Neuropeptides and the Microbiota-Gut-Brain Axis

  • Peter HolzerEmail author
  • Aitak Farzi
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 817)


Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gut-brain axis address four information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and four information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G protein-coupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides are likely to emerge as neural and endocrine messengers in orchestrating the microbiota-gut-brain axis in health and disease.


Chronic Fatigue Syndrome Vasoactive Intestinal Polypeptide Intestinal Microbiota Primary Afferent Neuron Enteroendocrine Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Agouti-related protein


Amine precursor uptake and decarboxylation


Brain-derived neurotrophic factor


Corticotropin-releasing factor


Gamma-aminobutyric acid




Microbe-associated molecular pattern


Neuropeptide Y


NMDA receptor subunit 2A


Nucleus tractus solitarii


Peptide YY


Toll-like receptor 4



This study was supported by the Zukunftsfonds Steiermark (grant 262), the Austrian Science Fund (FWF grants L25-B05, P23097-B18 and P25912-B23), and the Federal Ministry of Science and Research of the Republic of Austria (grant GZ 80.104/2-BrGT/2007).


  1. 1.
    Pearse AGE (1969) The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem 17(5):303–313PubMedGoogle Scholar
  2. 2.
    Strand FL (1999) Neuropeptides: regulators of physiological processes. MIT Press, CambridgeGoogle Scholar
  3. 3.
    Kastin AJ (2013) Handbook of biologically active peptides, 2nd edn. Academic, San DiegoGoogle Scholar
  4. 4.
    Burbach JP (2010) Neuropeptides from concept to online database Eur J Pharmacol 626(1):27–48
  5. 5.
    Mayer EA, Tillisch K (2011) The brain-gut axis in abdominal pain syndromes. Annu Rev Med 62:381–396PubMedGoogle Scholar
  6. 6.
    Holzer P, Reichmann F, Farzi A (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46(6):261–274PubMedCentralPubMedGoogle Scholar
  7. 7.
    Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13(10):701–712PubMedGoogle Scholar
  8. 8.
    Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10(11):735–742PubMedGoogle Scholar
  9. 9.
    Gorkiewicz G, Thallinger GG, Trajanoski S, Lackner S, Stocker G, Hinterleitner T, Gülly C, Högenauer C (2013) Alterations in the colonic microbiota in response to osmotic diarrhea. PLoS One 8(2):e55817PubMedCentralPubMedGoogle Scholar
  10. 10.
    Field BC, Chaudhri OB, Bloom SR (2010) Bowels control brain: gut hormones and obesity. Nat Rev Endocrinol 6(8):444–453PubMedGoogle Scholar
  11. 11.
    Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 106(10):3698–3703PubMedCentralPubMedGoogle Scholar
  12. 12.
    Antunes LC, Han J, Ferreira RB, Lolić P, Borchers CH, Finlay BB (2011) Effect of antibiotic treatment on the intestinal metabolome. Antimicrob Agents Chemother 55(4):1494–1503PubMedCentralPubMedGoogle Scholar
  13. 13.
    Tremaroli V, Bäckhed F (2012) Functional interactions between the gut microbiota and host metabolism. Nature 489(7415):242–249PubMedGoogle Scholar
  14. 14.
    Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336(6086):1262–1267PubMedGoogle Scholar
  15. 15.
    Marcobal A, Kashyap PC, Nelson TA, Aronov PA, Donia MS, Spormann A, Fischbach MA, Sonnenburg JL (2013) A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice. ISME J 7:1933–1943PubMedGoogle Scholar
  16. 16.
    Matsumoto M, Kibe R, Ooga T, Aiba Y, Sawaki E, Koga Y, Benno Y (2013) Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study. Front Syst Neurosci 7:9PubMedCentralPubMedGoogle Scholar
  17. 17.
    Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16(2):228–231PubMedGoogle Scholar
  18. 18.
    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56PubMedCentralPubMedGoogle Scholar
  19. 19.
    McCusker RH, Kelley KW (2013) Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol 216(Pt 1):84–98PubMedCentralPubMedGoogle Scholar
  20. 20.
    Painsipp E, Herzog H, Holzer P (2008) Implication of neuropeptide-Y Y2 receptors in the effects of immune stress on emotional, locomotor and social behavior of mice. Neuropharmacology 55(1):117–126PubMedGoogle Scholar
  21. 21.
    Painsipp E, Herzog H, Holzer P (2010) Evidence from knockout mice that neuropeptide-Y Y2 and Y4 receptor signalling prevents long-term depression-like behavior caused by immune challenge. J Psychopharmacol 24(10):1551–1560PubMedGoogle Scholar
  22. 22.
    Painsipp E, Köfer MJ, Sinner F, Holzer P (2011) Prolonged depression-like behavior caused by immune challenge: influence of mouse strain and social environment. PLoS One 6(6):e20719PubMedCentralPubMedGoogle Scholar
  23. 23.
    Kubera M, Curzytek K, Duda W, Leskiewicz M, Basta-Kaim A, Budziszewska B, Roman A, Zajicova A, Holan V, Szczesny E, Lason W, Maes M (2013) A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months. Brain Behav Immun 31:96–104PubMedGoogle Scholar
  24. 24.
    Tarr AJ, Chen Q, Wang Y, Sheridan JF, Quan N (2012) Neural and behavioral responses to low-grade inflammation. Behav Brain Res 235(2):334–341PubMedCentralPubMedGoogle Scholar
  25. 25.
    Holzer P, Danzer M, Schicho R, Samberger C, Painsipp E, Lippe IT (2004) Vagal afferent input from the acid-challenged rat stomach to the brainstem: enhancement by interleukin-1beta. Neuroscience 129:439–445PubMedGoogle Scholar
  26. 26.
    Hughes PA, Harrington AM, Castro J, Liebregts T, Adam B, Grasby DJ, Isaacs NJ, Maldeniya L, Martin CM, Persson J, Andrews JM, Holtmann G, Blackshaw LA, Brierley SM (2013) Sensory neuro-immune interactions differ between irritable bowel syndrome subtypes. Gut 62:1456–1465PubMedGoogle Scholar
  27. 27.
    Abreu MT (2010) Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10(2):131–144PubMedGoogle Scholar
  28. 28.
    Marques R, Boneca IG (2011) Expression and functional importance of innate immune receptors by intestinal epithelial cells. Cell Mol Life Sci 68(22):3661–3673PubMedGoogle Scholar
  29. 29.
    Barajon I, Serrao G, Arnaboldi F, Opizzi E, Ripamonti G, Balsari A, Rumio C (2009) Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia. J Histochem Cytochem 57(11):1013–1023PubMedCentralPubMedGoogle Scholar
  30. 30.
    Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S (2012) Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology 143(4):1006–1016.e4Google Scholar
  31. 31.
    van Noort JM, Bsibsi M (2009) Toll-like receptors in the CNS: implications for neurodegeneration and repair. Prog Brain Res 175:139–148PubMedGoogle Scholar
  32. 32.
    Arroyo DS, Soria JA, Gaviglio EA, Rodriguez-Galan MC, Iribarren P (2011) Toll-like receptors are key players in neurodegeneration. Int Immunopharmacol 11(10):1415–1421PubMedCentralPubMedGoogle Scholar
  33. 33.
    Mallard C (2012) Innate immune regulation by toll-like receptors in the brain. ISRN Neurol 2012:701950PubMedCentralPubMedGoogle Scholar
  34. 34.
    Maes M, Kubera M, Leunis JC, Berk M (2012) Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 141(1):55–62PubMedGoogle Scholar
  35. 35.
    Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M (2012) Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord 136(3):909–917PubMedGoogle Scholar
  36. 36.
    Lyte M (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays 33(8):574–581PubMedGoogle Scholar
  37. 37.
    Forsythe P, Kunze WA (2013) Voices from within: gut microbes and the CNS. Cell Mol Life Sci 70(1):55–69PubMedGoogle Scholar
  38. 38.
    Asano Y, Hiramoto T, Nishino R, Aiba Y, Kimura T, Yoshihara K, Koga Y, Sudo N (2012) 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 303(11):G1288–G1295PubMedGoogle Scholar
  39. 39.
    Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C (2012) Gamma-aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 113(2):411–417PubMedGoogle Scholar
  40. 40.
    Yurdaydin C, Walsh TJ, Engler HD, Ha JH, Li Y, Jones EA, Basile AS (1995) Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res 679(1):42–48PubMedGoogle Scholar
  41. 41.
    Hu Y, Phelan V, Ntai I, Farnet CM, Zazopoulos E, Bachmann BO (2007) Benzodiazepine biosynthesis in Streptomyces refuineus. Chem Biol 14(6):691–701PubMedGoogle Scholar
  42. 42.
    Gerratana B (2012) Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines. Med Res Rev 32(2):254–293PubMedGoogle Scholar
  43. 43.
    Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF (2013) The microbiome-gut-brain axis during early-life regulates the hippocampal serotonergic system in a gender-dependent manner. Mol Psychiatry 18(6):666–673PubMedGoogle Scholar
  44. 44.
    Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87(4):1409–1439PubMedGoogle Scholar
  45. 45.
    Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI (2008) Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A 105:16767–16772PubMedCentralPubMedGoogle Scholar
  46. 46.
    Reolon GK, Maurmann N, Werenicz A, Garcia VA, Schröder N, Wood MA, Roesler R (2011) Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats. Behav Brain Res 221(1):329–332PubMedCentralPubMedGoogle Scholar
  47. 47.
    Gundersen BB, Blendy JA (2009) Effects of the histone deacetylase inhibitor sodium butyrate in models of depression and anxiety. Neuropharmacology 57(1):67–74PubMedCentralPubMedGoogle Scholar
  48. 48.
    Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, MacFabe DF (2012) The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflammation 9:153PubMedCentralPubMedGoogle Scholar
  49. 49.
    MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP (2011) Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: relevance to autism spectrum disorder. Behav Brain Res 217(1):47–54PubMedGoogle Scholar
  50. 50.
    Cani PD, Lecourt E, Dewulf EM, Sohet FM, Pachikian BD, Naslain D, De Backer F, Neyrinck AM, Delzenne NM (2009) Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr 90(5):1236–1243PubMedGoogle Scholar
  51. 51.
    Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58(8):1091–1103PubMedCentralPubMedGoogle Scholar
  52. 52.
    Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD (2010) The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 6:392PubMedCentralPubMedGoogle Scholar
  53. 53.
    Cani PD, Delzenne NM (2011) The gut microbiome as therapeutic target. Pharmacol Ther 130(2):202–212PubMedGoogle Scholar
  54. 54.
    Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, Harnedy N, O’Connor K, O’Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O’Toole PW (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488(7410):178–184PubMedGoogle Scholar
  55. 55.
    Queipo-Ortuño MI, Seoane LM, Murri M, Pardo M, Gomez-Zumaquero JM, Cardona F, Casanueva F, Tinahones FJ (2013) Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels. PLoS One 8(5):e65465PubMedCentralPubMedGoogle Scholar
  56. 56.
    Duca FA, Swartz TD, Sakar Y, Covasa M (2012) Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota. PLoS One 7(6):e39748PubMedCentralPubMedGoogle Scholar
  57. 57.
    Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J Physiol 558(Pt 1):263–275PubMedCentralPubMedGoogle Scholar
  58. 58.
    Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23(3):255–264, e119Google Scholar
  59. 59.
    Heijtz RD, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108(7):3047–3052PubMedCentralGoogle Scholar
  60. 60.
    Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, MacQueen G, Sherman PM (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60(3):307–317PubMedGoogle Scholar
  61. 61.
    Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM (2011) The intestinal microbiota affect central levels of brain-derived neurotrophic factor and behavior in mice. Gastroenterology 141(2):599–609PubMedGoogle Scholar
  62. 62.
    Farzi A, Gorkiewicz G, Holzer P (2012) Non-absorbable oral antibiotic treatment in mice affects multiple levels of the microbiota-gut-brain axis. Neurogastroenterol Motil 24(Suppl 2):78Google Scholar
  63. 63.
    Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF (2011) 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 108(38):16050–16055PubMedCentralPubMedGoogle Scholar
  64. 64.
    Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, Deng Y, Blennerhassett PA, Fahnestock M, Moine D, Berger B, Huizinga JD, Kunze W, McLean PG, Bergonzelli GE, Collins SM, Verdu EF (2011) The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 23(12):1132–1139Google Scholar
  65. 65.
    Verdú EF, Bercik P, Verma-Gandhu M, Huang XX, Blennerhassett P, Jackson W, Mao Y, Wang L, Rochat F, Collins SM (2006) Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 55(2):182–190PubMedCentralPubMedGoogle Scholar
  66. 66.
    Amaral FA, Sachs D, Costa VV, Fagundes CT, Cisalpino D, Cunha TM, Ferreira SH, Cunha FQ, Silva TA, Nicoli JR, Vieira LQ, Souza DG, Teixeira MM (2008) Commensal microbiota is fundamental for the development of inflammatory pain. Proc Natl Acad Sci U S A 105(6):2193–2197PubMedCentralPubMedGoogle Scholar
  67. 67.
    Ma X, Mao YK, Wang B, Huizinga JD, Bienenstock J, Kunze W (2009) Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli. Am J Physiol Gastrointest Liver Physiol 296(4):G868–G875PubMedGoogle Scholar
  68. 68.
    Duncker SC, Kamiya T, Wang L, Yang P, Bienenstock J (2011) Probiotic Lactobacillus reuteri alleviates the response to gastric distension in rats. J Nutr 141(10):1813–1818PubMedGoogle Scholar
  69. 69.
    Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P (2007) Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 13(1):35–37PubMedGoogle Scholar
  70. 70.
    Horvath A, Dziechciarz P, Szajewska H (2011) Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood. Aliment Pharmacol Ther 33(12):1302–1310PubMedGoogle Scholar
  71. 71.
    Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh CS (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478(7368):250–254PubMedCentralPubMedGoogle Scholar
  72. 72.
    Sathyabama S, Khan N, Agrewala JN (2014) Friendly pathogens: prevent or provoke autoimmunity. Crit Rev Microbiol 40:273–280Google Scholar
  73. 73.
    Chervonsky AV (2013) Microbiota and autoimmunity. Cold Spring Harb Perspect Biol 5(3):a007294PubMedGoogle Scholar
  74. 74.
    Lee YK, Menezes JS, Umesaki Y, Mazmanian SK (2011) Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 108(Suppl 1):4615–4622PubMedCentralPubMedGoogle Scholar
  75. 75.
    Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479(7374):538–541PubMedGoogle Scholar
  76. 76.
    Fetissov SO, Harro J, Jaanisk M, Järv A, Podar I, Allik J, Nilsson I, Sakthivel P, Lefvert AK, Hökfelt T (2005) Autoantibodies against neuropeptides are associated with psychological traits in eating disorders. Proc Natl Acad Sci U S A 102(41):14865–14870PubMedCentralPubMedGoogle Scholar
  77. 77.
    Fetissov SO, Hamze Sinno M, Coëffier M, Bole-Feysot C, Ducrotté P, Hökfelt T, Déchelotte P (2008) Autoantibodies against appetite-regulating peptide hormones and neuropeptides: putative modulation by gut microflora. Nutrition 24(4):348–359PubMedGoogle Scholar
  78. 78.
    Fetissov SO, Hamze Sinno M, Coquerel Q, Do Rego JC, Coëffier M, Gilbert D, Hökfelt T, Déchelotte P (2008) Emerging role of autoantibodies against appetite-regulating neuropeptides in eating disorders. Nutrition 24(9):854–859PubMedGoogle Scholar
  79. 79.
    Alexander SPH, Mathie A, Peters JA (2011) Guide to receptors and channels (GRAC), 5th edn. Br J Pharmacol 164(Suppl 1):S1–S324PubMedGoogle Scholar
  80. 80.
    Wettstein JG, Earley B, Junien JL (1995) Central nervous system pharmacology of neuropeptide Y. Pharmacol Ther 65(3):397–414PubMedGoogle Scholar
  81. 81.
    Kask A, Harro J, von Hörsten S, Redrobe JP, Dumont Y, Quirion R (2002) The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y. Neurosci Biobehav Rev 26(3):259–283PubMedGoogle Scholar
  82. 82.
    Redrobe JP, Carvajal C, Kask A, Dumont Y, Quirion R (2004) Neuropeptide Y and its receptor subtypes in the central nervous system: emphasis on their role in animal models of psychiatric disorders. Handb Exp Pharmacol 162:101–136Google Scholar
  83. 83.
    Eaton K, Sallee FR, Sah R (2007) Relevance of neuropeptide Y (NPY) in psychiatry. Curr Top Med Chem 7(17):1645–1659Google Scholar
  84. 84.
    Morales-Medina JC, Dumont Y, Quirion R (2010) A possible role of neuropeptide Y in depression and stress. Brain Res 1314:194–205PubMedGoogle Scholar
  85. 85.
    Tasan RO, Lin S, Hetzenauer A, Singewald N, Herzog H, Sperk G (2009) Increased novelty-induced motor activity and reduced depression-like behavior in neuropeptide Y (NPY)-Y4 receptor knockout mice. Neuroscience 158(4):1717–1730PubMedCentralPubMedGoogle Scholar
  86. 86.
    El Karim IA, Linden GJ, Orr DF, Lundy FT (2008) Antimicrobial activity of neuropeptides against a range of micro-organisms from skin, oral, respiratory and gastrointestinal tract sites. J Neuroimmunol 200(1–2):11–16PubMedGoogle Scholar
  87. 87.
    Bedoui S, von Hörsten S, Gebhardt T (2007) A role for neuropeptide Y (NPY) in phagocytosis: implications for innate and adaptive immunity. Peptides 28(2):373–376PubMedGoogle Scholar
  88. 88.
    Wheway J, Herzog H, Mackay F (2007) NPY and receptors in immune and inflammatory diseases. Curr Top Med Chem 7(17):1743–1752PubMedGoogle Scholar
  89. 89.
    Dimitrijević M, Stanojević S (2013) The intriguing mission of neuropeptide Y in the immune system. Amino Acids 45(1):41–53PubMedGoogle Scholar
  90. 90.
    Wheway J, Mackay CR, Newton RA, Sainsbury A, Boey D, Herzog H, Mackay F (2005) A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. J Exp Med 202(11):1527–1538PubMedCentralPubMedGoogle Scholar
  91. 91.
    Wheway J, Herzog H, Mackay F (2007) The Y1 receptor for NPY: a key modulator of the adaptive immune system. Peptides 28(2):453–458PubMedGoogle Scholar
  92. 92.
    Shibata M, Hisajima T, Nakano M, Goris RC, Funakoshi K (2008) Morphological relationships between peptidergic nerve fibers and immunoglobulin A-producing lymphocytes in the mouse intestine. Brain Behav Immun 22(2):158–166PubMedGoogle Scholar
  93. 93.
    Chandrasekharan B, Bala V, Kolachala VL, Vijay-Kumar M, Jones D, Gewirtz AT, Sitaraman SV, Srinivasan S (2008) Targeted deletion of neuropeptide Y (NPY) modulates experimental colitis. PLoS One 3(10):e3304PubMedCentralPubMedGoogle Scholar
  94. 94.
    Painsipp E, Herzog H, Sperk G, Holzer P (2011) Sex-dependent control of murine emotional-affective behaviour in health and colitis by peptide YY and neuropeptide Y. Br J Pharmacol 163(6):1302–1314PubMedCentralPubMedGoogle Scholar
  95. 95.
    Pang XH, Li TK, Xie Q, He FQ, Cui DJ, Chen YQ, Huang XL, Gan HT (2010) Amelioration of dextran sulfate sodium-induced colitis by neuropeptide Y antisense oligodeoxynucleotide. Int J Colorectal Dis 25(9):1047–1053PubMedGoogle Scholar
  96. 96.
    Hassani H, Lucas G, Rozell B, Ernfors P (2005) Attenuation of acute experimental colitis by preventing NPY Y1 receptor signaling. Am J Physiol Gastrointest Liver Physiol 288(3):G550–G556PubMedGoogle Scholar
  97. 97.
    Baticic L, Detel D, Kucic N, Buljevic S, Pugel EP, Varljen J (2011) Neuroimmunomodulative properties of dipeptidyl peptidase IV/CD26 in a TNBS-induced model of colitis in mice. J Cell Biochem 112(11):3322–3333PubMedGoogle Scholar
  98. 98.
    Klompus M, Ho W, Sharkey KA, McKay DM (2010) Antisecretory effects of neuropeptide Y in the mouse colon are region-specific and are lost in DSS-induced colitis. Regul Pept 165(2–3):138–145PubMedGoogle Scholar
  99. 99.
    Hirotani Y, Mikajiri K, Ikeda K, Myotoku M, Kurokawa N (2008) Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone. Yakugaku Zasshi 128(9):347–1353Google Scholar
  100. 100.
    Tari A, Teshima H, Sumii K, Haruma K, Ohgoshi H, Yoshihara M, Kajiyama G, Miyachi Y (1988) Peptide YY abnormalities in patients with ulcerative colitis. Jpn J Med 27(1):49–55PubMedGoogle Scholar
  101. 101.
    El-Salhy M, Danielsson A, Stenling R, Grimelius L (1997) Colonic endocrine cells in inflammatory bowel disease. J Intern Med 242(5):413–419PubMedGoogle Scholar
  102. 102.
    Schmidt PT, Ljung T, Hartmann B, Hare KJ, Holst JJ, Hellström PM (2005) Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY. Eur J Gastroenterol Hepatol 17(2):207–212PubMedGoogle Scholar
  103. 103.
    Adrian TE, Savage AP, Bacarese-Hamilton AJ, Wolfe K, Besterman HS, Bloom SR (1986) Peptide YY abnormalities in gastrointestinal diseases. Gastroenterology 90(2):379–384PubMedGoogle Scholar
  104. 104.
    Straub RH, Herfarth H, Falk W, Andus T, Schölmerich J (2002) Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease? J Neuroimmunol 126(1–2):116–125PubMedGoogle Scholar
  105. 105.
    Holzer P (2012) Neural regulation of gastrointestinal blood flow. In: Johnson LR (ed) Physiology of the gastrointestinal tract, 5th edn. Academic, Oxford, pp 817–845Google Scholar
  106. 106.
    Capuron L, Miller AH (2011) Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130(2):226–238PubMedCentralPubMedGoogle Scholar
  107. 107.
    Maes M, Song C, Yirmiya R (2012) Targeting IL-1 in depression. Expert Opin Ther Targets 16(11):1097–1112PubMedGoogle Scholar
  108. 108.
    Moreau M, André C, O’Connor JC, Dumich SA, Woods JA, Kelley KW, Dantzer R, Lestage J, Castanon N (2008) Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior. Brain Behav Immun 22(7):1087–1095PubMedCentralPubMedGoogle Scholar
  109. 109.
    McCarthy HD, Dryden S, Williams G (1995) Interleukin-1beta-induced anorexia and pyrexia in rat: relationship to hypothalamic neuropeptide Y. Am J Physiol 269(5 Pt 1):E852–E857PubMedGoogle Scholar
  110. 110.
    Sonti G, Ilyin SE, Plata-Salaman CR (1996) Neuropeptide Y blocks and reverses interleukin-1beta-induced anorexia in rats. Peptides 17(3):517–520PubMedGoogle Scholar
  111. 111.
    McMahon CD, Buxton DF, Elsasser TH, Gunter DR, Sanders LG, Steele BP, Sartin JL (1999) Neuropeptide Y restores appetite and alters concentrations of GH after central administration to endotoxic sheep. J Endocrinol 161(2):333–339PubMedGoogle Scholar
  112. 112.
    Painsipp E, Köfer MJ, Farzi A, Dischinger US, Sinner F, Sperk G, Herzog H, Holzer P (2013) Neuropeptide Y and peptide YY protect from weight loss caused by Bacille Calmette-Guérin in mice. Br J Pharmacol 170:1014–1026Google Scholar
  113. 113.
    Brumovsky P, Shi TS, Landry M, Villar MJ, Hökfelt T (2007) Neuropeptide tyrosine and pain. Trends Pharmacol Sci 28(2):93–102PubMedGoogle Scholar
  114. 114.
    Smith PA, Moran TD, Abdulla F, Tumber KK, Taylor BK (2007) Spinal mechanisms of NPY analgesia. Peptides 28(2):464–474PubMedGoogle Scholar
  115. 115.
    Painsipp E, Sperk G, Herzog H, Holzer P (2010) Delayed stress-induced differences in locomotor and depression-related behaviour in female neuropeptide-Y Y1 receptor knockout mice. J Psychopharmacol 24(10):1541–1549PubMedGoogle Scholar
  116. 116.
    Solway B, Bose SC, Corder G, Donahue RR, Taylor BK (2011) Tonic inhibition of chronic pain by neuropeptide Y. Proc Natl Acad Sci U S A 108(17):7224–7229PubMedCentralPubMedGoogle Scholar
  117. 117.
    Ji RR, Zhang X, Wiesenfeld-Hallin Z, Hökfelt T (1994) Expression of neuropeptide Y and neuropeptide Y (Y1) receptor mRNA in rat spinal cord and dorsal root ganglia following peripheral tissue inflammation. J Neurosci 14(11 Pt 1):6423–6434PubMedGoogle Scholar
  118. 118.
    Holzer P (2008) The role of the vagus nerve in afferent signaling and homeostasis during visceral inflammation. In: Jancsó G (ed) Neurogenic inflammation in health and disease. Neuroimmune biology, vol 8. Elsevier, Amsterdam, pp 321–338Google Scholar
  119. 119.
    Wultsch T, Painsipp E, Thoeringer CK, Herzog H, Sperk G, Holzer P (2005) Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors. Neuroscience 136(4):1097–1107PubMedGoogle Scholar
  120. 120.
    Zhou Z, Zhu G, Hariri AR, Enoch M, Scott D, Sinha R, Virkkunen M, Mash DC, Lipsky RH, Hu XZ, Hodgkinson CA, Xu K, Buzas B, Yuan Q, Shen PH, Ferrell RE, Manuck SB, Brown SM, Hauger RL, Stohler CS, Zubieta JK, Goldman D (2008) Genetic variation in human NPY expression affects stress response and emotion. Nature 452(7190):997–1001PubMedCentralPubMedGoogle Scholar
  121. 121.
    Domschke K, Dannlowski U, Hohoff C, Ohrmann P, Bauer J, Kugel H, Zwanzger P, Heindel W, Deckert J, Arolt V, Suslow T, Baune BT (2010) Neuropeptide Y (NPY) gene: impact on emotional processing and treatment response in anxious depression. Eur Neuropsychopharmacol 20(5):301–309PubMedGoogle Scholar
  122. 122.
    Mickey BJ, Zhou Z, Heitzeg MM, Heinz E, Hodgkinson CA, Hsu DT, Langenecker SA, Love TM, Peciña M, Shafir T, Stohler CS, Goldman D, Zubieta JK (2011) Emotion processing, major depression, and functional genetic variation of neuropeptide Y. Arch Gen Psychiatry 68(2):158–166PubMedCentralPubMedGoogle Scholar
  123. 123.
    Morgan CA, Rasmusson AM, Winters B, Hauger RL, Morgan J, Hazlett G, Southwick S (2003) Trauma exposure rather than posttraumatic stress disorder is associated with reduced baseline plasma neuropeptide-Y levels. Biol Psychiatry 54(10):1087–1091PubMedGoogle Scholar
  124. 124.
    Yehuda R, Brand S, Yang RK (2006) Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol Psychiatry 59(7):660–663PubMedGoogle Scholar
  125. 125.
    Sah R, Ekhator NN, Strawn JR, Sallee FR, Baker DG, Horn PS, Geracioti TD (2009) Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder. Biol Psychiatry 66(7):705–707PubMedGoogle Scholar
  126. 126.
    Kiank C, Taché Y, Larauche M (2010) Stress-related modulation of inflammation in experimental models of bowel disease and post-infectious irritable bowel syndrome: role of corticotropin-releasing factor receptors. Brain Behav Immun 24(1):41–48PubMedCentralPubMedGoogle Scholar
  127. 127.
    Dinan TG, Cryan JF (2012) Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 37(9):1369–1378PubMedGoogle Scholar
  128. 128.
    Forbes S, Herzog H, Cox H (2012) A role for neuropeptide Y in the gender-specific gastrointestinal, corticosterone and feeding responses to stress. Br J Pharmacol 166(8):2307–2316PubMedCentralPubMedGoogle Scholar
  129. 129.
    Hirsch D, Zukowska Z (2012) NPY and stress 30 years later: the peripheral view. Cell Mol Neurobiol 32(5):645–659PubMedCentralPubMedGoogle Scholar
  130. 130.
    Painsipp E, Wultsch T, Shahbazian A, Edelsbrunner M, Kreissl MC, Schirbel A, Bock E, Pabst MA, Thoeringer CK, Huber HP, Holzer P (2007) Experimental gastritis in mice enhances anxiety in a gender-related manner. Neuroscience 150(3):522–536PubMedGoogle Scholar
  131. 131.
    Liang C, Luo H, Liu Y, Cao J, Xia H (2012) Plasma hormones facilitated the hypermotility of the colon in a chronic stress rat model. PLoS One 7(2):e31774PubMedCentralPubMedGoogle Scholar
  132. 132.
    Kirchner H, Tong J, Tschöp MH, Pfluger PT (2010) Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants. Am J Physiol Endocrinol Metab 298(5):E909–E919PubMedGoogle Scholar
  133. 133.
    Yulyaningsih E, Zhang L, Herzog H, Sainsbury A (2011) NPY receptors as potential targets for anti-obesity drug development. Br J Pharmacol 163(6):1170–1202PubMedCentralPubMedGoogle Scholar
  134. 134.
    Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M (2005) The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology 146(5):2369–2375PubMedGoogle Scholar
  135. 135.
    Ueno H, Yamaguchi H, Mizuta M, Nakazato M (2008) The role of PYY in feeding regulation. Regul Pept 145(1–3):12–16PubMedGoogle Scholar
  136. 136.
    Chee MJ, Colmers WF (2008) Y eat? Nutrition 24(9):869–877Google Scholar
  137. 137.
    Ballinger AB, Williams G, Corder R, El-Haj T, Farthing MJ (2001) Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat. Clin Sci (Lond) 100(2):221–229Google Scholar
  138. 138.
    Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM (2008) The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 11(7):752–753PubMedCentralPubMedGoogle Scholar
  139. 139.
    Batterham RL, ffytche DH, Rosenthal JM, Zelaya FO, Barker GJ, Withers DJ, Williams SC (2007) PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 450(7166):106–109PubMedGoogle Scholar
  140. 140.
    Möller C, Sommer W, Thorsell A, Rimondini R, Heilig M (2002) Anxiogenic-like action of centrally administered glucagon-like peptide-1 in a punished drinking test. Prog Neuropsychopharmacol Biol Psychiatry 26(1):119–122PubMedGoogle Scholar
  141. 141.
    Kinzig KP, D’Alessio DA, Herman JP, Sakai RR, Vahl TP, Figueiredo HF, Murphy EK, Seeley RJ (2003) CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. J Neurosci 23(15):6163–6170PubMedGoogle Scholar
  142. 142.
    Gulec G, Isbil-Buyukcoskun N, Kahveci N (2010) Effects of centrally-injected glucagon-like peptide-1 on pilocarpine-induced seizures, anxiety and locomotor and exploratory activity in rat. Neuropeptides 44(4):285–291PubMedGoogle Scholar
  143. 143.
    Iwai T, Hayashi Y, Narita S, Kasuya Y, Jin K, Tsugane M, Oka J (2009) Antidepressant-like effects of glucagon-like peptide-2 in mice occur via monoamine pathways. Behav Brain Res 204(1):235–240PubMedGoogle Scholar

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© Springer New York 2014

Authors and Affiliations

  1. 1.Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical PharmacologyMedical University of GrazGrazAustria

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