International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571

Review Article

Microbes-Gut-Brain Axis: A Possible Future Therapeutics Target for Gastrointestinal and Behavioral Disorder

Amit Ghosh1, Debapriya Bandyopadhyay2, Pranati Nanda1, Sushil Chandra Mahapatra1

1Department of Physiology, 2Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar-751019, Odisha

Corresponding Author: Amit Ghosh

Received: 04/12/2014 Revised: 26/12/2014 Accepted: 27/12/2014

ABSTRACT

Gut flora or, more appropriately, gut microbiota, is an ideal example of a symbiotic relationship between prokaryotic and eukaryotic organisms. Although microbes are considered as pathogens, but gut microbiota’s symbiotic co-evolution with humans over thousands of years has made it almost a virtual human organ, with unfailing existence and designated functions. Effective genetic variation of gut microbiota and their resulting metabolites has impact on host metabolism, maturation of immune system and even on behavioral development and patterns; indicating the existence of microbial-gut-brain axis. The understanding of microbial-gut-brain axis will pave the way for the researcher to develop new therapeutic strategy for the treatment of gastrointestinal disorders, metabolic disorders as well as mood and behavioral patterns.

Key word: Microbiota; Microbe-gut-brain axis; Behavioral disorder; Gastrointestinal disorder.

INTRODUCTION gut-brain axis. Influence of gut on Central The Gut-Brain interaction Nervous System (CNS) and vice versa has The optimum functioning of the been recognized by scientists quite early. ( 4) human body as a whole depends largely on The close functional relationship of the gut the regulation and coordination among with the CNS can be understood by the well various organ systems through neural experienced secretion of saliva at the signaling or chemical messengers. thought, sight or smell of certain foods and Interestingly, intestinal microbiota plays an also evident from the association of important role in maintaining interaction intestinal distress almost consistently at between two organs. ( 1) The microbes times of psychological stress. Moreover existing in the normal human intestine are gastrointestinal (GI) disorders are also ten times the total number of human body shown to trigger psychological anxiety ( 5- 7) cells and they carry 150 times more genetic and so on. material than the human genome. ( 2, 3) So gut Gut brain interaction is found to be microbiota behaves more like an organ, modulated by continuously modulating the functioning of (ENS) and chemical mediators like short

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chain fatty acids (SCFA). The ENS, also adrenal axis, intestinal microbiome, Short known as little brain of the gut consists of chain fatty acid (SCFA) and Immune related little more than 100 million neurons and has factors are the various known mediators of its own reflex arc. ( 8, 9) The ENS has a gut-brain interaction. ( 10, 12, 16) strategically place in brain-gut axis and The roles of microbiota in human extends from esophagus to anus. Digestive body are being explored by Human system is regulated intrinsically by the ENS microbiome project. In the meanwhile, this and extrinsically by the autonomic nervous review is an attempt to compile and system (ANS) mainly through the vagus. integrate the existing knowledge and 80% of vagus nerves are sensory, carrying understanding on the interaction of different information from gut to the CNS. ( 10) There domains of microbiota-gut-brain axis,which are Toll Like Receptor 4 (TLR4) on vagal may open new vistasfor treatment of the axis sensory nerve endings which can be dysfunction,in terms of diet and lifestyle stimulated by Pathogen Associated modifications or possible novel therapeutic Molecular Pattern (PAMP) recognition interventions. molecules. ( 11) Besides this a myriad of Intestinal Microbiota: SCFA like Propionic acid (PPA) and Butyric Coexisting among GI epithelial cell, acid (BA) are produced by gut microbial Immune cell, 500 million neurons and an metabolism, which regulate the secretion of ocean of chemical mediators, the intestinal intestinal neuropeptides like the microbiota modulate human physiology, Neuropeptide Y (NPY). Neuropeptides and subtly but definitely. By culture independent SCFA cross the blood brain barrier and has method ( 17) (16S ribosomal RNA and direct been shown to modulate CNS activity ( 12) in sequencing of genetic material) it has been several ways. The rest 20% of vagus also studied that human microbiota is composed known as its efferent arm, carry of trillions of bacteria of more than 1000 secretomotorfibres for vagovagal reflex different species. ( 2, 3, 18) Composition of regulating almost all related microbiota modulates the intestinal activity i.e, gastric, pancreatic and intestinal symbiotic micro-ecosystem. secretions, coordinated gastrointestinal A neonate’s intestine is sterile in motility for propulsion of food bolus etc. uterus and exposed to microbes during the ( 13, 14) Stimulation of has been process of delivery. The microbiota invades found by some workers to be having anti- and starts colonizing the growing human inflammatory effect on the gut. ( 15) intestine. The mechanism of delivery Coordination between gut and brain is (normal or cesarean) as well as exposed maintained by these myriad of delicate and environment after birth has significant less understood signaling processes. Brain influence on intestinal bacterial and gut interact with each other by composition. ( 19) Following spontaneous bidirectional communication and maintains vaginal birth, the neonate’s intestine what is called as a “psycho-gastro” relation. colonizes with bifidobacteria and Our mind is influenced by our gut: a “gut lactobacilli of maternal birth canal. ( 20) level feeling” in common parlance. Breast feeding or formula feeding followed Dysfunction of this axis triggers several by solid food establishes the next stage of pathophysiological conditions like Irritable intestinal microbiota colonization. Bowel Syndrome (IBS), Inflammatory Breastfeeding prevents the growth of Bowel Disorder (IBD), and anxiety. ( 5- 7) pathogenic microorganism and allows the Vagovagal reflex, hypothalamus–pituitary– colonization of bifidobacteria. Reportedly International Journal of Health Sciences & Research (www.ijhsr.org) 322 Vol.5; Issue: 1; January 2015

breastfed infants’ gut is more acidic as neuronal activation in vagal ganglia. ( 24) compared to formula fed infants. Intestinal Different types of neural pathway, especially microbiota composition is determined by vagal pathway are activated by pathogenic food habits, exposed environment and host and non-pathogenic bacteria. ( 22) genetic makeup. ( 21) The role of inhabiting Bidirectional interaction between microbiota in human intestinal symbiotic brain and gut is maintained and modulated micro-ecosystem just began to be elucidated. by neural pathways, endocrine system, and Recently few role of gut microbiota on immune system as well as by human physiology has been explored by differentchemical mediators like SCFA, using germ free mice model, metagenomics bacteria lipopolysaccharide (LPS) and other and findings of the Human microbiome signaling molecules. ( 22) Recent comparative project. Gut microbiota regulate the study between germ free mice (GFM) and development of gut immune system, mice with normal microbiota throw some endocrine system, gut motility and light on several molecular mechanisms that metabolism. Metabolic end products of gut modulate gut-brain axis. ( 25) Gut microbiota microbiota are utilized by colonic epithelial have been shown to be associated with cells as well as delivered to peripheral multicellular organisms from an early stage organs like liver where they modulate the of evolution. Long term symbiotic relation different metabolic pathways. Recently by between gut and microbes as well as their using germ free mice model and other co-evolution, make the human microbiome molecular level approach, some workers indispensible for maintaining the normal reported the extended role of intestinal physiological functions. So disturbance of microbiota in neural development and in the human microbiome may be associated with modulation of adult behavior. ( 22) Role of pathophysiological conditions. ( 23) microbiota on neural development (both structurally and functionally) add another domain to gut-brain axis which is renamed as microbiota-gut-brain axis. Microbiota-gut-brain axis: (Microbe modulate neuro-gastrointestinal interaction) The Enteric Nervous System (ENS) and in fact the entire enteric neuronal plexus develops from neural crest cells migrating into the bowel wall during embryonic development. ENS is a complex neural network in the gut which functions independently and modulated by autonomic input. Most of vagal fibers in gut are Fig. 1. Microbial-gut-brain axis and its modulators. afferent, which carry the sensory inputs to Nucleus of the solitary tract (NTS) which in- Microbe-gut-brain axis disorder turn transmits it to the CNS. Vagal input Experiment on germ free mice, regulates different types of emotional and modulation of gut microbiome by antibiotics behavioral state. ( 22, 23) Citrobacterrodentium and enteropathogenic bacterial infection infected CF-1 mice shows anxious like prove the correlation between behavior after 7-8 h of infection along with gastrointestinal disorders and mood International Journal of Health Sciences & Research (www.ijhsr.org) 323 Vol.5; Issue: 1; January 2015

disorders. Mood disorder is common in microbiota composition compared to gastrointestinal disorders like, dyspepsia and normal. ( 30) Due to heterogenous irritable bowel syndrome (IBS). Again, microbiome community in ASD there is no change in gut microbiome composition has specific trend identified yet, but it has been also been reported in a few neurological reported that gut microbiota and host conditions. Exploring gut microbes in metabolome may be associated with ASD. different diseased states and understanding ( 31) Due to change in gut microbiota how gut microbes modulate the gut-brain composition in ASD, the gut metabolites axis may help develop a new therapeutic and SCFA like PPA may change in subjects strategy for treatment. Different with ASD. PPA can cross the blood brain epidemiological behavioural studies on barrier and induce ASD like behavior. ( 32) human and animal models indicate that On the other hand pathophysiology mental disorders are closely associated with of irritable bowel syndrome (IBS) is intestinal disorders. considered as a disorder of complex Study of relation of Gut microbes interaction between gut and microbiota, with behavioral disorders elicited lot of ENS, CNS and mood disorder, which interesting information. In the colon, ultimately dysregulate microbial-gut-brain complex carbohydrates are digested and axis. In IBS different inflammatory mediator metabolized by microbes. Several SCFA, like Interleukins, , and protease like propionate, butyrate and acetate are secreted from activated lymphocyte and generated during this process. The SCFAs macrophage. Increased number of CD4+ apart from being a quick source of energy and CD8+ T cells expressing Gut homing for colonic enterocytes, are also absorbed receptor integrin β7, results in increased and transported via circulation to other presence of CD8 + T cells in lamina propria organs and even to the brain by crossing the and increase expression of ligand for blood brain barrier. So SCFA can modulate integrin β7 in colon in IBS patients. Besides the function of peripheral organ and CNS. this it is also foundthat genes associated Recently it has been reported that gut with the host defense mechanism against metabolite SCFA is associated with Autism microbial pathogenesis also differentially Spectrum Disorder (ASD). ( 31) Remarkably expressed themselves in colonic mucosa of 70% of autistic children have GI related subjects with IBD. ( 33) Different syndrome including abdominal distension, inflammatory mediators, short peptides and pain, irritability, constipation, diarrhea and lymphocyte act on the ENS, trigger feeding problem. ( 26) ASD is often abnormal sensory inputs in the afferent associated with chronic inflammatory vagus, which consequently trigger aberrant processes like nodular lymphoid hyperplasia secretomotor efferent vasovagal responses. (NLH), enterocolitis, mucosal infiltration of ENS also regulates serotonin release, which immune cells in small and large intestine. ( 27) may be disturbed in IBS. Besides this altered In ASD patient, oral non absorbable number of serotonin secreting antibiotics temporarily reduce the autistic enterochromaffin cells and their content in symptoms. ( 28) It has been reported that IBS also dysregulate the bidirectional gut- intracerebroventricular (ICV) infusions of brain interaction. ( 34- 37) enteric bacterial metabolite, propionic acid Symptomatic relief of IBS patient (PPA) induces ASD-like behavior in rats. ( 29) has been reported after administration of Studies of bacterial identification reported probiotics Bifidibacteriuminfantis 35624. ( 34) that subjects with ASD have different gut Compared to normal, the gut microbiome of International Journal of Health Sciences & Research (www.ijhsr.org) 324 Vol.5; Issue: 1; January 2015

subjects with IBS were found to have higher was inhibited by removal of the stress. ( 43, 44) levels of aerobic bacteria and decreased Stressors can activate HPA axis and level of Coliforms, Lactobacilli and sympatho-adrenomedullary system. These Bifidobacterium. ( 38- 40) End product of systems along with serotonergic signaling bacterial fermentation and metabolism also are heavily involved in mood and behavior regulate the sensorimotor function of gut. disorder in response to stress. ( 45, 46) Remarkably treatment with probiotics Psychological stress effect the intestinal relieves symptoms of different microbiota composition, alter the gastrointestinal disorder including IBS. ( 34, 41) Bacteroidesspp., Clostridium spp. in the caecum and also associated with increased number of pathogenic bacteria as well as decreased number of Lactobacilli. ( 47) Ingestion of Lactobacillus rhamnosus as well as cocktail of Lactobacillus helveticus and B. longum reduces anxiety and serum cortisol. ( 48, 49) So intestinal microbiota play an important role in gut brain axis, its composition may change in different gastrointestinal disorder and different organic or functional neurological abnormalities. Accumulating data now indicate that, the altered intestinal microbiota may even trigger obesity. The term obesity has been in Fig. 2: Bidirectional effect of abnormal axis function. our scientific lexicon for around 20 years now. Identifying the potential master Psychological stress is also known to regulator of obesity is of paramount be associated with IBS. In subjects with IBS importance to design the therapeutic small viscerally painful and stressful stimuli may molecule for the possible modalities of increase activation of anterior cingulate and management of obesity. Human intestine ( 41) in the prelimbic and infralimbic cortices. houses almost ̴ 10-100 trillion organism and Hypothalamic-Pituitary-Adrenal (HPA) axis 90% of which are Bacteroidetes, Firmicutes, may also get activated by different stressor and Actinobacter. Difference of gut in subjects with IBS, followed by microbiota composition between lean and glucocorticoid secretion which may alter obese individual has been reported by motility, immune response, composition of several research group. ( 50, 51) Gut microbial ( 34, 41) gut microbiota. Irritable bowel diseases diversity of obese individuals are less than (IBD) and co-existing anxiety and that in the normal. Though it is undeniable depressive disorders are also associated with that gut microorganisms influence obesity, gut inflammation, altered microbiota but the detailed molecular and cellular composition and dysregulation of brain-gut mechanisms underlying it are yet to be ( 42) axis. explored. Gut microbiota regulate host The axis disorders associated with immune response, energy harvesting from different psychological stressors, like small diet, and also regulate food intake by intestinal motility, migrating motor complex influencing brain-gut axis. Besides this (MMC) altered and small intestinal transit different physiological event like feeling International Journal of Health Sciences & Research (www.ijhsr.org) 325 Vol.5; Issue: 1; January 2015

hunger, satiety, food intake and energy communities are more steadfast than the homeostasis orchestrated by signaling others. Recently germ-free mice model molecule and vagovagal reflex between gut enriched our understanding about the effect and brain. It has been reported that ~383 of gut microbiota on physiology. However microbial genes are significantly associated the detail impact of gut microbiota and their with human obesity and majority of them product on gut-brain axis, immune system are affect in some way human intestinal and metabolism are yet to be explored. carbohydrate metabolism. ( 52) Several key Several studies indicate the association of regulator like gut metabolite (different gut microbiota with behavior and mood SCFA) and gut hormones (like Peptide YY, disorder as well as different metabolic GIP, Ghreline etc.) can cross blood-brain disorders. Our microbes are truly a part of us barrier and modulate neurological functions. and our personalities, and just as we are vast ( 53) Further research needs to be carried out in our variety, so, too, are they. As gut to identify the link between microbial microbiota can influence gut-brain axis and composition of the gut as well as production other physiological functions, altering gut and secretion of different gut metabolite and microbiota composition and use of different chemical mediators. prebiotics may be the future treatment of different metabolic, enteric and behavioral CONCLUSION disorders, but still there is major gap in the Results from different experimental translation of experimental research to and clinical studies as well as evidence from application. human microbiome project indicate the existence of microbe-gut-brain axis. REFERENCES Enormous development of sequencing 1. Sommer F., Bäckhed F. The gut technology and bioinformatics tools help microbiota - masters of host researcher to explore gut microbiota development and physiology. Nat Rev population in detail by metagenomic Microbiol. 2013 Apr; 11 (4):227-38. 2. Gill SR, Pop M, Deboy RT, Eckburg sequencing. Identification of metabolic PB, Turnbaugh PJ. et al. Metagenomic product of the gut microbiota just began to analysis of the human distal gut be elicited. And now it is being believed that microbiome. Science. 2006 Jun 2; 312 the gut Microbiome is a sum of our (5778):1355-9. experiences throughout our lives: the genes 3. Qin J, Li R, Raes J, Arumugam we inherited, the situations we faced, the M, Burgdorf KS, Manichanh C et al. A hands we shook and the food we ate. It is human gut microbial gene catalogue unlikely to produce one-size-for-all established by metagenomic sequencing. solutions to modern maladies. We keep Nature. 2010 Mar 4; 464(7285):59-65. trying to unearth the intricacies of Gut-Brain 4. O’Hara, A. M. & Shanahan, F. The gut cross talking with minimum effort, but flora as a forgotten organ. EMBO Rep. 2006 Jul; 7(7):688-93. biology is rarely that charitable. Therefore it 5. Finegold SM, Molitoris D, Song Y, Liu is still a mystery how fine alterations of our C, Vaisanen ML et al. Gastrointestinal diet, lifestyle and environment can nudge microflora studies in late-onset and shape the microbiota of our gut. One autism.Clin Infect Dis. 2002 Sep 1; way of understanding the situation would be 35(Suppl 1):S6-S16. to study the gut microbiome at regular 6. Mittal VA, Ellman LM, Cannon TD. intervals and appreciate how its members Gene-environment interaction and flicker over time, and whether some covariation in schizophrenia: The role of International Journal of Health Sciences & Research (www.ijhsr.org) 326 Vol.5; Issue: 1; January 2015

obstetric complications. Schizophr macrophages independent of the spleen. Bull. 2008 Nov; 34(6):1083-94. Gut; Jun 2014, Vol. 63 Issue 6, p938. 7. Goehler LE, Park SM, Opitz N, Lyte M, 16. Mayer EA. Gut feelings: the emerging Gaykema RP. Campylobacter jejuni biology of gut–brain communication. infection increases anxiety-like behavior Nat Rev Neurosci. 2011 Jul 13; 12(8): in the holeboard: Possible anatomical 453-66. substrates for viscerosensory modulation 17. Booijink CC, Zoetendal EG, of exploratory behavior. Brain Behav Kleerebezem M, de Vos WM. Microbial Immun. 2008 Mar; 22(3):354-66. communities in the human small 8. SchemannM., Reiche D., Neunlist M. intestine: coupling diversity to Properties and Functional Aspects of the metagenomics. Future Microbiol. 2007 Enteric Nervous System. Problems of Jun; 2(3):285-95. the in Anesthesia, 18. Huttenhower C. Structure, function and the Perioperative Period, and Intensive diversity of the healthy human Care. 1999, pp 3-11. microbiome. Nature. 2012 Jun 13; 9. Jonge W J. The Gut’s Little Brain in 486(7402):207-14. Control of Intestinal Immunity. ISRN 19. Mackie RI, Sghir A, Gaskins HR. Gastroenterology ISRN Gastroenterol. Developmental microbial ecology of the 2013 Apr 4; 2013: 630159. neonatal gastrointestinal tract. Am J 10. Cryan JF, Dinan TG. Mind-altering ClinNutr 1999; 69 (suppl):1035S–45S. microorganisms: the impact of the gut 20. Makino H, Kushiro A, Ishikawa E, microbiota on brain and behavior. Nat Kubota H, Gawad A, et al. Mother-to- Rev Neurosci. 2012 Oct; 13(10):701-12. Infant Transmission of Intestinal 11. Hosoi T, Okuma Y, Matsuda T, Nomura Bifidobacterial Strains Has an Impact on Y. Novel pathway for LPS-induced the Early Development of Vaginally afferent vagus nerve activation: possible Delivered Infant’s Microbiota. PLoS role of nodose ganglion. Auton One. 2013 Nov 14; 8 (11): e78331. Neurosci. 2005 Jun 15; 120(1-2):104-7. 21. Guaraldi F, Salvatori G. Effect of breast 12. Peter Holzer, Florian Reichmann, and formula feeding on gut microbiota AitakFarzi. Neuropeptide Y, peptide YY shaping in newborns. Frontiers in and pancreatic polypeptide in the gut– Cellular and Infection Microbiology. brain axis. Neuropeptides. 2012 Dec; Front Cell Infect Microbiol. 2012; 2: 94. 46(6):261-74. 22. Forsythe P, Kunze W. Voices from 13. John B. Furness. The enteric nervous within: gut microbes and the CNS. Cell system and neurogastroenterology. Nat Mol Life Sci. 2013 Jan; 70(1):55-69. Rev GastroenterolHepatol. 2012 Mar 6; 23. Collins SM, Bercik P. The Relationship 9(5):286-94. between Intestinal Microbiota and the 14. Li Y, Owyang C. Musings on the Central Nervous System in Normal wanderer: what's new in our Gastrointestinal Function and Disease. understanding of vago-vagal reflexes? Gastroenterology. 2009 May; 136 V. Remodeling of vagus and enteric (6):2003-14. neural circuitry after vagal injury. Am J 24. Lyte M, Li W, Opitz N, Gaykema RP, PhysiolGastrointest Liver Physiol. 2003 Goehler LE. Induction of anxiety-like Sep; 285(3):G461-9. behavior in mice during the initial stages 15. Matteoli G, Gomez-Pinilla PJ, of infection with the agent of murine Nemethova A, Di Giovangiulio M, colonic hyperplasia Citrobacterro- Cailotto C, et al. A distinct vagal anti- dentium. PhysiolBehav. 2006 Oct 30;89 inflammatory pathway modulates (3):350-7. intestinal muscularis resident 25. Heijtz RD, Wang S, Anuar F, Qian YU, Björkholm B, et al. Normal gut

International Journal of Health Sciences & Research (www.ijhsr.org) 327 Vol.5; Issue: 1; January 2015

microbiota modulates brain irritable bowel syndrome. Clin development and behavior. PNAS. GastroenterolHepatol. 2008 Feb; February 15, 2011. vol. 108, no. 7, 6(2):194-205. 3047–3052. 34. Prins A. The brain-gut interaction: the 26. Stephen J. Walker mail, John Fortunato, conversation and the implications. S Afr Lenny G. Gonzalez, Arthur Krigsman. J ClinNutr 2011;24(3): S8-S14. Identification of Unique Gene 35. De Giorgio R, Camilleri M. Human Expression Profile in Children with enteric neuropathies: morphology and Regressive Autism Spectrum Disorder molecular pathology. Neurogastro- (ASD) and Ileocolitis. PLOS ONE. enterol Motil. 2004 Oct; 16 (5):515-31. March 2013. Volume 8. Issue 3. e58058. 36. Mawe GM, Coates MD, Moses PL. 27. White JF. Intestinal pathophysiology in Review article: Intestinal Serotonin autism. ExpBiol Med (Maywood). 2003 Signaling in Irritable Bowel Syndrome. Jun;228(6):639-49. Aliment Pharmacol Ther. 2006; 28. Sandler RH, Finegold SM, Bolte ER, 23(8):1067-1076. Buchanan CP, Maxwell AP, et. al. 37. Lomax AE, Linden DR, Mawe GM, Short-term benefit from oral Sharkey KA. Effects of gastrointestinal vancomycin treatment of regressive- inflammation on enteroendocrine cells onset autism. J Child Neurol. 2000 Jul; and enteric neural reflex circuits. 15(7):429-35. AutonNeurosci. 2006 Jun 30; 126- 29. Thomas RH, Meeking MM, Mepham 127:250-7. JR, Tichenoff L, Possmayer F.et. al. The 38. Balsari A, Ceccarelli A, Dubini F, Fesce enteric bacterial metabolite propionic E, Poli G. The fecal microbial acid alters brain and plasma population in the irritable bowel phospholipid molecular species: further syndrome. Microbiologica 1982; 5: 185- development of a rodent model of 194. autism spectrum disorders. J 39. Si JM, Yu YC, Fan YJ, Chen SJ. Neuroinflammation. 2012 Jul 2; 9:153. Intestinal microecology and quality of 30. De Angelis M, Piccolo M, Vannini life in irritable bowel syndrome patients. L, Siragusa S, De Giacomo World J Gastroenterol 2004; 10:1802- A, Serrazzanetti DI. Fecal Microbiota 1805. and Metabolome of Children with 40. Mättö J, Maunuksela L, Kajander K, et Autism and Pervasive Developmental al. Composition and temporal stability Disorder Not Otherwise Specified. PLoS of gastrointestinal microbiota in irritable One. 2013 Oct 9; 8(10):e76993. bowel syndrome - a longitudinal study 31. Hsiao EY, McBride SW, Hsien in IBS and control subjects. FEMS S, Sharon G, Hyde ER. Microbiota Immunol Med Microbiol 2005; 43:213- Modulate Behavioral and Physiological 222. Abnormalities Associated with 41. Cryan JF, Dinan TG. Mind-altering Neurodevelopmental Disorders Cell. microorganisms: the impact of the gut 2013 Dec 19; 155(7):1451-63. microbiota on brain and behavior. Nat 32. MacFabe. D. F. Short-chain fatty acid Rev Neurosci. 2012 Oct; 13(10):701-12. fermentation products of the gut 42. Taché Y, Bernstein CN. Evidence for microbiome: implications in autism the role of the brain-gut axis in spectrum disorders. Microbial Ecology inflammatory bowel disease: depression in Health & Disease 2012, 23: 19260. as cause and effect? Gastroenterology. 33. Aerssens J, Camilleri M, Talloen 2009 Jun; 136(7):2058-61. W, Thielemans L, Göhlmann HW. 43. Muelas MS, Ramirez P, Parrilla P, Ruiz Alterations in mucosal immunity JM, Perez JM, Candel MF, Aguilar J, identified in the colon of patients with Carrasco L. Vagal system involvement

International Journal of Health Sciences & Research (www.ijhsr.org) 328 Vol.5; Issue: 1; January 2015

in changes in small bowel motility probiotic formulation (Lactobacillus during restraint stress: an experimental helveticus R0052 and study in the dog. Br J Surg 1993; 80: Bifidobacteriumlongum R0175) in rats 479-483. and human subjects. Br. J. Nutr. 105, 44. Wang SX, Wu WC. Effects of 755–764 (2011). psychological stress on small intestinal 49. Bravo JA, Forsythe P, Chew motility and bacteria and mucosa in MV, Escaravage E, Savignac HM, et al. mice. World J Gastroenterol. 2005 Apr Ingestion of Lactobacillus strain 7; 11(13):2016-21. regulates emotional behavior and central 45. Bandlapalli P, Banji D, Banji OJF, GABA receptor expression in a mouse Swetha D and Pratusha NG. Role of via the vagus nerve. Proc. Natl Acad. stress in pathophysiology of irritable Sci. USA 108, 16050–16055 (2011). bowel syndrome. IRJP. 2011. 2(5): 54– 50. Kosiewicz MM, Zirnheld AL, Alard P. 60. Gutmicrobiota, immunity,and disease: a 46. Rodríguez-Fandiño O, Hernández-Ruiz complex relationship. Front Microbiol. J, Schmulson M.From cytokines to toll- 2011; 2: 180. like receptors and beyond - current 51. Turnbaugh PJ, Gordon JI.The core gut knowledge and future research needs in microbiome, energy balance and irritable bowel syndrome. J obesity. J Physiol. 2009 Sep 1; 587(Pt NeurogastroenterolMotil. 2010. 6(4): 17):4153-8. 363–373. 52. Turnbaugh PJ, Hamady M, Yatsunenko 47. Phillips ML. Gut Reaction: T, Cantarel BL, Duncan A. et. al. A core Environmental Effects on the Human gut microbiome in obese and lean twins. Microbiota. Environmental Health Nature. 2009 Jan 22; 457(7228):480-4. Perspectives. 2009; 117(5):A198-A205. 53. Banks WA. The Blood-Brain Barrier: 48. Messaoudi M, Lalonde R, Violle Connecting the Gut and the Brain. Regul N, Javelot H, Desor D. et al. Assessment Pept. 2008 August 7; 149(1-3): 11–14. of psychotropic-like properties of a

How to cite this article: Ghosh A, Bandyopadhyay D, Nanda P et. al. Microbes-gut-brain axis: a possible future therapeutics target for gastrointestinal and behavioral disorder. Int J Health Sci Res. 2015; 5(1):321-329.

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International Journal of Health Sciences & Research (www.ijhsr.org) 329 Vol.5; Issue: 1; January 2015