May the Force Be With You: The Light and Dark Sides of the Microbiota-Gut-Brain Axis in Neuropsychiatry

Eoin Sherwin, Kiran V Sandhu, Timothy G Dinan, John F Cryan, Eoin Sherwin, Kiran V Sandhu, Timothy G Dinan, John F Cryan

Abstract

The role of the gut microbiota in health and disease is becoming increasingly recognized. The microbiota-gut-brain axis is a bi-directional pathway between the brain and the gastrointestinal system. The bacterial commensals in our gut can signal to the brain through a variety of mechanisms, which are slowly being resolved. These include the vagus nerve, immune mediators and microbial metabolites, which influence central processes such as neurotransmission and behaviour. Dysregulation in the composition of the gut microbiota has been identified in several neuropsychiatric disorders, such as autism, schizophrenia and depression. Moreover, preclinical studies suggest that they may be the driving force behind the behavioural abnormalities observed in these conditions. Understanding how bacterial commensals are involved in regulating brain function may lead to novel strategies for development of microbiota-based therapies for these neuropsychiatric disorders.

Conflict of interest statement

Compliance with Ethical Standards Funding Timothy Dinan and John Cryan are supported by the Science Foundation Ireland (SFI) [Grant Numbers 07/CE/B1368 and 12/RC/2273]; the Irish Health Research Board; the Department of Agriculture, Food and the Marine; and Enterprise Ireland. Open Access Fee was funded via the Centre grant to APC Microbiome Institute from Science Foundation Ireland. Conflict of interest Timothy Dinan and John Cryan are in receipt of research funding from 4D-Pharma, Mead Johnson, Suntory Wellness, Nutricia and Cremo. Timothy Dinan has been an invited speaker at meetings organized by Servier, Lundbeck, Janssen and AstraZeneca. John Cryan has been an invited speaker at meetings organized by Mead Johnson, Yakult, Alkermes and Janssen. Eoin Sherwin and Kiran Sandhu have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Key communication pathways of the microbiota–gut–brain axis. There are numerous mechanisms through which the bacterial commensals in our gut can signal to the brain. These include activation of the vagus nerve, production of immune mediators and microbial metabolites (i.e. short-chain fatty acids [SCFAs]), and enteroendocrine cell signalling. Through these routes of communication, the microbiota–gut–brain axis controls central physiological processes, such as neurotransmission, neurogenesis, neuroinflammation and neuroendocrine signalling. Dysregulation of the gut microbiota subsequently leads to alterations in all of these central processes. There have been numerous reports of alterations in the gut microbiota in neuropsychiatric conditions, which may account for the behavioural abnormalities that are characteristic of these conditions. Normalizing the composition of the gut microbiota with use of probiotics and prebiotics may represent a viable treatment option for neuropsychiatric conditions. 5-HT serotonin, CCK cholecystokinin, GABA γ-aminobutyric acid, GLP glucagon-like peptide, IL interleukin, PYY peptide YY, TNF tumour necrosis factor

References

    1. Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol. 2008;24(1):4–10. doi: 10.1097/MOG.0b013e3282f2b0e8.
    1. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature [Internet]. 2010;464(7285):59–65. doi:10.1038/nature08821.
    1. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PWJ. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology (Berl) [Internet]. 2015;232(10):1793–801. doi:10.1007/s00213-014-3810-0.
    1. El Aidy S, Dinan TG, Cryan JF. Immune modulation of the brain-gut-microbe axis. Front Microbiol [Internet]. 2014;5(April):3–6. doi:10.3389/fmicb.2014.00146/abstract.
    1. Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res [Internet]. Elsevier Ltd. 2015;63:1–9. Available from: .
    1. Sherwin E, Rea K, Dinan TG, Cryan JF. A gut (microbiome) feeling about the brain. Curr Opin Gastroenterol [Internet]. 2016;1. Available from: .
    1. Daulatzai MA. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochem Res [Internet]. 2014;39(4):624–44. doi:10.1007/s11064-014-1266-6.
    1. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Glarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015;9:392.
    1. Goehler LE, Gaykema RPA, Opitz N, Reddaway R, Badr N, Lyte M. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun. 2005;19(4):334–44.
    1. D’Mello C, Ronaghan N, Zaheer R, Dicay M, Le T, MacNaughton WK, et al. Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain. J Neurosci [Internet]. 2015;35(30):10821–30. doi:10.1523/JNEUROSCI.0575-15.2015.
    1. Bravo JA, Forsythe P, Chew M V, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci [Internet]. 2011;108(38):16050–5. Available from: .
    1. Dinan TG, Cryan JF. The impact of gut microbiota on brain and behaviour. Curr Opin Clin Nutr Metab Care [Internet]. 2015;18(6):552–8. Available from: .
    1. Poutahidis T, Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim YM, Chatzigiagkos A, Alm EJ, Erdman SE. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS One [Internet]. 2013;8(10):e78898. doi:10.1371/journal.pone.0078898.
    1. Marvel FA, Chen CC, Badr N, Gaykema RPA, Goehler LE. Reversible inactivation of the dorsal vagal complex blocks lipopolysaccharide-induced social withdrawal and c-Fos expression in central autonomic nuclei. Brain Behav Immun. 2004;18(2):123–134. doi: 10.1016/j.bbi.2003.09.004.
    1. Klarer M, Arnold M, Günther L, Winter C, Langhans W, Meyer U. Gut vagal afferents differentially modulate innate anxiety and learned fear. J Neurosci [Internet]. 2014;34(21):7067–76. Available from: .
    1. Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23(12):1132–1139. doi: 10.1111/j.1365-2982.2011.01796.x.
    1. Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology [Internet]. 2011;141(2):599–609.e3. Available from: .
    1. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour—epigenetic regulation of the gut-brain axis. Genes Brain Behav [Internet]. 2014;13(1):69–86. doi:10.1111/gbb.12109.
    1. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121(January):91–119. doi: 10.1016/B978-0-12-800100-4.00003-9.
    1. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell [Internet]. 2014;156(1-2):84–96. Available from: .
    1. DeCastro M, Nankova BB, Shah P, Patel P, Mally P V, Mishra R, et al. Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. Brain Res Mol Brain Res [Internet]. 2005;142(1):28–38. Available from: .
    1. Shah P, Nankova BB, Parab S, La Gamma EF. Short chain fatty acids induce TH gene expression via ERK-dependent phosphorylation of CREB protein. Brain Res [Internet]. 2006;1107(1):13–23. Available from: .
    1. Nankova BB, Agarwal R, MacFabe DF, La Gamma EF. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells—possible relevance to autism spectrum disorders. PLoS One [Internet]. 2014;9(8):e103740. Available from: .
    1. El-Ansary AK, Bacha A, Kotb M. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. J Neuroinflamm [Internet]. BioMed Central Ltd; 2012;9(1):74. Available from: .
    1. Schroeder FA, Lin CL, Crusio WE, Akbarian S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry. 2007;62(1):1.
    1. Gundersen BB, Blendy JA. Effects of the histone deacetylase inhibitor sodium butyrate in models of depression and anxiety. Neuropharmacology [Internet]. Elsevier Ltd. 2009;57(1):67–74. doi:10.1016/j.neuropharm.2009.04.008.
    1. Macfabe DF. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis [Internet]. 2012;23:1–24. Available from: .
    1. Kratsman N, Getselter D, Elliott E. Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacology [Internet]. Elsevier Ltd. 2016;102:136–45. Available from: .
    1. Huuskonen J, Suuronen T, Nuutinen T, Kyrylenko S, Salminen A. Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol [Internet]. 2004;141(5):874–80. Available from: .
    1. Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci [Internet]. 2015;18(7):965–77. doi:10.1038/nn.4030.
    1. de Almeida LMV, Funchal C, Gottfried C, Wajner M, Pessoa-Pureur R. Propionic acid induces cytoskeletal alterations in cultured astrocytes from rat cerebral cortex. Metab Brain Dis [Internet]. 2006;21(1):51–62. Available from: .
    1. Shultz SR, MacFabe DF, Martin S, Jackson J, Taylor R, Boon F, et al. Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: further development of a rodent model of autism. Behav Brain Res [Internet]. 2009;200(1):33–41. doi:10.1016/j.bbr.2008.12.023.
    1. Kanski R, Sneeboer MAM, van Bodegraven EJ, Sluijs JA, Kropff W, Vermunt MW, et al. Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network. J Cell Sci [Internet]. 2014;127(Pt 20):4368–80. Available from: .
    1. Latorre R, Sternini C, De Giorgio R, Greenwood-Van Meerveld B. Enteroendocrine cells: a review of their role in brain–gut communication. Neurogastroenterol Motil [Internet]. 2015. doi:10.1111/nmo.12754.
    1. Sternini C, Anselmi L, Rozengurt E. Enteroendocrine cells: a site of “taste” in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):73–78. doi: 10.1097/MED.0b013e3282f43a73.
    1. Bauer PV, Hamr SC, Duca FA. Regulation of energy balance by a gut–brain axis and involvement of the gut microbiota. Cell Mol Life Sci [Internet]. Springer Basel. 2015. doi:10.1007/s00018-015-2083-z.
    1. Duca FA, Swartz TD, Sakar Y, Covasa M. Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota. PLoS One. 2012;7(6):e39748. doi: 10.1371/journal.pone.0039748.
    1. Breton J, Tennoune N, Lucas N, Francois M, Legrand R, Jacquemot J, et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab [Internet]. 2016;23:1–11.
    1. Panaro BL, Tough IR, Engelstoft MS, Matthews RT, Digby GJ, Møller CL, et al. The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab [Internet]. Elsevier Inc. 2014;20(6):1018–29. doi:10.1016/j.cmet.2014.10.004.
    1. Swartz TD, Duca FA, de Wouters T, Sakar Y, Covasa M. Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and increased sucrose intake in mice lacking gut microbiota. Br J Nutr [Internet]. 2012;107(5):621–30. Available from: .
    1. Nøhr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, Husted AS, et al. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology [Internet]. 2013;154(10):3552–64. doi:10.1210/en.2013-1142.
    1. Cani PD, Dewever C, Delzenne NM. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br J Nutr [Internet]. 2004;92(03):521. Available from: .
    1. Cani PD, Neyrinck AM, Maton N, Delzenne NM. Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like peptide-1. Obes Res [Internet]. 2005;13(6):1000–7. Available from: .
    1. Cani PD, Joly E, Horsmans Y, Delzenne NM. Oligofructose promotes satiety in healthy human: a pilot study. Eur J Clin Nutr. 2006;60(5):567–572. doi: 10.1038/sj.ejcn.1602350.
    1. O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain–gut–microbiome axis. Behav Brain Res [Internet]. Elsevier B.V. 2015;277:32–48. Available from: .
    1. Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond B Biol Sci [Internet]. 2013;368(1615):20120536. Available from: .
    1. Dantzer R, Connor JCO, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology. 2012;36(3):426–436. doi: 10.1016/j.psyneuen.2010.09.012.
    1. Schwarcz R, Bruno JP, Muchowski PJ, Wu H-Q. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci [Internet]. Nature Publishing Group. 2012 [cited 2012 Oct 24];13(7):465–77. Available from: .
    1. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci [Internet]. 2009;106(10):3698–703. Available from: .
    1. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry [Internet]. Nature Publishing Group. 2013;18(6):666–73. doi:10.1038/mp.2012.77.
    1. Yano JM, Yu K, Mazmanian SK, Hsiao Correspondence EY, Donaldson GP, Shastri GG, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell [Internet]. Elsevier. 2015;161(2):264–76. doi:10.1016/j.cell.2015.02.047.
    1. Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res [Internet]. Elsevier Ltd. 2008;43(2):164–74. Available from: .
    1. Valladares R, Bojilova L, Potts AH, Cameron E, Gardner C, Lorca G, et al. Lactobacillus johnsonii inhibits indoleamine 2,3-dioxygenase and alters tryptophan metabolite levels in BioBreeding rats. FASEB J [Internet]. 2013;27(4):1711–20. Available from: .
    1. McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav [Internet]. 2008;7(2):152–63. doi:10.1111/j.1601-183X.2007.00330.x.
    1. Slavin J. Fiber and prebiotics: mechanisms and health benefits. Nutrients [Internet]. 2013;5(4):1417–35. Available from: .
    1. Depeint F, Tzortzis G, Vulevic J, Gibson GR. Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of. Am J Clin Nutr. 2008;87:785–791.
    1. Ramnani P, Costabile A, Bustillo AGR, Gibson GR. A randomised, double-blind, cross-over study investigating the prebiotic effect of agave fructans in healthy human subjects. J Nutr Sci [Internet]. 2015;4:e10. Available from: .
    1. Nyangale EP, Farmer S, Keller D, Chernoff D, Gibson GR. Effect of prebiotics on the fecal microbiota of elderly volunteers after dietary supplementation of Bacillus coagulans GBI-30, 6086. Anaerobe [Internet]. Elsevier Ltd. 2014;30:75–81. Available from: .
    1. Vulevic J, Juric A, Walton GE, Claus SP, Tzortzis G, Toward RE, et al. Influence of galacto-oligosaccharide mixture (B-GOS) on gut microbiota, immune parameters and metabonomics in elderly persons. Br J Nutr [Internet]. 2015;114(04):586–95. Available from: .
    1. Hopkins MJ, Sharp R, Macfarlane GT. Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut [Internet]. 2001;48(2):198–205. Available from: .
    1. Scott KP, Antoine J-M, Midtvedt T, van Hemert S. Manipulating the gut microbiota to maintain health and treat disease. Microb Ecol Health Dis [Internet]. 2015;26:25877. Available from: .
    1. Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut [Internet]. 2009;58(8):1091–103. Available from: .
    1. Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect [Internet]. Elsevier Masson SAS. 2014;44(1):1–8. doi:10.1016/j.medmal.2013.10.002.
    1. Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology [Internet]. Elsevier Inc. 2013;144(7):1394–401.e4. doi:10.1053/j.gastro.2013.02.043.
    1. Savignac HM, Kiely B, Dinan TG, Cryan JF. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil [Internet]. 2014;26(11):1615–27. Available from: .
    1. Smith CJ, Emge JR, Berzins K, Lung L, Khamishon R, Shah P, et al. Probiotics normalize the gut–brain–microbiota axis in immunodeficient mice. AJP Gastrointest Liver Physiol [Internet]. 2014;307(8):G793–802. doi:10.1152/ajpgi.00238.2014.
    1. Qin H-L, Shen T-Y, Gao Z-G, Fan X-B, Hang X-M, Jiang Y-Q, et al. Effect of lactobacillus on the gut microflora and barrier function of the rats with abdominal infection. World J Gastroenterol [Internet]. 2005;11(17):2591–6. Available from: .
    1. Distrutti E, O’Reilly J-A, McDonald C, Cipriani S, Renga B, Lynch MA, et al. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP. PLoS One [Internet]. 2014;9(9):e106503. doi:10.1371/journal.pone.0106503.
    1. Ohland CL, Jobin C. Microbial activities and intestinal homeostasis: a delicate balance between health and disease. Cell Mol Gastroenterol Hepatol. 2015;1(1):28–40. doi:10.1016/j.jcmgh.2014.11.004.
    1. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, Jafari P, Akbari H, Taghizadeh M, et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32(3):315–20. doi:10.1016/j.nut.2015.09.003.
    1. Manichanh C, Reeder J, Gibert P, Varela E, Llopis M, Antolin M, et al. Reshaping the gut microbiome with bacterial transplantation and antibiotic intake. Genome Res. 2010;20(10):1411–1419. doi: 10.1101/gr.107987.110.
    1. Panda S, El Khader I, Casellas F, López Vivancos J, García Cors M, Santiago A, et al. Short-term effect of antibiotics on human gut microbiota. PLoS One [Internet]. 2014;9(4):e95476. doi:10.1371/journal.pone.0095476.
    1. Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun [Internet]. Nature Publishing Group. 2016;7:1–8. doi:10.1038/ncomms10410.
    1. Cox LM, Yamanishi S, Sohn J, Alekseyenko A V., Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell [Internet]. 2014;158(4):705–21. Available from: .
    1. Tochitani S, Ikeno T, Ito T, Sakurai A, Yamauchi T, Matsuzaki H. Administration of non-absorbable antibiotics to pregnant mice to perturb the maternal gut microbiota is associated with alterations in offspring behavior. PLoS One [Internet]. 2016;11(1):e0138293. doi:10.1371/journal.pone.0138293.
    1. O’Mahony SM, Felice VD, Nally K, Savignac HM, Claesson MJ, Scully P, et al. Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats. Neuroscience [Internet]. IBRO; 2014;277:885–901. Available from: .
    1. Desbonnet L, Clarke G, Traplin A, O’Sullivan O, Crispie F, Moloney RD, et al. Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav Immun [Internet]. Elsevier Inc. 2015;48:165–73. Available from: .
    1. Verdú EF, Bercik P, Verma-Gandhu M, Huang X-X, Blennerhassett P, Jackson W, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55(2):182–190. doi: 10.1136/gut.2005.066100.
    1. Luczynski P, Neufeld KM, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol. 2016
    1. Möhler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology [Internet]. Elsevier Ltd. 2012 [cited 2013 Sep 20];62(1):42–53. Available from: .
    1. Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol [Internet]. 2012;113(2):411–7. doi:10.1111/j.1365-2672.2012.05344.x.
    1. Hiraga K, Ueno Y, Oda K. Glutamate decarboxylase from Lactobacillus brevis: activation by ammonium sulfate. Biosci Biotechnol Biochem. 2008;72(5):1299–1306. doi: 10.1271/bbb.70782.
    1. Komatsuzaki N, Nakamura T, Kimura T, Shima J. Characterization of glutamate decarboxylase from a high gamma-aminobutyric acid (GABA)-producer, Lactobacillus paracasei. Biosci Biotechnol Biochem. 2008;72(2):278–285. doi: 10.1271/bbb.70163.
    1. Boonstra E, de Kleijn R, Colzato LS, Alkemade A, Forstmann BU, Nieuwenhuis S. Neurotransmitters as food supplements: the effects of GABA on brain and behavior. Front Psychol [Internet]. 2015;6(October):6–11. doi:10.3389/fpsyg.2015.01520.
    1. Takanaga H, Ohtsuki S, Hosoya KI, Terasaki T. GAT2/BGT-1 as a system responsible for the transport of gamma-aminobutyric acid at the mouse blood-brain barrier. J Cereb Blood Flow Metab. 2001;21(10):1232–1239. doi: 10.1097/00004647-200110000-00012.
    1. Janik R, Thomason LA, Stanisz AM, Forsythe P, Bienenstock J, Stanisz GJ. Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate. Neuroimage [Internet]. Elsevier B.V.; 2015;125:988–95. doi:10.1016/j.neuroimage.2015.11.018.
    1. Asano Y, Hiramoto T, Nishino R, Aiba Y, Kimura T, Yoshihara K, et al. Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am J Physiol Gastrointest Liver Physiol [Internet]. 2012;303(11):G1288–95. Available from: .
    1. Hernández-Romero D, Sanchez-Amat A, Solano F. A tyrosinase with an abnormally high tyrosine hydroxylase/dopa oxidase ratio: role of the seventh histidine and accessibility to the active site. FEBS J. 2006;273(2):257–270. doi: 10.1111/j.1742-4658.2005.05038.x.
    1. Kuley E, Balıkcı E, Özoğul I, Gökdogan S, Ozoğul F. Stimulation of cadaverine production by foodborne pathogens in the presence of Lactobacillus, Lactococcus, and Streptococcus spp. J Food Sci [Internet]. 2012;77(12):M650–8. Available from: .
    1. Matsumoto M, Kibe R, Ooga T, Aiba Y, Sawaki E, Koga Y, et al. Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study. Front Syst Neurosci [Internet]. 2013;7(April):1–19. doi:10.3389/fnsys.2013.00009/abstract.
    1. Nishino R, Mikami K, Takahashi H, Tomonaga S, Furuse M, Hiramoto T, et al. Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterol Motil. 2013;25(6):521–528. doi: 10.1111/nmo.12110.
    1. Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol. 2001;63(6):637–672. doi: 10.1016/S0301-0082(00)00039-3.
    1. Thomas CM, Hong T, van Pijkeren JP, Hemarajata P, Trinh DV, Hu W, et al. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One [Internet]. 2012;7(2):e31951. doi:10.1371/journal.pone.0031951.
    1. Handley SA, Dube PH, Miller VL. Histamine signaling through the H(2) receptor in the Peyer’s patch is important for controlling Yersinia enterocolitica infection. Proc Natl Acad Sci [Internet]. 2006;103(24):9268–73. Available from: .
    1. Diebel LN, Liberati DM, Hall-Zimmerman L. H2 blockers decrease gut mucus production and lead to barrier dysfunction in vitro. Surgery [Internet]. Mosby Inc. 2011;150(4):736–43. Available from: .
    1. Mcintosh K, Reed DE, Schneider T, Dang F, Keshteli AH, et al. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 2016
    1. Zhang L, Song J, Hou X. Mast cells and irritable bowel syndrome: from the bench to the bedside. J Neurogastroenterol Motil. 2016;22(2):181–92.
    1. Luczynski P, O'Whelan S, O'Sullivan C, Clarke G, Shanahan F, Dinan TG, Cryan JF. Adult microbiota-deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur J Neurosci. 2016; ahead of print.
    1. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil [Internet]. 2011;23(3):255–e119. doi:10.1111/j.1365-2982.2010.01620.x.
    1. Savignac HM, Corona G, Mills H, Chen L, Spencer JPE, Tzortzis G, et al. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem Int [Internet]. Elsevier Ltd. 2013;63(8):756–64. Available from: .
    1. Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X, et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology [Internet]. 2010;139(6):2102–12.e1. Available from: .
    1. Liang S, Wang T, Hu X, Luo J, Li W, Wu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience [Internet]. 2015;(September). Available from: .
    1. Aguilera M, Cerdà-Cuéllar M, Martínez V. Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice. Gut Microbes. 2015;6(1):10–23. doi: 10.4161/19490976.2014.990790.
    1. Brun P, Gobbo S, Caputi V, Spagnol L, Schirato G, Pasqualin M, et al. Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells. Mol Cell Neurosci [Internet]. Elsevier Inc. 2015;68:24–35. Available from: .
    1. Cryan JF, Dinan TG. Gut microbiota: microbiota and neuroimmune signalling—Metchnikoff to microglia. Nat Rev Gastroenterol Hepatol [Internet]. Nature Publishing Group. 2015;12(9):494–6. doi:10.1038/nrgastro.2015.127.
    1. Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress. 2016
    1. Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol [Internet]. 2012 [cited 2012 Nov 1];92(September):1–17. Available from: .
    1. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol [Internet]. Nature Publishing Group; 2016;16(1):22–34. Available from: .
    1. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21(8):2580–2588.
    1. Bruce-Keller AJ, Salbaum JM, Luo M, Blanchard E, Taylor CM, Welsh DA, et al. Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol Psychiatry [Internet]. Elsevier. 2015;77(7):607–15. Available from: .
    1. Hoban AE, Stilling RM, Ryan FJ, Shanahan F, Dinan TG, Claesson MJ, et al. Regulation of prefrontal cortex myelination by the microbiota. Nature Publishing Group. 2016;6(4):e774–9. doi:10.1038/tp.2016.42.
    1. Ochoa-Repáraz J, Mielcarz DW, Wang Y, Begum-Haque S, Dasgupta S, Kasper DL, et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 2010;3(5):487–495. doi: 10.1038/mi.2010.29.
    1. Wang Y, Telesford KM, Ochoa-Repáraz J, Haque-Begum S, Christy M, Kasper EJ, et al. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat Commun [Internet]. 2014;5:4432. Available from: .
    1. Lavasani S, Dzhambazov B, Nouri M, Fåk F, Buske S, Molin G, et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One [Internet]. 2010;5(2):e9009. Available from: .
    1. Zunszain PA, Anacker C, Cattaneo A, Carvalho LA, Pariante CM. Glucocorticoids, cytokines and brain abnormalities in depression. Prog Neuropsychopharmacol Biol Psychiatry [Internet]. Elsevier Inc. 2011 [cited 2012 Nov 29];35(3):722–9. Available from: .
    1. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu X-N, et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J Physiol [Internet]. 2004;558(1):263–75. doi:10.1113/jphysiol.2004.063388.
    1. Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Daugé V, et al. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology. 2014;42:207–217. doi: 10.1016/j.psyneuen.2014.01.014.
    1. Barouei J, Moussavi M, Hodgson DM. Effect of maternal probiotic intervention on HPA axis, immunity and gut microbiota in a rat model of irritable bowel syndrome. PLoS One [Internet]. 2012;7(10):e46051. Available from: .
    1. Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L, et al. Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology [Internet]. 2012;37(11):1885–95. Available from: .
    1. Ait-Belgnaoui A, Colom A, Braniste V, Ramalho L, Marrot A, Cartier C, et al. Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterol Motil [Internet]. 2014;26(4):510–20. doi:10.1111/nmo.12295.
    1. Tarr AJ, Galley JD, Fisher SE, Chichlowski M, Berg BM, Bailey MT. The prebiotics 3′sialyllactose and 6′sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut–brain axis. Brain Behav Immun [Internet]. Elsevier Inc. 2015;50:166–77. Available from: .
    1. Buffington SA, Viana G, Prisco D, Auchtung TA, Ajami NJ, Petrosino JF, et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring article microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell [Internet]. Elsevier Inc. 2016;165(7):1762–75. doi:10.1016/j.cell.2016.06.001.
    1. Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav [Internet]. Elsevier Inc. 2015;138:179–87. Available from: .
    1. Holzer P, Farzi A. Neuropeptides and the microbiota-gut-brain axis. Adv Exp Med Biol [Internet]. 2014;817:39–71. doi:10.1007/978-1-4939-0897-4.
    1. Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linløkken A, Wilson R, et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil [Internet]. 2014;26(8):1155–62. doi:10.1111/nmo.12378.
    1. Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun [Internet]. Elsevier Inc. 2015;48:186–94. Available from: .
    1. Maes M, Kubera M, Leunis JC, Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord [Internet]. Elsevier B.V. 2012;141(1):55–62. doi:10.1016/j.jad.2012.02.023.
    1. O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho A-M, Quigley EMM, et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry [Internet]. Society of Biological Psychiatry. 2009;65(3):263–7. Available from: .
    1. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience [Internet]. Elsevier Inc. 2010;170(4):1179–88. Available from: .
    1. O’Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation as a model of brain–gut axis dysfunction. Psychopharmacology (Berl) [Internet]. 2011;214(1):71–88. doi:10.1007/s00213-010-2010-9.
    1. De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, et al. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun [Internet]. 2015;6:7735. doi:10.1038/ncomms8735.
    1. Bailey MT, Coe CL. The integrity of the intestinal microflora in infant rhesus. Dev Psychobiol. 1999;35:146–155. doi: 10.1002/(SICI)1098-2302(199909)35:2<146::AID-DEV7>;2-G.
    1. Harkin A, Kelly JP, Leonard BE. A review of the relevance and validity of olfactory bulbectomy as a model of depression. Clin Neurosci Res. 2003;3:253–262. doi: 10.1016/S1566-2772(03)00087-2.
    1. Park AJ, Collins J, Blennerhassett PA, Ghia JE, Verdu EF, Bercik P, et al. Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterol Motil [Internet]. 2013;25(9):733–e575. doi:10.1111/nmo.12153.
    1. Dinan TG, Cryan JF. Melancholic microbes: a link between gut microbiota and depression? Neurogastroenterol Motil. 2013;25(9):713–719. doi: 10.1111/nmo.12198.
    1. Bharwani A, Mian MF, Foster JA, Surette MG, Bienenstock J, Forsythe P. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology [Internet]. Elsevier Ltd; 2016;63:217–27. Available from: .
    1. Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun [Internet]. Elsevier Inc. 2011;25(3):397–407. Available from: .
    1. Philips JGP. The treatment of melancholia by the lactic acid Bacillus. Br J Psychiatry. 1910;56 (234):422-NP. doi:10.1192/bjp.56.234.422.
    1. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun [Internet]. Elsevier Inc. 2015;48:258–64. Available from: .
    1. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105(5):755–764. doi: 10.1017/S0007114510004319.
    1. Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog [Internet]. 2009;1(1):6. Available from: .
    1. Benton D, Williams C, Brown A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr. 2007;61(3):355–361. doi: 10.1038/sj.ejcn.1602546.
    1. Liu Y-W, Liu W-H, Wu C-C, Juan Y-C, Wu Y-C, Tsai H-P, et al. Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice. Brain Res [Internet]. Elsevier; 2016;1631:1–12. Available from: .
    1. Wang T, Hu X, Liang S, Li W, Wu X, Wang L, et al. Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rats. Benef Microbes [Internet]. 2015;6(5):707–17. doi:10.3920/BM2014.0177.
    1. Wei Y, Melas PA, Wegener G, Mathé AA, Lavebratt C. Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene. Int J Neuropsychopharmacol [Internet]. 2014;18(2):pyu032. Available from: .
    1. Fowler T, Zammit S, Owen MJ, Rasmussen F. A population-based study of shared genetic variation between premorbid IQ and psychosis among male twin pairs and sibling pairs from Sweden. Arch Gen Psychiatry [Internet]. 2012;69(5):460–6. Available from: .
    1. Gershon ES, Alliey-Rodriguez N, Liu C. After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. Am J Psychiatry. 2011;168(3):253–256. doi: 10.1176/appi.ajp.2010.10091340.
    1. Severance EG, Yolken RH, Eaton WW. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res [Internet]. Elsevier B.V. 2014. doi:10.1016/j.schres.2014.06.027.
    1. Severance EG, Prandovszky E, Castiglione J, Yolken RH. Gastroenterology issues in schizophrenia: why the gut matters. Curr Psychiatry Rep. 2015;17(5):1–10.
    1. Diaz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A. Normal gut microbiota modulates brain development and behavior. 2011;108(7):1–6.
    1. Borre YE, O’Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med [Internet]. Elsevier Ltd. 2014;20(9):509–18. Available from: .
    1. Biasucci G, Rubini M, Riboni S, Morelli L, Bessi E, Retetangos C. Mode of delivery affects the bacterial community in the newborn gut. Early Hum Dev [Internet]. Elsevier Ltd. 2010;86(Suppl. 1):13–5. doi:10.1016/j.earlhumdev.2010.01.004.
    1. Liu D, Yu J, Li L, Ai Q, Feng J, Song C, et al. Bacterial community structure associated with elective cesarean section versus vaginal delivery in chinese newborns. J Pediatr Gastroenterol Nutr [Internet]. 2015;60(2):240–6. Available from: .
    1. O’Neill SM, Curran EA, Dalman C, Kenny LC, Kearney PM, Clarke G, et al. Birth by caesarean section and the risk of adult psychosis: a population-based cohort study. Schizophr Bull. 2016;42(3):633–641. doi: 10.1093/schbul/sbv152.
    1. Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010;13(3):135–143. doi: 10.1179/147683010X12611460763968.
    1. Bhadra R, Cobb DA, Weiss LM, Khan IA. Psychiatric disorders in toxoplasma seropositive patients—the CD8 connection. Schizophr Bull. 2013;39(3):485–489. doi: 10.1093/schbul/sbt006.
    1. Fond G, Macgregor A, Tamouza R, Hamdani N, Meary A, Leboyer M, et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014;264(2):179–183. doi: 10.1007/s00406-013-0413-4.
    1. Heimesaat MM, Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J, et al. Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol [Internet]. 2006;177(12):8785–95. Available from: .
    1. Hand TW, Santos LM Dos, Bouladoux N, Molloy MJ, Pagán AJ, Pepper M, et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science. 2012;337(September):1553–7 (80-).
    1. Yolken RH, Severance EG, Sabunciyan S, Gressitt KL, Chen O, Stallings C, et al. Metagenomic sequencing indicates that the oropharyngeal phageome of individuals with schizophrenia differs from that of controls. Schizophr Bull. 2015;41(5):1153–1161. doi: 10.1093/schbul/sbu197.
    1. Selle K, Klaenhammer TR. Genomic and phenotypic evidence for probiotic influences of Lactobacillus gasseri on human health. Fed Eur Microbiol Soc. 2013;37:915–935.
    1. Schoepf D, Hardeep U, Potluri R, Heun R. Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions. Eur Arch Psychiatry Clin Neurosci. 2014;264:3–28. doi: 10.1007/s00406-013-0436-x.
    1. Albaugh VL, Judson JG, She P, Lang CH, Maresca KP, Joyal JL, et al. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatry [Internet]. Nature Publishing Group. 2011;16(5):569–81. Available from: .
    1. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci. 2004;101(44):15718–15723. doi: 10.1073/pnas.0407076101.
    1. Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci. 2007;104(3):979–984. doi: 10.1073/pnas.0605374104.
    1. Nieuwdorp M, Gilijamse PW, Pai N, Kaplan LM. Role of the microbiome in energy regulation and metabolism. Gastroenterology. Elsevier, Inc. 2014;146(6):1525–33.
    1. Davey KJ, O’Mahony SM, Schellekens H, O’Sullivan O, Bienenstock J, Cotter PD, et al. Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology. 2012;221(1):155–169. doi: 10.1007/s00213-011-2555-2.
    1. Davey KJ, Cotter PD, O’Sullivan O, Crispie F, Dinan TG, Cryan JF, et al. Antipsychotics and the gut microbiome: olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat. Transl Psychiatry [Internet]. 2013;3(August):e309. Available from: .
    1. Haack S, Seeringer A, Thürmann PA, Becker T, Kirchheiner J. Sex-specific differences in side effects of psychotropic drugs: genes or gender? Pharmacogenomics. 2009;10(9):1511–26.
    1. Coury DL, Ashwood P, Fasano A, Fuchs G, Geraghty M, Kaul A, et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics [Internet]. 2012;130(Supplement):S160–8. Available from: .
    1. Finegold SM, Downes J, Summanen PH. Microbiology of regressive autism. Anaerobe [Internet]. Elsevier Ltd. 2012;18(2):260–2. Available from: .
    1. Wang L, Conlon MA, Christophersen CT, Sorich MJ, Angley MT. Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomark Med [Internet]. 2014;8(3):331–44. Available from: .
    1. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe [Internet]. Elsevier Ltd. 2010;16(4):444–53. Available from: .
    1. Parracho HM. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol [Internet]. 2005;54(10):987–91. doi:10.1099/jmm.0.46101-0.
    1. Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Väisänen ML, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000;15(7):429–435. doi: 10.1177/088307380001500701.
    1. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci. 2012;57(8):2096–2102. doi: 10.1007/s10620-012-2167-7.
    1. de Theije CGM, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J, et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun [Internet]. Elsevier Inc. 2014;37:197–206. Available from: .
    1. de Theije CGM, Koelink PJ, Korte-Bouws GAH, Lopes da Silva S, Korte SM, Olivier B, et al. Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun [Internet]. Elsevier Inc. 2014;37:240–7. Available from: .
    1. Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, Ashwood P. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Transl Psychiatry [Internet]. Nature Publishing Group. 2013;3(3):e240. Available from: .
    1. Machado CJ, Whitaker AM, Smith SEP, Patterson PH, Bauman MD. Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol Psychiatry [Internet]. Elsevier. 2015;77(9):823–32. Available from: .
    1. Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2010;40(12):1423–1430. doi: 10.1007/s10803-010-1006-y.
    1. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell [Internet]. Elsevier Inc. 2013;155(7):1451–63. Available from: .
    1. Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, et al. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflamm. 2012;9(1):153. doi: 10.1186/1742-2094-9-153.
    1. Foley KA, MacFabe DF, Kavaliers M, Ossenkopp K-P. Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: relevance to autism spectrum disorders. Behav Brain Res [Internet]. Elsevier B.V. 2015;278:244–56. Available from: .
    1. MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb Ecol Health Dis [Internet]. 2015;26:28177. Available from: .
    1. White SW, Oswald D, Ollendick T, Scahill L. Anxiety in children and adolescents with autism spectrum disorders. Clin Psychol Rev [Internet]. Elsevier Ltd. 2009;29(3):216–29. Available from: .
    1. Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? BioEssays [Internet]. 2014;36(10):933–9. doi:10.1002/bies.201400075.
    1. Son JS, Zheng LJ, Rowehl LM, Tian X, Zhang Y, Zhu W, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS One. 2015;10(10):1–19.
    1. Parracho HMRT, Gibson GR, Knott F, Bosscher D, Kleerebezem M, McCartney AL. A double-blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders. Int J Probiotics Prebiotics. 2010;5(2):69–74.
    1. Kałuzna-Czaplińska J, Błaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012;28(2):124–126. doi: 10.1016/j.nut.2011.08.002.
    1. Dinan TG, Cryan JF. Mood by microbe: towards clinical translation. Genome Med [Internet]. Genome Med. 2016;36–8. doi:10.1186/s13073-016-0292-1.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する