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Cited by 143Gut microbiota and healthProbiotics and Fermented FoodsGastrointestinal motility and disorders

Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice

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Smith, Carli J., Emge, Jacob R., Berzins, Katrina, Lung, Lydia, Khamishon, Rebecca, Shah, Paarth, Rodrigues, David M., Sousa, Andrew J. +4 more·2014·American Journal of Physiology-Gastrointestinal and Liver Physiology
DOI 10.1152/ajpgi.00238.2014PMC PMC4200314
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Abstract

The gut-brain-microbiota axis is increasingly recognized as an important regulator of intestinal physiology. Exposure to psychological stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and causes altered intestinal barrier function, intestinal dysbiosis, and behavioral changes. The primary aim of this study was to determine whether the effects of psychological stress on intestinal physiology and behavior, including anxiety and memory, are mediated by the adaptive immune system. Furthermore, we wanted to determine whether treatment with probiotics would normalize these effects. Here we demonstrate that B and T cell-deficient Rag1 −/− mice displayed altered baseline behaviors, including memory and anxiety, accompanied by an overactive HPA axis, increased intestinal secretory state, dysbiosis, and decreased hippocampal c-Fos expression. Both local (intestinal physiology and microbiota) and central (behavioral and hippocampal c-Fos) changes were normalized by pretreatment with probiotics, indicating an overall benefit on health conferred by changes in the microbiota, independent of lymphocytes. Taken together, these findings indicate a role for adaptive immune cells in maintaining normal intestinal and brain health in mice and show that probiotics can overcome this immune-mediated deficit in the gut-brain-microbiota axis.

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  • Lymphocyte deficiency results in impairments in behavior, which can be normalized by probiotic treatment, implicating a specific role of adaptive immunity in the microbiota-gut-brain axis.

    “This study, therefore, establishes that lymphocyte deficiency results in impairments in behavior, which can be normalized by probiotic treatment, implicating a specific role of adaptive immunity in the microbiota-gut-brain axis (Smith et al., 2014).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Smith et al., 2014

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  1. [2]Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141: 599–609, 609.e1–3, 2011 [DOI] [PubMed] [Google Scholar]
  2. [3]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. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 23: 1132–1139, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. [4]Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144: 36–49, 2013 [DOI] [PubMed] [Google Scholar]
  4. [5]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 USA 108: 16050–16055, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. [7]Cameron HL, Perdue MH. Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2. J Pharmacol Exp Ther 314: 214–220, 2005 [DOI] [PubMed] [Google Scholar]
  6. [8]Cao Y, Shen J, Ran ZH. Association between reduction and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Gastroenterol Res Pract 2014: 872725, 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. [9]Chen Y, Fenoglio KA, Dube CM, Grigoriadis DE, Baram TZ. Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent. Mol Psychiatry 11: 992–1002, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. [10]Chow J, Lee SM, Shen Y, Khosravi A, Mazmanian SK. Host-bacterial symbiosis in health and disease. Adv Immunol 107: 243–274, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. [11]Countryman RA, Kaban NL, Colombo PJ. Hippocampal c-fos is necessary for long-term memory of a socially transmitted food preference. Neurobiol Learn Mem 84: 175–183, 2005 [DOI] [PubMed] [Google Scholar]
  10. [12]Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13: 701–712, 2012 [DOI] [PubMed] [Google Scholar]
  11. [13]De Kloet ER, Derijk R. Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance. Ann NY Acad Sci 1032: 14–34, 2004 [DOI] [PubMed] [Google Scholar]
  12. [14]De Palma G, Collins SM, Bercik P, Verdu EF. The Microbiota-Gut-Brain axis in gastrointestinal disorders: Stressed bugs, stressed brain or both? J Physiol 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. [15]Deltheil T, Guiard BP, Cerdan J, David DJ, Tanaka KF, Reperant C, Guilloux JP, Coudore F, Hen R, Gardier AM. Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice. Neuropharmacology 55: 1006–1014, 2008 [DOI] [PubMed] [Google Scholar]
  14. [16]Demaude J, Leveque M, Chaumaz G, Eutamene H, Fioramonti J, Bueno L, Ferrier L. Acute stress increases colonic paracellular permeability in mice through a mast cell-independent mechanism: involvement of pancreatic trypsin. Life Sci 84: 847–852, 2009 [DOI] [PubMed] [Google Scholar]
  15. [18]Estienne M, Claustre J, Clain-Gardechaux G, Paquet A, Tache Y, Fioramonti J, Plaisancie P. Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides. Gut 59: 744–751, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. [20]Floch MH, Walker WA, Madsen K, Sanders ME, Macfarlane GT, Flint HJ, Dieleman LA, Ringel Y, Guandalini S, Kelly CP, Brandt LJ. Recommendations for probiotic use—2011 update. J Clin Gastroenterol 45 Suppl: S168–S171, 2011 [DOI] [PubMed] [Google Scholar]
  17. [21]Fuentes S, Egert M, Jimenez-Valera M, Monteoliva-Sanchez M, Ruiz-Bravo A, Smidt H. A strain of Lactobacillus plantarum affects segmented filamentous bacteria in the intestine of immunosuppressed mice. FEMS Microbiol Ecol 63: 65–72, 2008 [DOI] [PubMed] [Google Scholar]
  18. [22]Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 56: 1522–1528, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. [24]Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol 7: 503–514, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [26]Gareau MG, Wine E, Reardon C, Sherman PM. Probiotics prevent death caused by Citrobacter rodentium infection in neonatal mice. J Infect Dis 201: 81–91, 2010 [DOI] [PubMed] [Google Scholar]
  21. [28]Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 10: 159–169, 2010 [DOI] [PubMed] [Google Scholar]
  22. [29]Jarchum I, Pamer EG. Regulation of innate and adaptive immunity by the commensal microbiota. Curr Opin Immunol 23: 353–360, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [30]Johnson-Henry KC, Nadjafi M, Avitzur Y, Mitchell DJ, Ngan BY, Galindo-Mata E, Jones NL, Sherman PM. Amelioration of the effects of Citrobacter rodentium infection in mice by pretreatment with probiotics. J Infect Dis 191: 2106–2117, 2005 [DOI] [PubMed] [Google Scholar]
  24. [31]Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA 101: 8180–8185, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [33]Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol 62: 591–599, 2011 [PubMed] [Google Scholar]
  26. [35]Martinez-Medina M, Aldeguer X, Gonzalez-Huix F, Acero D, Garcia-Gil LJ. Abnormal microbiota composition in the ileocolonic mucosa of Crohn's disease patients as revealed by polymerase chain reaction-denaturing gradient gel electrophoresis. Inflamm Bowel Dis 12: 1136–1145, 2006 [DOI] [PubMed] [Google Scholar]
  27. [36]Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877, 1992 [DOI] [PubMed] [Google Scholar]
  28. [38]Olano-Martin E, Mountzouris KC, Gibson GR, Rastall RA. In vitro fermentability of dextran, oligodextran and maltodextrin by human gut bacteria. Br J Nutr 83: 247–255, 2000 [DOI] [PubMed] [Google Scholar]
  29. [39]Schaaf MJ, Sibug RM, Duurland R, Fluttert MF, Oitzl MS, De Kloet ER, Vreugdenhil E. Corticosterone effects on BDNF mRNA expression in the rat hippocampus during morris water maze training. Stress 3: 173–183, 1999 [DOI] [PubMed] [Google Scholar]
  30. [40]Schnupf P, Gaboriau-Routhiau V, Cerf-Bensussan N. Host interactions with Segmented Filamentous Bacteria: an unusual trade-off that drives the postnatal maturation of the gut immune system. Semin Immunol 25: 342–351, 2013 [DOI] [PubMed] [Google Scholar]
  31. [41]Schwartz M, Shechter R. Protective autoimmunity functions by intracranial immunosurveillance to support the mind: the missing link between health and disease. Mol Psychiatry 15: 342–354, 2010 [DOI] [PubMed] [Google Scholar]
  32. [42]Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of action of probiotics. Nutr Clin Pract 24: 10–14, 2009 [DOI] [PubMed] [Google Scholar]
  33. [43]Stasi C, Orlandelli E. Role of the brain-gut axis in the pathophysiology of Crohn's disease. Dig Dis 26: 156–166, 2008 [DOI] [PubMed] [Google Scholar]
  34. [44]Suzuki K, Meek B, Doi Y, Muramatsu M, Chiba T, Honjo T, Fagarasan S. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci USA 101: 1981–1986, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. [45]Wood SK, Woods JH. Corticotropin-releasing factor receptor-1: a therapeutic target for cardiac autonomic disturbances. Expert Opin Ther Targets 11: 1401–1413, 2007 [DOI] [PubMed] [Google Scholar]
  36. [46]Zareie M, Johnson-Henry K, Jury J, Yang PC, Ngan BY, McKay DM, Soderholm JD, Perdue MH, Sherman PM. Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut 55: 1553–1560, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

Cited by

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Authors
Smith, C. J., Emge, J. R., Berzins, K., Lung, L., Khamishon, R., Shah, P., Rodrigues, D. M., Sousa, A. J., Reardon, C., Sherman, P. M., Barrett, K. E., & Gareau, M. G.
Affiliations
  • University of California San Diego (US)
  • University of Toronto (CA)
Corresponding author
Gareau, Mélanie G.
ORCID
Venue
American Journal of Physiology-Gastrointestinal and Liver Physiology
Publisher
American Physiological Society
Published
2014-10-15
Volume
307
Issue
8
Pages
G793-G802
ISSN
  • 0193-1857 (ISSN-L)
  • 1522-1547
DOI
10.1152/ajpgi.00238.2014
PMC
PMC4200314
OpenAlex
W2132630422
Cited by
143
References
11
Citations by year
2026: 5 · 2025: 8 · 2024: 11 · 2023: 10 · 2022: 22 · 2021: 10 · 2020: 21 · 2019: 14 · 2018: 14 · 2017: 8 · 2016: 14 · 2015: 5 · 2014: 1
FWCI
3.83
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Crohn's and Colitis Foundation (253542)
  • Canadian Institutes of Health Research
  • Science and Technology Facilities Council (ST/F012381/1, ST/I504908/1)
  • National Cancer Institute (P01CA095616)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
gut-brain-microbiota axis, probiotics, psychological stress, hypothalamic-pituitary-adrenal axis, Rag1-deficient mice, gut dysbiosis, anxiety, memory, intestinal barrier function, adaptive immunity, intestinal physiology
MeSH terms
Animals, Anxiety, Female, Hypothalamo-Hypophyseal System, Intestinal Mucosa, Intestines, Lymphocytes, Male, Memory, Mice, Inbred C57BL, Stress, Psychological, Proto-Oncogene Proteins c-fos, Homeodomain Proteins, Probiotics, Mice, Adaptive Immunity, Microbiota

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