitis 11:737–750

    PubMed  PubMed Central  Google Scholar 

  72. Zhou W, Liu X, Zhang X, Tang J, Li Z, Wang Q, Hu R (2017) Oroxylin A inhibits colitis by inactivating NLRP3 inflammasome. Oncotarget 8:58903–58917

    PubMed  PubMed Central  Google Scholar 

  73. Chapman CG, Pekow J (2015) The emerging role of miRNAs in inflammatory bowel disease: a review. Ther Adv Gastroenter 8:4–22

    Article  CAS  Google Scholar 

  74. Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, Biette K, Jedlicka P et al (2017) Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med 214:1737–1752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Powell N, Walker MM, Talley NJ (2017) The mucosal immune system: master regulator of bidirectional gut-brain communications. Nat Rev Gastroenterol Hepatol 14:143–159

    Article  CAS  PubMed  Google Scholar 

  76. De Theije CGM, Wu J, Silva SL, Kamphuis PJ, Garssen J, Korte SM, Kraneveld AD (2011) Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol 668:570–580

    Article  CAS  Google Scholar 

  77. Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nature Neurosci 20:145–155

    Article  CAS  PubMed  Google Scholar 

  78. Vuong HE, Hsiao EY (2017) Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry 81:411–423

    Article  PubMed  Google Scholar 

  79. Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, Joussen O, Leoncini S et al (2017) New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5:24–35

    Article  PubMed  PubMed Central  Google Scholar 

  80. Luna RA, Oezguen N, Balderas M, Venkatachalam A, Runge JK, Versalovic J, Veenstra-VanderWeele J, Anderson GM et al (2017) Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell Mol Gastroenterol Hepatol 3:218–230

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912

    Article  CAS  PubMed  Google Scholar 

  83. Sochocka M, Diniz BS, Leszek J (2017) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54:8071–8089

    Article  CAS  PubMed  Google Scholar 

  84. Schwartz M, Deczkowska A (2016) Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37:668–679

    Article  CAS  PubMed  Google Scholar 

  85. Weil RS, Lashley TL, Bras J, Schrag AE, Schott JM (2017) Current concepts and controversies in the pathogenesis of Parkinson’s disease dementia and dementia with Lewy bodies. F1000Res 6:1604–1616

    Article  PubMed  PubMed Central  Google Scholar 

  86. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, Wang ZY, Roybon L et al (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805–820

    Article  PubMed  Google Scholar 

  87. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S et al (2015) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Dis 30:350–358

    Article  Google Scholar 

  88. Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S (2016) From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry 21:738–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388:505–517

    Article  CAS  PubMed  Google Scholar 

  90. Harach T, Marungruang N, Duthilleu N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fak F et al (2017) Reduction of Abeta amyloid pathology in APPS1 transgenic mice in the absence of gut microbiota. Sci Rep 7:41802–41817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S et al (2017) Gut microbiome alterations in Alzheimer’s disease. Sci Rep 7:13537–13548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhan X, Stamova B, Sharp FR (2018) Lipopolysaccharide associates with amyloid plaques, neurons and oligodendrocytes in Alzheimer’s disease brain: a review. Front Aging Neurosci 10:42–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dowlati Y, Herrmann N, Swargfager W, Liu H, Sham L, Reim EK, Lanctôt KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457

    Article  CAS  PubMed  Google Scholar 

  94. Howren MB, Lamki DM, Suls J (2009) Associations of depression with c-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71:171–186

    Article  CAS  PubMed  Google Scholar 

  95. Vannucchi MG, Evangelista S (2018) Experimental models of irrritable bowel syndrome and the role of the enteric neurotransmission. J Clinic Med 7:4–16

    Article  CAS  Google Scholar 

  96. Distrutti E, Monaldi L, Ricci P, Fiorucci S (2016) Gut microbiota role in irritable bowel syndrome: new therapeutic strategies. World J Gastroenterol 22:2219–2241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liang S, Wu X, Wang T, Jin F (2018) Recognizing depression from the microbiota-gut-brain axis. Int J Mol Sci 19:1592–1608

    Article  CAS  PubMed Central  Google Scholar 

  98. Patel RM, Denning PW (2013) Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence? Clin Perinatol 40:11–25

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ringel Y, Quigley EMM, Lin HC (2012) Using probiotics in gastrointestinal disorders. Am J Gastroenterol Suppl 1:34–40

    Article  CAS  Google Scholar 

  100. Umbrello G, Esposito S (2016) Microbiota and neurologic diseases: potential effects of probiotics. J Transl Med 14:298–309

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hsiao EY (2014) Gastrointestinal issues in autism spectrum disorder. Harv Rev Psychiatry 22:104–111

    Article  PubMed  Google Scholar 

  102. Rosenfeld CS (2015) Microbiome disturbances and autism spectrum disorders. Drug Metab Dispos 43:1557–1571

    Article  CAS  PubMed  Google Scholar 

  103. Shaaban SY, El Gendy YG, Mehanna NS, El-Senousy WM, El-Feki HSA, Saad K, El-Asheer OM (2017) The role of probiotics in children with autism spectrum disorder: a prospective, open-label study. Nutr Neurosci 7:1–6

    Google Scholar 

  104. Grimaldi R, Gibson GR, Vulevic J, Giallourou N, Castro-Mejia JL, Hansen LH, Gibson EL, Nielson DS et al (2018) A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome 6:133–146

    Article  PubMed  PubMed Central  Google Scholar 

  105. Li Q, Han Y, Dy ABC, Hagerman RJ (2017) The gut microbiota and autism spectrum disorders. Front Cell Neurosci 11:120–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Parashar A, Udayabanu M (2017) Gut microbiota: implications in Parkinson’s disease. Parkinsonism Relat Disord 38:1–7

    Article  PubMed  PubMed Central  Google Scholar 

  107. Perez-Pardo P, Kliest T, Dodiya HB, Broersen LM, Garssen J, Keshavarzian A, Kraneveld AD (2017) The gut-brain axis in Parkinson’s disease: possibilities for food-based therapies. Eur J Pharmacol 817:86–95

    Article  CAS  PubMed  Google Scholar 

  108. Bonfili L, Cecarini V, Berardi S, Scarpona S, Suchodolski JS, Nasuti C, Fiorini D, Boarelli MC et al (2017) Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci Rep 7:2426–2447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mangiola F, Ianiro G, Franceschi F, Fagiuoli S, Gasbarrini G, Gasbarrini A (2016) Gut microbiota in autism and mood disorders. World J Gastroenterol 22:361–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mason BL (2017) Feeding systems and the gut microbiome: gut-brain interactions with relevance to psychiatric conditions. Psychosomatics 58:574–580

    Article  PubMed  Google Scholar 

  111. Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, Murphy E, Cryan JF et al (2016) Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry 6:e939–e946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pirbaglou M, Katz J, de Souza RJ, Stearns JC, Motamed M, Ritvo P (2016) Probiotic supplementation can positively affect anxiety and depressive symptoms: a systematic review of randomized controlled trials. Nutr Res 36:889–898

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge the support of Dr. João Pinto in the artwork design.

Funding

This work was supported by the grant POCI-01-0145-FEDER-029089, funded by FCT (Portuguese Foundation for Science and Technology), by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE 2020, and by other national funds via FCT, under the project PTDC/SAU-OSM/102907/2008 and strategic project UID/NEU/04539/2013.

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  1. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Diana Serra, Leonor M. Almeida & Teresa C. P. Dinis

  2. Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Diana Serra, Leonor M. Almeida & Teresa C. P. Dinis

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  1. Diana Serra
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Serra, D., Almeida, L.M. & Dinis, T.C.P. The Impact of Chronic Intestinal Inflammation on Brain Disorders: the Microbiota-Gut-Brain Axis. Mol Neurobiol 56, 6941–6951 (2019). https://doi.org/10.1007/s12035-019-1572-8

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  • DOI: https://doi.org/10.1007/s12035-019-1572-8

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