Enteric nervous system, gut-brain connection and related neurodevelopmental disorders (Review paper)

Year 2020, Volume: 14 Issue: 1, 61 - 67, 30.04.2020

Ece Alım İsmail Gülekon Kerem Atalar Meltem Bahcelıoglu

Abstract

The vagus nerve is the primary neural medium which enables gastrointestinal tract and brain communication. Hippocampus, a region of the brain commonly linked to memory function, is activated by vagus nerve-mediated gastrointestinal signals. Vagal afferent information is received by the medial solitary nucleus and is then transmitted via ascending neural pathways to different regions of the forebrain and hindbrain. Explanation of the exact mechanisms of microbiota and amygdala communication requires further research. By linking microbial activities to progressive structural and functional events in the brain in mice models and in humans, we can suggest that intestinal microbiota is an important contributor to neurodevelopment and neurodegeneration. Further researches revealing these relations may provide new approaches for understanding neurodegenerative, psychiatric and behavioral diseases.

Keywords

enteric nervous system, gut-brain connection, neurodegenerative disease, vagus nerve

References

• Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 2012;9:286-94.
• Lake JI, Heuckeroth RO. Enteric nervous system development: migration, differentiation, and disease. Am J Physiol Liver Physiol 2013;305:G1-G24.
• Langley J. Langley, JN. The Autonomic Nervous System, Part 1 [1921]. Cornell Univ. Library; Digital Collections 2010, p:2-3.
• Furness J. The Enteric Nervous System. Scholarpedia, Blackwell Publishing 2006;2: 4064.
• Gershon MD. The enteric nervous system: a second brain. Hosp Pract (1995) 1999 15;34:31-2
• Furness JB, Callaghan BP, Rivera LR, Cho H-J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol 2014;817:39-71.
• Gershon MD. Developmental determinants of the independence and complexity of the enteric nervous system. Trends Neurosci 2010;33:446-56.
• Forsythe P, Bienenstock J, Kunze WA. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol 2014;817:115-33.
• Furness JB, Costa M. Types of nerves in the enteric nervous system. Neuroscience 1980;5:1-20.
• Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst 2000;81:87-96.
• Furness JB, Clerc N, Gola M, Kunze WAA, Fletcher EL. Identification of component neurons and organisation of enteric nerve circuits. In: Krammer HJ, Singer MV (Eds) Neurogastroenterology — From the Basics to the Clinics, Kluwer Academic. Dordrecht 2000; p.134–47.
• Kunze WA, Furness JB. The enteric nervous system and regulation of intestinal motility. Annu Rev Physiol 1999;61:117-142.
• Pompolo S, Furness JB. Ultrastructure and synaptic relationships of calbindin-reactive, Dogiel type II neurons, in myenteric ganglia of guinea-pig small intestine. J Neurocytol 1988;17:771-782.
• Lomax AE, Sharkey KA, Bertrand PP, Low AM, Bornstein JC, Furness JB. Correlation of morphology, electrophysiology and chemistry of neurons in the myenteric plexus of the guinea-pig distal colon. J Auton Nerv Syst 1999;76:45-61.
• Song Z-M, Brookes SJ, Ramsay G, Costa M. Characterization of myenteric interneurons with somatostatin immunoreactivity in the guinea-pig small intestine. Neuroscience 1997;80:907-23.
• Portbury AL, Pompolo S, Furness JB, Stebbing MJ, Kunze WA, Bornstein JC, Hughes S. Cholinergic, somatostatin-immunoreactive interneurons in the guinea pig intestine: morphology, ultrastructure, connections and projections. J Anat 1995;187:303-21.
• Furness JB, Johnson PJ, Pompolo S, Bornstein JC. Evidence that enteric motility reflexes can be initiated through entirely intrinsic mechanisms in the guinea-pig small intestine. Neurogastroenterol Motil 1995;7:89-96.
• Crema A, Frigo Gm, Lecchini S. A pharmacological analysis of the peristaltic reflex in the isolated colon of the guinea-pig or cat. Br J Pharmacol 1970;39:334-45.
• Powley TL, Phillips RJ. Gastric satiation is volumetric, intestinal satiation is nutritive. Physiol Behav 2004;82:69-74.
• Brookes SJH, Spencer NJ, Costa M, Zagorodnyuk VP. Extrinsic primary afferent signalling in the gut. Nat Rev Gastroenterol Hepatol 2013;10:286-96.
• Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 2016;166:209-21.
• Suarez AN, Hsu TM, Liu CM, Noble EE, Cortella AM, Nakamoto EM, Hahn JD, Lartigue G, Kanoski SE. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun 2018;9:2181.
• Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab 2012;16:296-309.
• Min DK, Tuor UI, Chelikani PK. Gastric distention induced functional magnetic resonance signal changes in the rodent brain. Neuroscience 2011;179:151-8.
• Kanoski SE, Grill HJ. Hippocampus contributions to food intake control: mnemonic, neuroanatomical, and endocrine mechanisms. Biol Psychiatry 2017;81:748-56.
• Min DK, Tuor UI, Koopmans HS, Chelikani PK. Changes in differential functional magnetic resonance signals in the rodent brain elicited by mixed-nutrient or protein-enriched meals. Gastroenterology 2011;141:1832-41.
• Wang G-J, Yang J, Volkow ND, Telang F, Ma Y, Zhu W, Wong CT, Tomasi D, Thanos PK, Fowler JS. Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry. Proc Natl Acad Sci U S A 2006;103:15641-5.
• Clark KB, Krahl SE, Smith DC, Jensen RA. Post-training unilateral vagal stimulation enhances retention performance in the rat. Neurobiol Learn Mem 1995;63:213-6.
• Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci 1999;2:94-8.
• Clark KB, Smith DC, Hassert DL, Browning RA, Naritoku DK, Jensen RA. Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat. Neurobiol Learn Mem 1998;70:364-73.
• Castle M, Comoli E, Loewy AD. Autonomic brainstem nuclei are linked to the hippocampus. Neuroscience 2005;134:657-69.
• Rinaman L. Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Res 2010;1350:18-34.
• Mello-Carpes PB, Izquierdo I. The nucleus of the solitary tract→nucleus paragigantocellularis→locus coeruleus→CA1 region of dorsal hippocampus pathway is important for consolidation of object recognition memory. Neurobiol Learn Mem 2013;100:56-63.
• Xu L, Sun X, Lu J, Tang M, Chen JDZ. Effects of gastric electric stimulation on gastric distention responsive neurons and expressions of CCK in rodent hippocampus. Obesity (Silver Spring) 2008;16:951-7.
• Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson Jr RK, Goodman R. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 2000;47:276-86.
• George MS, Sackeim HA, Rush AJ, Marangell LB, Nahas Z, Husain MM, Lisanby S, Burt T, Goldman J, Ballenger JC. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry 2000;47:287-95.
• Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 2015;17:565-76.
• Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015;161:264-76.
• Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 2014;34:15490-6.
• Davis M, Walker DL, Miles L, Grillon C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 2010;35:105-35.
• LeDoux J. The emotional brain, fear, and the amygdala. Cell Mol Neurobiol 2003;23:727-38.
• Knapska E, Radwanska K, Werka T, Kaczmarek L. Functional internal complexity of amygdala: focus on gene activity mapping after behavioral training and drugs of abuse. Physiol Rev 2007;87:1113-73.
• Berntson GG, Sarter M, Cacioppo JT. Ascending visceral regulation of cortical affective information processing. Eur J Neurosci 2003;18:2103-9.
• Hassert DL, Miyashita T, Williams CL. The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. Behav Neurosci 2004;118:79-88.
• Peña DF, Childs JE, Willett S, Vital A, McIntyre CK, Kroener S. Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala. Front Behav Neurosci 2014;8:327.
• Liu J, Fang J, Wang Z, Rong P, Hong Y, Fan Y, Wang X, Park J, Jin Y, Liu C, Zhu B, Kong J. Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression. J Affect Disord 2016;205:319-26.
• Klarer M, Arnold M, Günther L, Winter C, Langhans W, Meyer U. Gut vagal afferents differentially modulate innate anxiety and learned fear. J Neurosci 2014;34:7067-76.
• Luczynski P, Whelan SO, O’Sullivan C,larke 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;44:2654-66.
• Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 2013;144:1394-401.
• Stilling RM, Ryan FJ, Hoban AE, Shanahan F, Clarke G, Claesson MJ, Dinan TG, Cryan JF. Microbes & neurodevelopment – absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun 2015;50:209-20.
• Hoban AE, Stilling RM, M. Moloney G, Moloney RD, Shanahan F, Dinan TG, Cryan JF, Clarke G. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome 2017;5:102.
• Hulvershorn LA, Mennes M, Castellanos FX, Di Martino A, Milham MP, Hummer TA, Roy AK. Abnormal amygdala functional connectivity associated with emotional lability in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2014;53:351-61.
• Liu H, Tang Y, Womer F, Fan G, Lu T, Driesen N, Ren L, Wang Y, He Y, Blumberg HP, Xu K, Wang F. Differentiating patterns of amygdala-frontal functional connectivity in schizophrenia and bipolar disorder. Schizophr Bull 2014;40:469-77.
• Lawrie SM, Whalley HC, Job DE, Johnstone EC. Structural and functional abnormalities of the amygdala in schizophrenia. Ann N Y Acad Sci 2003;985:445-60.
• Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci 2008;31:137-45.
• Kleinhans NM, Reiter MA, Neuhaus E, Pauley G, Martin N, Dager S, Estes A. Subregional differences in intrinsic amygdala hyperconnectivity and hypoconnectivity in autism spectrum disorder. Autism Res 2016;9:760-72.
• Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014;157:121-41.
• Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535:75-84.
• Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016;16:341-52.
• Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012;10:735-42.
• Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701-12.
• Geschwind DH, Rakic P. Cortical evolution: judge the brain by its cover. Neuron 2013;80:633-47.
• Marín O, Rubenstein JLR. Cell migration in the forebrain. Annu Rev Neurosci 2003;26:441-83.
• Chang C-Y, Ke D-S, Chen J-Y. Essential fatty acids and human brain. Acta Neurol Taiwan 2009;18:231-41.
• Zeisel SH. Nutritional importance of choline for brain development. J Am Coll Nutr 2004;23:621S-6S.
• Borre YE, O’Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med 2014;20:509-18.
• Luczynski P, McVey Neufeld K-A, 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;19:pyw020.
• Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013;36:305-12.
• Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;9:313-23.
• Krajmalnik-Brown R, Lozupone C, Kang D-W, Adams JB. Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. Microb Ecol Health Dis 2015;26:26914.
• Severance EG, Yolken RH, Eaton WW. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res 2016;176:23-35.
• Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM. Colonic bacterial composition in Parkinson’s disease. Mov Disord 2015;30:1351-60.
• 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 2011;25:397-407.
• Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 2015;28:203-9.
• Moussaoui N, Braniste V, Ait-Belgnaoui A, Gabanou M, Sekkal S, Olier M, Theodorou V, Mart,n PGP, Houdeau E. Changes in intestinal glucocorticoid sensitivity in early life shape the risk of epithelial barrier defect in maternal-deprived rats. PLoS One 2014;9:e88382.
• Park AJ, Collins J, Blennerhassett PA, Ghia JE, Bercik P, Collins SM. Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterol Motil 2013;25:733-e575.
• De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, Denou E, Silva MA, Santacruz A, Sanz Y, Surette MG, Verdu EF, Collins SM, Bercik P. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun 2015;6:7735.
• Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Marci J, McCoy KD, Verdu EF, Collins SM. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011;141:599-609.
• Gacias M, Gaspari S, Santos P-MG,Tamburini S, Andrade M, Zhang F, Shen N, Tolstikov V, Kiebish MA, Dupree JL, Zachariou V, Clemente JC, Casaccia P. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife 2016;5:e13442.
• Sudo N, Chida Y, Aiba Y, Sonoda JS, Oyama N, Yu X-N, Kubo C. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558:263-75.
• Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011;108:16050-5.
• 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 2010;170:1179-88.
• Mello BSF, Monte AS, McIntyre RS, et al. Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration. J Psychiatr Res 2013;47:1521-9.
• Mussell M, Kroenke K, Spitzer RL, Williams JBW, Herzog W, Löwe B. Gastrointestinal symptoms in primary care: Prevalence and association with depression and anxiety. J Psychosom Res 2008;64:605-12.
• Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci 2015;38:637-58.
• Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015;18:965-77.
• Matcovitch-Natan O, Winter DR, Giladi A, et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 2016;353:aad8670.
• Kelly JR, Borre Y, O’ Brien C, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 2016;82:109-18.