Gut-Brain Axis: The Role of Gut Microbiota in Psychiatric Disorders

Yıl 2015, Cilt: 7 Sayı: 4, 461 - 472, 15.08.2015

Alper Evrensel Mehmet Emin Ceylan

https://doi.org/10.5455/cap.20150128123852

Öz

Gut microbiota is essential to human health, playing a major and important role in the bidirectional communication between the gut and the brain. There is significant evidence linking gut microbiota and metabolic disorders such as obesity, diabetes and neuropsychiatric disorders such as schizophrenia, autism, anxiety, depression. New studies show microbiota can activate immune system, neural pathways and central nervous system signaling systems, including commensal, probiotic and pathogenic microorganisms in the gastrointestinal tract. This microorganisms are capable of producing and delivering neuroactive substances such as gamma-aminobutyric acid and serotonin, which act on the gut-brain axis. Preclinical evaluation in rodents suggests that certain probiotics possess antidepressant or anxiolytic activity. Effects may be mediated via the vagus nerve, spinal cord, immune system or neuroendocrine systems. Here we review recent literature that examines the impact of gut microbiota on the brain, behavior and psychiatric disorders.

 

Anahtar Kelimeler

Gut-brain axis, microbiota, psychiatric disorders

Bağırsak Beyin Ekseni: Psikiyatrik Bozukluklarda Bağırsak Mikrobiyotasının Rolü

Öz

Bağırsak mikrobiyotası beyin ve bağırsak arasında karşılıklı bir ilişki oluşturarak insan sağlığı üzerinde temel ve önemli bir rol oynar. Obesite, diyabet gibi metabolik hastalıklar ve şizofreni, otizm, anksiye-te, depresyon gibi neuropsikiyatrik bozukluklarla bağırsak mikrobiyotası arasında bağlantı olduğuna ilişkin güçlü kanıtlar vardır. Yeni araştırmalar gastrointestinal sistemde yaşayan dost, zararlı ve probiyotik mikroorganizmaların bağışıklık sistemini, nöral yolakları ve peşi sıra merkezi sinir sistemini uyardığını ortaya koymaktadır. Bu mikroorganizmalar bağırsak beyin ekseninde rol oynayan gama-aminobutirik asit ve serotonin gibi nöroaktif maddeleri üretmektedir. Preklinik hayvan deneyleri bazı probiyotik bakterilerin anksiyolitik ve antidepresan etkiye sahip olduğunu göstermektedir. Bu maka-lede bağırsak mikrobiyotasının beyin, davranış ve psikiyatrik bozukluklar üzerine etkisi gözden geçirilmiştir.

 

Anahtar Kelimeler

Bağırsak-beyin ekseni, mikrobiyota, psikiyatrik bozukluklar

Kaynakça

• 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.
• Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L et al. (2012) Prevention of gut leakiness by intestinal microbiota modulation leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology, 37:1885-1895.
• Backhed F, Manchester JK, Semenkovich CF, Gordon JI (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A, 104:979-984.
• Bailey MT, Coe CL (1999) Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol, 35:146-155.
• Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C (2012) γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol, 113:411-417.
• Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Maylan S et al. (2013) So depression is an inflammatory disease, but where does the inflammation come from? BMC Med, 11:200.
• Borre YE, O’keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF (2014) Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med, 20:509-518.
• Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR et al. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, 405, 458–462
• Brandt LJ (2013) American Journal of Gastroenterology Lecture: intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile Infection. AmJ Gastroenterol, 108:177-185.
• Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG et al. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA, 108:16050- 16055.
• Bruce-Keller AJ, Salbaum JM, Luo M, Blanchard E, Taylor CM, Welsh DA et al. (2015). Obese-type gut microbionta induced neurobehavioral changes in the absence of obesity. Biol Psychiatry, 77:607-615.
• Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F et al. (2013) The microbiome-gut–brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry, 18:666-673.
• Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP et al. (2011) Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull, 37:94-100.
• Carvalho FA, Aitken JD, Vijay-Kumar M, Gewirtz AT (2012) Toll-like receptor-gut microbiota interactions: perturb at your own risk Annu Rev Physiol, 74:177-198.
• Catassi C, Bai JC, Bonaz B, Bouma G, Calabro A, Carroccio A et al. (2013) Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients, 5:3839-3853.
• Collins SM, Bercik P (2009) The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology, 136:2003-2014.
• Costello EK, Stagaman K, Dethlefsen L, Bohannanm J, Relman DA (2012) The application of ecological theory toward an understanding of the human microbiome. Science, 336:1255-1262.
• Dash S, Clarke G, Berk M, Jacka FN (2015) The gut microbiome and diet in psychiatry: focus on depression. Curr Opin Psychiatry, 28:16.
• David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE et al. (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature, 505:559-563.
• Davey KJ, O’Mahony SM, Schellekens H, O’Sullivan O, Bienenstock J, Cotter PD et al. (2013) Olanzapine induced weight gain in the rat: Impact on inflammatory, metabolic and microbiota parameters. Psychopharmacology (Berl), 221:155-169.
• de Theije CGM, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J et al. (2014a) Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun, 37:197-206.
• de Theije CGM, Koelink PJ, Korte-Bouws GAH, Lopes da Silva S, Korte SM, Olivier B et al. (2014b) Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun, 37:240-247.
• de Vos WM, de Vos EA (2012): Role of the intestinal microbiome in health and disease: From correlation to causation. Nutr Rev, 70:45-56.
• Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG (2008): The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. J Psychiatr Res, 43:164-174.
• Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG (2010) Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience, 170:1179-1188.
• Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A et al. (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A, 108:3047-3052.
• Dinan TG, Quigley EM (2011) Probiotics in the treatment of depression: Science or science fiction? Aust N Z J Psychiatry, 45:1023- 1025.
• Dokuyucu R, Kokacya H, Inanır S, Copoglu US Erbas O (2014) Antipsychotic-like effect of minocycline in the rat model. Int J Clin Exp Med, 7:3354-3361.
• Douglas-Escobar M, Elliott E, Neu J (2013) Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr, 167:374– 379.
• Fetissov SO, Dechelotte P (2011) The new link between gut–brain axis and neuropsychiatric disorders. Curr Opin Clin Nutr Metab Care, 14:477-482.
• Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD et al. (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe, 16:444-453.
• Flint HJ (2012) The impact of nutrition on the human microbiome. Nutr Rev, 70:10-13.
• Fond G, Boukouaci W, Chevalier G, Regnault A, Eberl G, Hamdani N (2014) The ‘‘psychomicrobiotic’’: Targeting microbiota in major psychiatric disorders: A systematic review. Pathol Biol (Paris), Epub ahead of print.
• Heijtz RD, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA, 108:3047-3052.
• Hornig M (2013) The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol, 25:488-795.
• Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T et al. (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155:1451-1463.
• Jhamnani K, Shivakumar V, Kalmady S, Rao NP, Venkatasubramanian G (2013) Successful use of add-on minocycline for treatment of persistent negative symptoms in schizophrenia. J Neuropsychiatry Clin Neurosci, 25:E06-7.
• Jin SZ, Wu N, Xu Q, Zhang X, Ju GZ, Law MH et al. (2012) A study of circulating gliadin antibodies in schizophrenia among a Chinese population. Schizophr Bull, 38:514-8.
• Jumpstart Consortium Human Microbiome Project Data Generation Working Group (2012) Evaluation of 16S rDNA-based community profiling for human microbiome research. PLoS One, 7:e39315.
• Kang SS, Jeraldo PR, Kurti A, Miller ME, Cook MD, Whitlock K et al. (2014) Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener, 9:36.
• Khanna S, Tosh PK (2014) A clinican’s primer on the role of the microbiome in human health and disease. Mayo Clin Proc, 89:107- 114.
• Khodaie-Ardakani MR, Mirshafiee O, Farokhnia M, Tajdini M, Hosseini SM, Modabbernia A et al. (2014) Minocycline add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo- controlled study. Psychiatry Res, 215:540-546.
• Kimura I, Ozawa K, Inoue D, Imamura K, Kimura K, Maeda T et al. (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun, 4:1829.
• Kopp MV, Goldstein M, Dietschek A, Sofke J, Heinzmann A, Urbanek R (2008) Lactobacillus GG has in vitro effects on enhanced interleukin-10 and interferon-gamma release of mononuclear cells but no in vivo effects in supplemented mothers and their neonates. Clin Exp Allergy, 38:602-610.
• Leclercq S, De Saeger C, Delzenne N, de Tmary P, Starkel P (2014a) Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry, 76:725-33.
• Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Starkel P (2014b) Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA, 111:E4485-93
• Levkovich T, Poutahidis T, Smillie C, Varian BJ, Ibrahim YM, Lakritz JR, et al. (2013) Probiotic bacteria induce a 'glow of health'. PLoS One, 8:e53867.
• Li W, Dowd SE, Scurlock B, Acosta-Martinez V, Lyte M (2009) Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria. Physiol Behav, 96:557-567.
• Liu F, Guo X, Wu R, Ou J, Zheng Y, Zhang B et al. (2014) Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: a double blind, randomized, controlled trial. Schizophr Res, 153:169-176.
• Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R (2012) Diversity, stability and resilience of the human gut microbiota. Nature, 489:220–230.
• Lucas K, Maes M (2013) Role of the toll like receptor (TLR) radical cyclein chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol, 48:190–204.
• Lyte M (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. Bioessays, 33:574-581.
• Lyte M, Varcoe JJ, Bailey MT (1998) Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol Behav, 65:63-68.
• Macfabe DF (2012) Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis, 23:19260.
• Macfarlane S, Macfarlane GT (2003) Regulation of short-chain fatty acid production. Proc Nutr Soc, 62:67-72.
• Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E (2005) The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway. Int Immunopharmacol, 5:609-618.
• Martinez I, Lattimer JM, Hubach KL, Case JA, Yang J, Weber JG et al. (2013) Gut microbiome composition is linked to whole grain- induced immunological improvements. ISME J, 7:269-280.
• Macpherson AJ, Uhr T (2002) Gut flora–mechanisms of regulation. Eur J Surg, Suppl. 587:53–57.
• McCusker RH, Kelley KW (2013) Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol, 216:84-98.
• McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG (2011) Enhanced peripheral toll-like receptor responses in psychosis: Further evidence of a pro-inflammatory phenotype. Transl Psychiatry, 1:e36.
• McNutt MD, Liu S, Manatunga A, Royster EB, Raison CL, Woolwine BJ et al. (2012) Neurobehavioral effects of interferon-α in patients with hepatitis-C: Symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology, 37:1444-1454.
• Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A et al. (2011a) Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr, 105:755-764.
• Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H, Rougeot C (2011b) Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes, 2:256-261.
• Morgan AP, Crowley JJ, Nonneman RJ, Quackenbush CR, Miller CN, Ryan AK et al. (2014) The antipsychotic olanzapine ınteracts with the gut microbiome to cause weight gain in mouse. PLoS One, 9:e115225.
• Muccioli GG, Naslain D, Backhed F, Reigstad CS, Lambert DM, Delzenne NM et al. (2010) The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol, 6:392.
• Na KS, Jung HY, Kim YK (2014) The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry, 48:277-286.
• Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linlokken A, Wilson Ret al. (2014) Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil, 26:1155-1162.
• Neish AS (2009) Microbes in gastrointestinal health and disease. Gastroenterology, 136:65-80.
• Nemani K, Hosseini Ghomi R, McCormick B, Fan X (2015) Schizophrenia and the gut-brain axis. Prog Neuro-Psychopharmacol Biol Psychiatry, 56:155-160
• Neufeld KA, Kang N, Bienenstock J, Foster JA (2011) Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol, 4:492-494.
• Niebuhr DW, Li Y, Cowan DN, Weber NS, Fisher JA, Ford GM et al. (2011) Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res, 128:51-5.
• O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K et al. (2005) Lactobacillus and bifidobacterium in irritable bowel syndrome: Symptom responses and relationship to cytokine profiles. Gastroenterology, 128:541–551.
• O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM et al. (2009) Early life stress alters behavior, immunity, and microbiota in rats: Implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry, 65:263-267.
• O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res, Epub 2014 Jul 29.
• Ohland CL, Kish L, Bell H, Thiesen A, Hotte N, Pankiv E (2013) Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology, 38:1738-1747.
• Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A et al. (2012) Microbial exposure during early life has persistent effects on natural killer T cell function. Science, 336:489-493.
• Perez-Burgos A, Wang B, Mao YK, Mistry B, Mcvey Neufeld KA, Bienenstock J et al. (2013) Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents. Am J Physiol Gastrointest Liver Physiol, 304:G211-G220.
• Philips J (1910) The treatment of melancholia by the lactic acid bacillus. J Mental Sci, 56:422-431.
• Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry, 63:801-808.
• Qurashi I, Collins J, Chaudhry I, Husain N (2014) Promising use of minocycline augmentation with clozapine in treatment-resistant schizophrenia. J Psychopharmacol, 28:707-708.
• Reandon S (2014) Gut-brain link grabs neuroscientists. Nature, 515:175-177.
• Rook GA (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol, 160:70-79.
• Rook GA, Lowry, CA, Raison CL (2015) Hygiene and early childhood influences on the subsequent function of the immune system. Brain Res, 1617:47-62.
• Rook GA, Martinelli R, Brunet LR (2003) Innate immune responses to mycobacteria and the downregulation of atopic responses. Curr Opin Allergy Clin Immunol, 3:337-342.
• Round JL, O'Connell RM, Mazmanian SK (2010) Coordination of tolerogenic immune responses by the commensal microbiota. J Autoimmun, 34:220-225.
• 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, 148:130-137.
• Severance EG, Yolken RH, Eaton WW (2014) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res, doi:10.1016/j.schres.2014.06.027.
• Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M (2013) Therapeutic potential of fecal microbiota transplantation. Gastroenterology, 145:946-53.
• Smythies LE, Smythies JR (2014) Microbiota, the immune system, black moods and the brain melancholia updated. Front Hum Neurosci, 8:720.
• Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN et al. (2004) Postnatal microbial colonization programs the hypothalamic– pituitary–adrenal system for stress response in mice. J Physiol, 558:263-275.
• Strachan DP (1989) Hay fever, hygiene, and household size. Br Med J, 299:1259-1260.
• Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell, 140:805-820.
• Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B et al. (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology, 144:1394-1401.
• Tosh PK, McDonald LC (2012) Infection control in the multidrug resistant era: tending the human microbiome. Clin Infect Dis, 54:707-713.
• Udina M, Castellvi P, Moreno-Espana J, Navines R, Valdes M, Forns X et al. (2012) Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry, 73:1128-1138.
• Vanderhoof JA, Young R (2008) Probiotics in the United States. Clin Infect Dis, 46:67-72.
• Wang X, Wang BR, Zhang XJ, Xu Z, Ding YQ, Ju G (2002) Evidences for vagus nerve in maintenance of immune balance and transmission of immune information from gut to brain in STM-infected rats. World J Gastroenterol, 8:540-545
• Wren AM, Bloom SR (2007) Gut hormones and appetite control. Gastroenterology, 132:2116-2130.