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

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Microbes-Gut-Brain Axis: a Possible Future Therapeutics Target for Gastrointestinal and Behavioral Disorder 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 Enteric Nervous System continuously modulating the functioning of (ENS) and chemical mediators like short International Journal of Health Sciences & Research (www.ijhsr.org) 321 Vol.5; Issue: 1; January 2015 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 digestion 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 vagus nerve 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
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