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


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.

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  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 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.

  5. 5.

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

  6. 6.

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

  7. 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.

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 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.

  13. 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.

  14. 14.

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

  15. 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.

  16. 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.

  17. 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.

  18. 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. 19.

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

  20. 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.

  21. 21.

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

  22. 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.

  23. 23.

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

  24. 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.

  25. 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. 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.

  27. 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.

  28. 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.

  29. 29.

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

  30. 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.

  31. 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.

  32. 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.

  33. 33.

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

  34. 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.

  35. 35.

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

  36. 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 44.

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

  45. 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.

  46. 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.

  47. 47.

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

  48. 48.

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

  49. 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.

  50. 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.

  51. 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.

  52. 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.

  53. 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.

  54. 54.

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

  55. 55.

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

  56. 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.

  57. 57.

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

  58. 58.

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

  59. 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.

  60. 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.

  61. 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.

  62. 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.

  63. 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.

  64. 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.

  65. 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.

  66. 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. 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.

  68. 68.

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

  69. 69.

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

  70. 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.

  71. 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.

  72. 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.

  73. 73.

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

  74. 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.

  75. 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.

  76. 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. 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.

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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.

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The authors declare that they have no conflict of interest.

Correspondence to Seema Bhatnagar.

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