Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats

Abstract

Chronic exposure to stress is associated with increased incidence of depression, generalized anxiety, and PTSD. However, stress induces vulnerability to such disorders only in a sub-population of individuals, as others remain resilient. Inflammation has emerged as a putative mechanism for promoting stress vulnerability. Using a rodent model of social defeat, we have previously shown that rats with short-defeat latencies (SL/vulnerable rats) show increased anxiety- and depression-like behaviors, and these behaviors are mediated by inflammation in the ventral hippocampus. The other half of socially defeated rats show long-latencies to defeat (LL/resilient) and are similar to controls. Because gut microbiota are important activators of inflammatory substances, we assessed the role of the gut microbiome in mediating vulnerability to repeated social defeat stress. We analyzed the fecal microbiome of control, SL/vulnerable, and LL/resilient rats using shotgun metagenome sequencing and observed increased expression of immune-modulating microbiota, such as Clostridia, in SL/vulnerable rats. We then tested the importance of gut microbiota to the SL/vulnerable phenotype. In otherwise naive rats treated with microbiota from SL/vulnerable rats, there was higher microglial density and IL-1β expression in the vHPC, and higher depression-like behaviors relative to rats that received microbiota from LL/resilient rats, non-stressed control rats, or vehicle-treated rats. However, anxiety-like behavior during social interaction was not altered by transplant of the microbiome of SL/vulnerable rats into non-stressed rats. Taken together, the results suggest the gut microbiome contributes to the depression-like behavior and inflammatory processes in the vHPC of stress vulnerable individuals.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Hammen C. Stress and depression. Annu Rev Clin Psychol. 2005;1:293–319.

    Article  PubMed  Google Scholar 

  2. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35:169–91.

    Article  PubMed  Google Scholar 

  3. van Praag HM. Can stress cause depression? Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:891–907.

    Article  PubMed  CAS  Google Scholar 

  4. Bowen MT, Dass SA, Booth J, Suraev A, Vyas A, McGregor IS. Active coping toward predatory stress is associated with lower corticosterone and progesterone plasma levels and decreased methylation in the medial amygdala vasopressin system. Horm Behav. 2014;66:561–6.

    Article  CAS  PubMed  Google Scholar 

  5. Fleshner M, Maier SF, Lyons DM, Raskind MA. The neurobiology of the stress-resistant brain. Stress. 2011;14:498–502.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Koolhaas JM. Coping style and immunity in animals: making sense of individual variation. Brain Behav Immun. 2008;22:662–7.

    Article  CAS  PubMed  Google Scholar 

  7. Ono Y, Lin HC, Tzen KY, Chen HH, Yang PF, Lai WS, et al. Active coping with stress suppresses glucose metabolism in the rat hypothalamus. Stress. 2012;15:207–17.

    Article  CAS  PubMed  Google Scholar 

  8. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229.

    Article  CAS  PubMed  Google Scholar 

  10. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep. 2011;13:467–75.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Asnis GM, De La Garza R 2nd. Interferon-induced depression: strategies in treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:808–18.

    Article  CAS  PubMed  Google Scholar 

  12. Ma L, Demin KA, Kolesnikova TO, Khatsko SL, Zhu X, Yuan X, et al. Animal inflammation-based models of depression and their application to drug discovery. Expert Opin Drug Discov. 2017;12:995–1009.

    Article  CAS  PubMed  Google Scholar 

  13. Pearson-Leary J, Eacret D, Chen R, Takano H, Nicholas B, Bhatnagar S. Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress. Transl Psychiatry. 2017;7:e1160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57:173–85.

    Article  CAS  PubMed  Google Scholar 

  15. Felger JC, Haroon E, Miller AH. Risk and resilience: animal models shed light on the pivotal role of inflammation in individual differences in stress-induced depression. Biol Psychiatry. 2015;78:7–9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Piletz JE, Halaris A, Iqbal O, Hoppensteadt D, Fareed J, Zhu H, et al. Pro-inflammatory biomakers in depression: treatment with venlafaxine. World J Biol Psychiatry. 2009;10:313–23.

    Article  PubMed  Google Scholar 

  17. Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J, et al. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry. 2016;21:797–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wood SK, Wood CS, Lombard CM, Lee CS, Zhang XY, Finnell JE, et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats. Biol Psychiatry. 2015;78:38–48.

  19. Ja Foster, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12.

    Article  CAS  Google Scholar 

  20. Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016;21:738–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dickerson F, Severance E, Yolken R. The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun. 2017;62:46–52.

    Article  CAS  PubMed  Google Scholar 

  22. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA. 2011;108:16050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liang X, FitzGerald GA. Timing the microbes: the circadian rhythm of the gut microbiome. J Biol Rhythms. 2017;32:505–515.

  24. Wood SK, Walker HE, Valentino RJ, Bhatnagar S. Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor. Endocrinology. 2010;151:1795–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen RJKG, Sengupta A, Heydendael W, Nicholas B, Beltrami S, Luz S, et al. MicroRNAs as biomarkers of resilience or vulnerability to stress. Neuroscience. 2015;305:36–48.

  26. Stanley D, Geier MS, Chen H, Hughes RJ, Moore RJ. Comparison of fecal and cecal microbiotas reveals qualitative similarities but quantitative differences. BMC Microbiol. 2015;15:51.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Manichanh C, Reeder J, Gibert P, Varela E, Llopis M, Antolin M, et al. Reshaping the gut microbiome with bacterial transplantation and antibiotic intake. Genome Res. 2010;20:1411–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Thomas V, Clark J, Dore J. Fecal microbiota analysis: an overview of sample collection methods and sequencing strategies. Future Microbiol. 2015;10:1485–504.

    Article  CAS  PubMed  Google Scholar 

  29. Wood SK. Individual differences in the neurobiology of social stress: implications for depression-cardiovascular disease comorbidity. Curr Neuropharmacol. 2014;12:205–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wood SK, Bhatnagar S. Resilience to the effects of social stress: evidence from clinical and preclinical studies on the role of coping strategies. Neurobiol Stress. 2015;1:164–73.

    Article  PubMed  Google Scholar 

  31. Wood SK, Wood CS, Lombard CM, Lee CS, Zhang XY, Finnell JE, et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats. Biol Psychiatry. 2015;78:38–48.

    Article  CAS  PubMed  Google Scholar 

  32. Meeker HC, Chadman KK, Heaney AT, Carp RI. Assessment of social interaction and anxiety-like behavior in senescence-accelerated-prone and -resistant mice. Physiol Behav. 2013;118:97–102.

    Article  CAS  PubMed  Google Scholar 

  33. File SE, Hyde JR. Can social interaction be used to measure anxiety? Br J Pharmacol. 1978;62:19–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Angelis L, File SE. Acute and chronic effects of three benzodiazepines in the social interaction anxiety test in mice. Psychopharmacol (Berl). 1979;64:127–9.

    Article  Google Scholar 

  35. Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacol (Berl). 2005;177:245–55.

    Article  CAS  Google Scholar 

  36. Lurie I, Yang YX, Haynes K, Mamtani R, Boursi B. Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study. J Clin Psychiatry. 2015;76:1522–8.

    Article  PubMed  Google Scholar 

  37. Lopez P, Halary S, Bapteste E. Highly divergent ancient gene families in metagenomic samples are compatible with additional divisions of life. Biol Direct. 2015;10:64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Gonzalez LE, Andrews N, File SE. 5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze. Brain Res. 1996;732:145–53.

    Article  CAS  PubMed  Google Scholar 

  39. Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacol (Berl). 1995;121:66–72.

    Article  CAS  Google Scholar 

  40. Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev. 2005;29:547–69.

    Article  CAS  PubMed  Google Scholar 

  41. Jankord R, Solomon MB, Albertz J, Flak JN, Zhang R, Herman JP. Stress vulnerability during adolescent development in rats. Endocrinology. 2011;152:629–38.

    Article  CAS  PubMed  Google Scholar 

  42. Han A, Yeo H, Park MJ, Kim SH, Choi HJ, Hong CW, et al. IL-4/10 prevents stress vulnerability following imipramine discontinuation. J Neuroinflamm. 2015;12:197.

    Article  CAS  Google Scholar 

  43. Norden DM, Trojanowski PJ, Villanueva E, Navarro E, Godbout JP. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia. 2016;64:300–16.

    Article  PubMed  Google Scholar 

  44. Jeong HK, Ji K, Min K, Joe EH. Brain inflammation and microglia: facts and misconceptions. Exp Neurobiol. 2013;22:59–67.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Le Blon D, Hoornaert C, Daans J, Santermans E, Hens N, Goossens H, et al. Distinct spatial distribution of microglia and macrophages following mesenchymal stem cell implantation in mouse brain. Immunol Cell Biol. 2014;92:650–8.

    Article  PubMed  CAS  Google Scholar 

  46. Tynan RJ, Naicker S, Hinwood M, Nalivaiko E, Buller KM, Pow DV, et al. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun. 2010;24:1058–68.

    Article  CAS  PubMed  Google Scholar 

  47. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.

    Article  CAS  PubMed  Google Scholar 

  48. Klein R, Roggendorf W. Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: a double labeling study. Acta Neuropathol. 2001;101:245–8.

    Article  CAS  PubMed  Google Scholar 

  49. Piskunov A, Stepanichev M, Tishkina A, Novikova M, Levshina I, Gulyaeva N. Chronic combined stress induces selective and long-lasting inflammatory response evoked by changes in corticosterone accumulation and signaling in rat hippocampus. Metab Brain Dis. 2016;31:445–54.

    Article  CAS  PubMed  Google Scholar 

  50. Watson P, Shirreffs SM, Maughan RJ. Blood-brain barrier integrity may be threatened by exercise in a warm environment. Am J Physiol Regul Integr Comp Physiol. 2005;288:R1689–94.

    Article  CAS  PubMed  Google Scholar 

  51. Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT, Langford D. Blood biomarkers for brain injury: what are we measuring? Neurosci Biobehav Rev. 2016;68:460–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Blyth BJ, Farhavar A, Gee C, Hawthorn B, He H, Nayak A, et al. Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J Neurotrauma. 2009;26:1497–507.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bargerstock E, Puvenna V, Iffland P, Falcone T, Hossain M, Vetter S, et al. Is peripheral immunity regulated by blood-brain barrier permeability changes? PLoS ONE. 2014;9:e101477.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Xanthos DN, Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15:43–53.

    Article  CAS  PubMed  Google Scholar 

  55. Abbott NJ. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol. 2000;20:131–47.

    Article  CAS  PubMed  Google Scholar 

  56. Venkatesan C, Chrzaszcz M, Choi N, Wainwright MS. Chronic upregulation of activated microglia immunoreactive for galectin-3/Mac-2 and nerve growth factor following diffuse axonal injury. J Neuroinflamm. 2010;7:32.

    Article  CAS  Google Scholar 

  57. Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78:151–6.

    Article  CAS  PubMed  Google Scholar 

  58. Lalani I, Bhol K, Ahmed AR. Interleukin-10: biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol. 1997;79:469–83.

    Article  CAS  PubMed  Google Scholar 

  59. Lee J, Yang W, Hostetler A, Schultz N, Suckow MA, Stewart KL, et al. Characterization of the anti-inflammatory Lactobacillus reuteri BM36301 and its probiotic benefits on aged mice. BMC Microbiol. 2016;16:69.

    PubMed  PubMed Central  Google Scholar 

  60. Archer AC, Muthukumar SP, Halami PM. Anti-inflammatory potential of probiotic Lactobacillus spp. on carrageenan induced paw edema in Wistar rats. Int J Biol Macromol. 2015;81:530–7.

    Article  CAS  PubMed  Google Scholar 

  61. Li H, Zhang L, Chen L, Zhu Q, Wang W, Qiao J. Lactobacillus acidophilus alleviates the inflammatory response to enterotoxigenic Escherichia coli K88 via inhibition of the NF-kappaB and p38 mitogen-activated protein kinase signaling pathways in piglets. BMC Microbiol. 2016;16:273.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Maukonen J, Satokari R, Matto J, Soderlund H, Mattila-Sandholm T, Saarela M. Prevalence and temporal stability of selected clostridial groups in irritable bowel syndrome in relation to predominant faecal bacteria. J Med Microbiol. 2006;55(Pt 5):625–33.

    Article  CAS  PubMed  Google Scholar 

  63. Rao K, Erb-Downward JR, Walk ST, Micic D, Falkowski N, Santhosh K, et al. The systemic inflammatory response to Clostridium difficile infection. PLoS ONE. 2014;9:e92578.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Yu H, Chen K, Sun Y, Carter M, Garey KW, Savidge TC, et al. Cytokines are markers of the Clostridium difficile-induced inflammatory response and predict disease severity. Clin Vaccin Immunol. 2017;24:e00037–17.

    Article  CAS  Google Scholar 

  65. Huang EY, Inoue T, Va Leone, Dalal S, Touw K, Wang Y, et al. Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. Inflamm Bowel Dis. 2015;21:963–72.

    Article  PubMed  Google Scholar 

  66. Mudd AT, Berding K, Wang M, Donovan SM, Dilger RN. Serum cortisol mediates the relationship between fecal Ruminococcus and brain N-acetylaspartate in the young pig. Gut Microbes. 2017; 8:589–600.

  67. Bharwani A, Mian MF, Foster JA, Surette MG, Bienenstock J, Forsythe P. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology. 2016;63:217–27.

    Article  CAS  PubMed  Google Scholar 

  68. Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflamm. 2004;1:14.

    Article  CAS  Google Scholar 

  69. Graeber MB, Li W, Rodriguez ML. Role of microglia in CNS inflammation. FEBS Lett. 2011;585:3798–805.

    Article  CAS  PubMed  Google Scholar 

  70. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflamm. 2015;12:114.

    Article  CAS  Google Scholar 

  71. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500:232–6.

    Article  CAS  PubMed  Google Scholar 

  72. Furusawa Y, Obata Y, Fukuda S, Ta Endo, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–50.

    Article  CAS  PubMed  Google Scholar 

  73. Lopetuso LR, Scaldaferri F, Petito V, Gasbarrini A. Commensal Clostridia: leading players in the maintenance of gut homeostasis. Gut Pathog. 2013;5:1.

    Article  CAS  Google Scholar 

  74. Macfabe DF. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis. 2012;23:1–24.

    Google Scholar 

  75. Umesaki Y, Setoyama H, Matsumoto S, Imaoka A, Itoh K. Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system. Infect Immun. 1999;67:3504–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:1–11.

  77. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G, et al. Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol Psychiatry. 2017;82:472–87.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Defense Advanced Research Projects Agency (DARPA) and the U.S. Army Research Office under grant number W911NF1010093 to SB. We would like to thank Victoria Siu, Zoe Temple, and Ria Chhabra for assistance with data analysis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Seema Bhatnagar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pearson-Leary, J., Zhao, C., Bittinger, K. et al. The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry 25, 1068–1079 (2020). https://doi.org/10.1038/s41380-019-0380-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0380-x

This article is cited by

Search

Quick links