Abstract
The body is colonized by a vast population of genetically diverse microbes, the majority of which reside within the intestines to comprise the intestinal microbiota. During periods of homeostasis, these microbes reside within stable climax communities, but exposure to physical, physiological, as well as psychological stressors can significantly impact the structure of the intestinal microbiota. This has been demonstrated in humans and laboratory animals, with the most consistent finding being a reduction in the abundance of bacteria in the genus Lactobacillus. Whether stressor exposure also changes the function of the microbiota, has not been as highly studied. The studies presented in this review suggest that stressor-induced disruption of the intestinal microbiota leads to increased susceptibility to enteric infection and overproduction of inflammatory mediators that can induce behavioral abnormalities, such as anxiety-like behavior. Studies involving germfree mice also demonstrate that the microbiota are necessary for stressor-induced increases in innate immunity to occur. Exposing mice to a social stressor enhances splenic macrophage microbicidal activity, but this effect fails to occur in germfree mice. These studies suggest a paradigm in which stressor exposure alters homeostatic interactions between the intestinal microbiota and mucosal immune system and leads to the translocation of pathogenic, and/or commensal, microbes from the lumen of the intestines to the interior of the body where they trigger systemic inflammatory responses and anxiety-like behavior. Restoring homeostasis in the intestines, either by removing the microbiota or by administering probiotic microorganisms, can ameliorate the stressor effects.
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Abbreviations
- ACTH:
-
Adrenocorticotrophic hormone
- CFU:
-
Colony forming units
- CRH:
-
Corticotrophin release hormone
- DGGE:
-
Denaturing gradient gel electrophoresis
- GABA:
-
γ-Amino butyric acid
- GI:
-
Gastrointestinal
- HPA:
-
Hypothalamic-pituitary-adrenal
- iNOS:
-
Inducible nitric oxide synthase
- mRNA:
-
Messenger ribonucleic acid
- NE:
-
Norepinephrine
- SDR:
-
Social disruption
- SNS:
-
Sympathetic nervous system
- TNF-α:
-
Tumor necrosis factor alpha
References
Huffnagle GB (2010) The microbiota and allergies/asthma. PLoS Pathog 6(5):e1000549
Allison SD, Martiny JB (2008) Colloquium paper: resistance, resilience, and redundancy in microbial communities. Proc Natl Acad Sci U S A 105(Suppl 1):11512–11519
Antonopoulos DA, Huse SM, Morrison HG, Schmidt TM, Sogin ML, Young VB (2009) Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect Immun 77(6):2367–2375
Dethlefsen L, Huse S, Sogin ML, Relman DA (2008) The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6(11):e280
Turnbaugh PJ, Backhed F, Fulton L, Gordon JI (2008) Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3(4):213–223
Beaumont W (1838) Experiments and observations on the gastric juice and the physiology of digestion. Edinburgh, London
Badgley LE, Spiro HM, Senay EC (1969) Effect of mental arithmetic on gastric secretion. Psychophysiology 5(6):633–637
Holtmann G, Kriebel R, Singer MV (1990) Mental stress and gastric acid secretion. Do personality traits influence the response? Dig Dis Sci 35(8):998–1007
Yang H, Yuan PQ, Wang L, Tache Y (2000) Activation of the parapyramidal region in the ventral medulla stimulates gastric acid secretion through vagal pathways in rats. Neuroscience 95(3):773–779
Tache Y, Martinez V, Million M, Wang L (2001) Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol 280(2):G173–G177
Tache Y, Perdue MH (2004) Role of peripheral CRF signalling pathways in stress-related alterations of gut motility and mucosal function. Neurogastroenterol Motil 16(Suppl 1):137–142
O’Malley D, Julio-Pieper M, Gibney SM, Dinan TG, Cryan JF (2010) Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour. Stress 13(2):114–122
Shigeshiro M, Tanabe S, Suzuki T (2012) Repeated exposure to water immersion stress reduces the Muc2 gene level in the rat colon via two distinct mechanisms. Brain Behav Immun 26(7):1061–1065
Drasar BS, Shiner M, McLeod GM (1969) Studies on the intestinal flora. I. The bacterial flora of the gastrointestinal tract in healthy and achlorhydric persons. Gastroenterology 56(1):71–79
Berg RD (1996) The indigenous gastrointestinal microflora. Trends Microbiol 4(11):430–435
Stephen AM, Wiggins HS, Cummings JH (1987) Effect of changing transit time on colonic microbial metabolism in man. Gut 28(5):601–609
Sonnenburg JL, Xu J, Leip DD et al (2005) Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307(5717):1955–1959
Mackenzie DA, Jeffers F, Parker ML et al (2010) Strain-specific diversity of mucus-binding proteins in the adhesion and aggregation properties of Lactobacillus reuteri. Microbiology 156(Pt 11):3368–3378
Lyte M (2004) Microbial endocrinology and infectious disease in the 21st century. Trends Microbiol 12(1):14–20
Lyte M, Bailey MT (1997) Neuroendocrine-bacterial interactions in a neurotoxin-induced model of trauma. J Surg Res 70(2):195–201
Pullinger GD, Carnell SC, Sharaff FF et al (2010) Norepinephrine augments Salmonella enterica-induced enteritis in a manner associated with increased net replication but independent of the putative adrenergic sensor kinases QseC and QseE. Infect Immun 78(1):372–380
Tannock GW, Savage DC (1974) Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract. Infect Immun 9(3):591–598
Everson CA, Toth LA (2000) Systemic bacterial invasion induced by sleep deprivation. Am J Physiol Regul Integr Comp Physiol 278(4):R905–R916
Lizko NN (1987) Stress and intestinal microflora. Nahrung 31(5–6):443–447
Holdeman LV, Good IJ, Moore WE (1976) Human fecal flora: variation in bacterial composition within individuals and a possible effect of emotional stress. Appl Environ Microbiol 31(3):359–375
Bailey MT, Coe CL (1999) Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol 35(2):146–155
Bailey MT, Lubach GR, Coe CL (2004) Prenatal stress alters bacterial colonization of the gut in infant monkeys. J Pediatr Gastroenterol Nutr 38(4):414–421
Sakuma K, Funabashi H, Matsuoka H, Saito M (2013) Potential use of Lactobacillus cell density in feces as a non-invasive bio-indicator for evaluating environmental stress during mouse breeding. Biocontrol Sci 18(2):101–104
Aguilera M, Vergara P, Martinez V (2013) Environment-related adaptive changes of gut commensal microbiota do not alter colonic toll-like receptors but modulate the local expression of sensory-related systems in rats. Microb Ecol 66(1):232–243
Knowles SR, Nelson EA, Palombo EA (2008) Investigating the role of perceived stress on bacterial flora activity and salivary cortisol secretion: a possible mechanism underlying susceptibility to illness. Biol Psychol 77(2):132–137
Sartor RB (2006) Microbial and dietary factors in the pathogenesis of chronic, immune-mediated intestinal inflammation. Adv Exp Med Biol 579:35–54
Nocker A, Burr M, Camper AK (2007) Genotypic microbial community profiling: a critical technical review. Microb Ecol 54(2):276–289
O’Mahony SM, Marchesi JR, Scully P et al (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 65(3):263–267
Bailey MT, Dowd SE, Parry NM, Galley JD, Schauer DB, Lyte M (2010) Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infect Immun 78(4):1509–1519
Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M (2011) Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 25(3):397–407
Buynitsky T, Mostofsky DI (2009) Restraint stress in biobehavioral research: recent developments. Neurosci Biobehav Rev 33(7):1089–1098
Dobbs CM, Vasquez M, Glaser R, Sheridan JF (1993) Mechanisms of stress-induced modulation of viral pathogenesis and immunity. J Neuroimmunol 48(2):151–160
Dobbs CM, Feng N, Beck FM, Sheridan JF (1996) Neuroendocrine regulation of cytokine production during experimental influenza viral infection: effects of restraint stress-induced elevation in endogenous corticosterone. J Immunol 157(5):1870–1877
Padgett DA, MacCallum RC, Sheridan JF (1998) Stress exacerbates age-related decrements in the immune response to an experimental influenza viral infection. J Gerontol A Biol Sci Med Sci 53(5):B347–B353
Sartor RB (2012) Gut microbiota: diet promotes dysbiosis and colitis in susceptible hosts. Nat Rev Gastroenterol Hepatol 9(10):561–562
Chang JY, Antonopoulos DA, Kalra A et al (2008) Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 197(3):435–438
Borenshtein D, McBee ME, Schauer DB (2008) Utility of the Citrobacter rodentium infection model in laboratory mice. Curr Opin Gastroenterol 24(1):32–37
Luperchio SA, Schauer DB (2001) Molecular pathogenesis of Citrobacter rodentium and transmissible murine colonic hyperplasia. Microbes Infect 3(4):333–340
Mundy R, MacDonald TT, Dougan G, Frankel G, Wiles S (2005) Citrobacter rodentium of mice and man. Cell Microbiol 7(12):1697–1706
Eckmann L (2006) Animal models of inflammatory bowel disease: lessons from enteric infections. Ann N Y Acad Sci 1072:28–38
Mackos AR, Eubank TD, Parry NM, Bailey MT (2013) Probiotic Lactobacillus reuteri attenuates the stressor-enhanced severity of Citrobacter rodentium infection. Infect Immun 81:3253–3263
Cameron HL, Perdue MH (2005) Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2. J Pharmacol Exp Ther 314(1):214–220
Santos J, Yang PC, Soderholm JD, Benjamin M, Perdue MH (2001) Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat. Gut 48(5):630–636
Soderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH (2002) Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283(6):G1257–G1263
Eaton KA, Honkala A, Auchtung TA, Britton RA (2011) Probiotic Lactobacillus reuteri ameliorates disease due to enterohemorrhagic Escherichia coli in germfree mice. Infect Immun 79(1):185–191
Bohus B, Koolhaas JM, Heijnen CJ, de Boer O (1993) Immunological responses to social stress: dependence on social environment and coping abilities. Neuropsychobiology 28(1–2):95–99
de Groot J, van Milligen FJ, Moonen-Leusen BW, Thomas G, Koolhaas JM (1999) A single social defeat transiently suppresses the anti-viral immune response in mice. J Neuroimmunol 95(1–2):143–151
Korte SM, Smit J, Bouws GAH, Koolhaas JM, Bohus B (1990) Behavioral and neuroendocrine response to psychosocial stress in male rats: the effects of the 5-HT1A agonistic ipsapirone. Horm Behav 24:554–567
Sgoifo A, Stilli D, de Boer SF, Koolhaas JM, Musso E (1998) Acute social stress and cardiac electrical activity in rats. Aggress Behav 24:287–296
Kinsey SG, Bailey MT, Sheridan JF, Padgett DA, Avitsur R (2007) Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice. Brain Behav Immun 21(4):458–466
Wohleb ES, Hanke ML, Corona AW et al (2011) beta-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 31(17):6277–6288
Bailey MT, Avitsur R, Engler H, Padgett DA, Sheridan JF (2004) Physical defeat reduces the sensitivity of murine splenocytes to the suppressive effects of corticosterone. Brain Behav Immun 18(5):416–424
Engler H, Engler A, Bailey MT, Sheridan JF (2005) Tissue-specific alterations in the glucocorticoid sensitivity of immune cells following repeated social defeat in mice. J Neuroimmunol 163(1–2):110–119
Hanke ML, Powell ND, Stiner LM, Bailey MT, Sheridan JF (2012) Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress. Brain Behav Immun 26(7):1150–1159
Avitsur R, Kavelaars A, Heijnen C, Sheridan JF (2005) Social stress and the regulation of tumor necrosis factor-alpha secretion. Brain Behav Immun 19(4):311–317
Engler H, Bailey MT, Engler A, Stiner-Jones LM, Quan N, Sheridan JF (2008) Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen. Psychoneuroendocrinology 33(1):108–117
Stark JL, Avitsur R, Hunzeker J, Padgett DA, Sheridan JF (2002) Interleukin-6 and the development of social disruption-induced glucocorticoid resistance. J Neuroimmunol 124(1–2):9–15
Brydon L, Edwards S, Mohamed-Ali V, Steptoe A (2004) Socioeconomic status and stress-induced increases in interleukin-6. Brain Behav Immun 18(3):281–290
Brydon L, Steptoe A (2005) Stress-induced increases in interleukin-6 and fibrinogen predict ambulatory blood pressure at 3-year follow-up. J Hypertens 23(5):1001–1007
Steptoe A, Hamer M, Chida Y (2007) The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 21(7):901–912
Avitsur R, Stark JL, Dhabhar FS, Padgett DA, Sheridan JF (2002) Social disruption-induced glucocorticoid resistance: kinetics and site specificity. J Neuroimmunol 124(1–2):54–61
Bailey MT, Engler H, Powell ND, Padgett DA, Sheridan JF (2007) Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway. Am J Physiol Regul Integr Comp Physiol 293(3):R1180–R1190
Bailey MT, Kinsey SG, Padgett DA, Sheridan JF, Leblebicioglu B (2009) Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b + cells. Physiol Behav 98(3):351–358
Stark JL, Avitsur R, Padgett DA, Campbell KA, Beck FM, Sheridan JF (2001) Social stress induces glucocorticoid resistance in macrophages. Am J Physiol Regul Integr Comp Physiol 280(6):R1799–R1805
Platt AM, Bain CC, Bordon Y, Sester DP, Mowat AM (2010) An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J Immunol 184(12):6843–6854
Jones SE, Versalovic J (2009) Probiotic Lactobacillus reuteri biofilms produce antimicrobial and anti-inflammatory factors. BMC Microbiol 9:35
Lin YP, Thibodeaux CH, Pena JA, Ferry GD, Versalovic J (2008) Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c-Jun. Inflamm Bowel Dis 14(8):1068–1083
Thomas CM, Hong T, van Pijkeren JP et al (2012) Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One 7(2):e31951
Spinler JK, Taweechotipatr M, Rognerud CL, Ou CN, Tumwasorn S, Versalovic J (2008) Human-derived probiotic Lactobacillus reuteri demonstrate antimicrobial activities targeting diverse enteric bacterial pathogens. Anaerobe 14(3):166–171
Sudo N, Chida Y, Aiba Y et al (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1):263–275
Padgett DA, Glaser R (2003) How stress influences the immune response. Trends Immunol 24(8):444–448
Reber SO, Peters S, Slattery DA et al (2011) Mucosal immunosuppression and epithelial barrier defects are key events in murine psychosocial stress-induced colitis. Brain Behav Immun 25(6):1153–1161
Lyte M (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays 33(8):574–581
Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (2003) Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A 100(15):9090–9095
Brydon L, Edwards S, Jia H et al (2005) Psychological stress activates interleukin-1beta gene expression in human mononuclear cells. Brain Behav Immun 19(6):540–546
Maslanik T, Tannura K, Mahaffey L et al (2012) Commensal bacteria and MAMPs are necessary for stress-induced increases in IL-1beta and IL-18 but not IL-6, IL-10 or MCP-1. PLoS One 7(12):e50636
Maslanik T, Mahaffey L, Tannura K, Beninson L, Greenwood BN, Fleshner M (2013) The inflammasome and danger associated molecular patterns (DAMPs) are implicated in cytokine and chemokine responses following stressor exposure. Brain Behav Immun 28:54–62
Fleshner M (2013) Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome. Brain Behav Immun 27(1):1–7
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):228–231
Allen RG, Lafuse WP, Galley JD, Ali MM, Ahmer BM, Bailey MT (2012) The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity. Brain Behav Immun 26(3):371–382
Allen RG, Lafuse WP, Powell ND et al (2012) Stressor-induced increase in microbicidal activity of splenic macrophages is dependent upon peroxynitrite production. Infect Immun 80(10):3429–3437
Ahrne S, Hagslatt ML (2011) Effect of lactobacilli on paracellular permeability in the gut. Nutrients 3(1):104–117
Bailey MT, Engler H, Sheridan JF (2006) Stress induces the translocation of cutaneous and gastrointestinal microflora to secondary lymphoid organs of C57BL/6 mice. J Neuroimmunol 171(1–2):29–37
Ando T, Brown RF, Berg RD, Dunn AJ (2000) Bacterial translocation can increase plasma corticosterone and brain catecholamine and indoleamine metabolism. Am J Physiol Regul Integr Comp Physiol 279(6):R2164–R2172
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Bailey, M.T. (2014). Influence of Stressor-Induced Nervous System Activation on the Intestinal Microbiota and the Importance for Immunomodulation. In: Lyte, M., Cryan, J. (eds) Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. Advances in Experimental Medicine and Biology(), vol 817. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0897-4_12
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