The hygiene or “Old Friends” hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress-related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions. We highlight potential mechanisms, involving bacterially derived metabolites, bacterial antigens, and helminthic antigens, through which these inputs promote immunoregulation. Though findings are encouraging, significant human subjects’ research is required to evaluate the potential impact of Old Friends, including environmental microbial inputs, on biological signatures and clinically meaningful mental health prevention and intervention outcomes.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34. This study outlines the current evidence for inflammation in the etiology and pathophysiology of depression and the rationale for anti-inflammatory and immunoregulatory approaches to treatment of depression.
Fernandes BS, Steiner J, Bernstein HG, Dodd S, Pasco JA, Dean OM, et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics:meta-analysis and implications. Mol Psychiatry. 2016;21:554–64.
Maes M, Ombelet W, Libbrecht I, Stevens K, Kenis G, De Jongh R, et al. Effects of pregnancy and delivery on serum concentrations of Clara Cell Protein (CC16), an endogenous anticytokine: lower serum CC16 is related to postpartum depression. Psychiatry Res. 1999;87:117–27.
Bufalino C, Hepgul N, Aguglia E, Pariante CM. The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun. 2013;31:31–47.
Raison CL, Miller AH. The evolutionary significance of depression in pathogen host defense (PATHOS-D). Mol Psychiatry. 2013;18:15–37.
Rook GA, Lowry CA, Raison CL. Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res. 1617;2014:47–62.
Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, et al. Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study. Am J Psychiatry. 2016;173:44–52.
Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.
Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–52.
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatmentresistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41. This study shows that treatment with an antibody targeting TNF can be beneficial in a subset of depressed patients with increased inflammation.
Kohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71:1381–91.
Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane VA, Cleare AJ. Inflammation and clinical response to treatment in depression: a meta-analysis. Eur Neuropsychopharmacol. 2015;25:1532–43.
Willette AA, Lubach GR, Knickmeyer RC, Short SJ, Styner M, Gilmore JH, et al. Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia. Behav Brain Res. 2011;219:108–15.
Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–702.
Meyer U, Feldon J, Dammann O. Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatr Res. 2011;69:26R–33.
Quan N, Banks WA. Brain-immune communication pathways. Brain Behav Immun. 2007;21:727–35.
Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun. 2011;25:1272–8 Curr Envir Health Rpt.
Bryleva EY, Brundin L. Kynurenine pathway metabolites and suicidality. Neuropharmacology. 2016. doi:10.1016/j.neuropharm.2016.01.034.
D'Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor alpha signaling during peripheral organ inflammation. J Neurosci. 2009;29:2089–102.
Rook GA, Adams V, Hunt J, Palmer R, Martinelli R, Brunet LR. Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders. Springer Semin Immunopathol. 2004;25:237–55.
Raison CL, Lowry CA, Rook GA. Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression. Arch Gen Psychiatry. 2010;67:1211–24.
Rook GA, Lowry CA. The hygiene hypothesis and psychiatric disorders. Trends Immunol. 2008;29:150–8.
Rook GA, Raison CL, Lowry CA. Can we vaccinate against depression? Drug Discov Today. 2012;17:451–8.
Rook GA, Lowry CA, Raison CL. Microbial ‘Old Friends’, immunoregulation and stress resilience. Evol Med Public Health. 2013;2013:46–64.
Rook GA, Raison CL, Lowry CA. Microbial ‘Old Friends’, immunoregulation and socioeconomic status. Clin Exp Immunol. 2014;177:1–12.
Rook GA, Raison CL, Lowry CA. Microbiota, immunoregulatory Old Friends and psychiatric disorders. Adv Exp Med Biol. 2014;817:319–56.
Rook GA, Lowry CA, Raison CL. Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res. 2015;1617:47–62.
Rook GAW, Lowry CA. The hygiene hypothesis and affective and anxiety disorders. In: Rook GAW, editor. The hygiene hypothesis and Darwinian medicine, vol. 1. Basel: Birkhauser Publishing; 2009.
Rook GAW, Raison CL, Lowry CA. Childhood microbial experience, immunoregulation, inflammation and adult susceptibility to psychosocial stressors and depression in rich and poor countries. Evol Med Public Health. 2013;2013:14–7.
Rook GAW, Raison CL, Lowry CA. In: Heidt PJ, Midtvedt T, Rusch V, Versalovic J, editors. Microbial “Old Friends”, immunoregulation and psychiatric disorders. Old Herborn University Press; 2013. p. 61–90. Old Herborn University Monograph, vol. 26.
Hoisington AJ, Brenner LA, Kinney KA, Postolache TT, Lowry CA. The microbiome of the built environment and mental health. Microbiome. 2015;3:1–12.
Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part I—autointoxication revisited. Gut Pathog. 2013;5:5.
Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III—convergence toward clinical trials. Gut Pathog. 2013;5:4.
Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part II—contemporary contextual research. Gut Pathog. 2013;5:3.
Logan AC. Dysbiotic drift: mental health, environmental grey space, and microbiota. J Physiol Anthropol. 2015;34:23.
Logan AC, Katzman MA, Balanza-Martinez V. Natural environments, ancestral diets, and microbial ecology: is there a modern “paleo-deficit disorder”? Part II. J Physiol Anthropol. 2015;34:9.
Logan AC, Jacka FN, Craig JM, Prescott SL. The microbiome and mental health: looking back, moving forwardwith lessons from allergic diseases. Clin Psychopharmacol Neurosci. 2016;14:131–47.
Williamson LL, McKenney EA, Holzknecht ZE, Belliveau C, Rawls JF, Poulton S, et al. Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection. Brain Behav Immun. 2016;51:14–28. This study demonstrates that exposure of breeding dams and their offspring to helminths prevents microglial sensitization and cognitive dysfunction in offspring following early life infection with E. coli.
Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax. 2000;55 Suppl 1:S2–10.
Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454:445–54.
Blaiss MS. Allergic rhinoconjunctivitis: burden of disease. Allergy Asthma Proc. 2007;28:393–7.
Blaiss MS. Pediatric allergic rhinitis: physical and mental complications. Allergy Asthma Proc. 2008;29:1–6.
Buske-Kirschbaum A, Ebrecht M, Kern S, Gierens A, Hellhammer DH. Personality characteristics in chronic and nonchronic allergic conditions. Brain Behav Immun. 2008;22:762–8.
Chida Y, Hamer M, Steptoe A. A bidirectional relationship between psychosocial factors and atopic disorders: a systematic review and meta-analysis. Psychosom Med. 2008;70:102–16.
Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc. 2007;28:3–9.
Wright RJ. Stress and atopic disorders. J Allergy Clin Immunol. 2005;116:1301–6.
Goodwin RD, Fergusson DM, Horwood LJ. Asthma and depressive and anxiety disorders among young persons in the community. Psychol Med. 2004;34:1465–74.
Goodwin RD. Self-reported hay fever and panic attacks in the community. Ann Allergy Asthma Immunol. 2002;88:556–9.
Palermo-Neto J, Guimaraes RK. Pavlovian conditioning of lung anaphylactic response in rats. Life Sci. 2000;68:611–23.
Tonelli LH, Katz M, Kovacsics CE, Gould TD, Joppy B, Hoshino A, et al. Allergic rhinitis induces anxiety-like behavior and altered social interaction in rodents. Brain Behav Immun. 2009;23:784–93.
Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016;351:933–9. This study shows that IL-17A from themother mediates development of an autism-like phenotype in a mouse model of maternal infection.
Mostafa GA, Al SA, Fouad NR. Frequency of CD4+ CD25high regulatory Tcells in the peripheral blood of Egyptian children with autism. J Child Neurol. 2010;25:328–35.
Al-Ayadhi LY, Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. J Neuroinflammation. 2012;9:158.
Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451–63. This study shows that exposure to immunoregulatory bacteria early in development can prevent some aspects of an autism-like phenotype in a mouse model of maternal infection.
Sutton CE, Mielke LA, Mills KH. IL-17-producing γδ T cells and innate lymphoid cells. Eur J Immunol. 2012;42:2221–31.
Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008;453:1051–7.
Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol. 2013;8:477–512.
Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, et al. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science. 2015;349:993–7. This study shows that individual species of immunoregulatory bacteria can restore RORγ+ Treg in germ-free mice.
Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, et al. MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science. 2015;349:989–93.
Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev Neurobiol. 2012;72:1272–6.
Beversdorf DQ, Manning SE, Hillier A, Anderson SL, Nordgren RE, Walters SE, et al. Timing of prenatal stressors and autism. J Autism Dev Disord. 2005;35:471–8.
Raz R, Roberts AL, Lyall K, Hart JE, Just AC, Laden F, et al. Autismspectrum disorder and particulatematter air pollution before, during, and after pregnancy: a nested case–control analysis within the Nurses’ Health Study II cohort. Environ Health Perspect. 2015;123:264–70.
Dietert RR, Dietert JM. Potential for early-life immune insult including developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability. J Toxicol Environ Health B Crit Rev. 2008;11:660–80.
Zijlmans MA, Korpela K, Riksen-Walravena JM, de Vosb WM. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology. 2015;53:233–45.
Taliou A, Zintzaras E, Lykouras L, Francis K. An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin Ther. 2013;35:592–602.
Tsilioni I, Taliou A, Francis K, Theoharides TC. Children with autism spectrum disorders, who improved with a luteolincontaining dietary formulation, show reduced serum levels of TNF and IL-6. Transl Psychiatry. 2015;5, e647.
Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Metaanalysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73:993–9.
Debnath M, Berk M. Th17 pathway - mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull. 2014;40:1412–21.
Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal antiinflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73:414–9.
Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Patterson PH. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry. 2014;75:332–41.
Machado CJ, Whitaker AM, Smith SE, Patterson PH, Bauman MD. Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol Psychiatry. 2015;77:823–32.
Weir RK, Forghany R, Smith SE, Patterson PH, McAllister AK, Schumann CM, et al. Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. Brain Behav Immun. 2015;48:139–46.
Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71:423–31. This study shows that elevated plasma CRP predicts subsequent risk for development of PTSD.
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci U S A. 2014;111:16136–41. This study demonstrates that individual differences in peripheral immune status, particularly LPS-induced release of IL-6, predict individual variability in development of anxiety and depressive-like behavioral responses to a subsequent psychosocial stressor in mice.
Kivimaki M, Shipley MJ, Batty GD, Hamer M, Akbaraly TN, Kumari M, et al. Long-term inflammation increases risk of common mental disorder: a cohort study. Mol Psychiatry. 2014;19:149–50.
Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med. 2014;76:181–9.
Breen MS, Maihofer AX, Glatt SJ, Tylee DS, Chandler SD, Tsuang MT, et al. Gene networks specific for innate immunity define post-traumatic stress disorder. Mol Psychiatry. 2015;20:1538–45.
Pervanidou P, Kolaitis G, Charitaki S, Margeli A, Ferentinos S, Bakoula C, et al. Elevatedmorning seruminterleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents sixmonths after amotor vehicle accident. Psychoneuroendocrinology. 2007;32:991–9.
Spitzer C, Barnow S, Volzke H, Wallaschofski H, John U, Freyberger HJ, et al. Association of posttraumatic stress disorder with low-grade elevation of C-reactive protein: evidence from the general population. J Psychiatr Res. 2010;44:15–21.
Heath NM, Chesney SA, Gerhart JI, Goldsmith RE, Luborsky JL, Stevens NR, et al. Interpersonal violence, PTSD, and inflammation: potential psychogenic pathways to higher C-reactive protein levels. Cytokine. 2013;63:172–8.
Baker DG, Nievergelt CM, O'Connor DT. Biomarkers of PTSD: neuropeptides and immune signaling. Neuropharmacology. 2012;62:663–73.
Andrews JA, Neises KD. Cells, biomarkers, and post-traumatic stress disorder: evidence for peripheral involvement in a central disease. J Neurochem. 2012;120:26–36.
Gola H, Engler H, Sommershof A, Adenauer H, Kolassa S, Schedlowski M, et al. Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry. 2013;13:40.
O'Donovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, et al. Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry. 2014;77:365–74.
Stein MB, Chen C-Y, Ursano RJ, Cai T, Gelernter J, Heeringa SG, et al. Genome-wide association studies of posttraumatic stress disorder in 2 cohorts of US Army soldiers. JAMA Psychiatry. 2016;E1–10. Published online May 11, 2016.
Lill CM, Schjeide BM, Graetz C, Liu T, Damotte V, Akkad DA, et al. Genome-wide significant association of ANKRD55rs6859219 and multiple sclerosis risk. J Med Genet. 2013;50:140–3.
Alloza I, Otaegui D, de Lapuente AL, Antiguedad A, Varade J, Nunez C, et al. ANKRD55 and DHCR7 are novel multiple sclerosis risk loci. Genes Immun. 2012;13:253–7.
Harder MN, Ribel-Madsen R, Justesen JM, Sparso T, Andersson EA, Grarup N, et al. Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased beta-cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort. J Clin Endocrinol Metab. 2013;98:E801–6.
Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 2011;7, e1002004.
Viatte S, Plant D, Bowes J, Lunt M, Eyre S, Barton A, et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann Rheum Dis. 2012;71:1984–90.
Gimeno D, Kivimaki M, Brunner EJ, Elovainio M, De VR, Steptoe A, et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med. 2009;39:413–23.
Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014;71:1121–8.
Amos T, Stein DJ, Ipser JC. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2014;7, CD006239.
Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;48:79–85.
Martinez I, Stegen JC, Maldonado-Gomez MX, Eren AM, Siba PM, Greenhill AR, et al. The gut microbiota of rural Papua New Guineans: composition, diversity patterns, and ecological processes. Cell Rep. 2015;11:527–38.
Clemente JC, Pehrsson EC, Blaser MJ, Sandhu K, Gao Z, Wang B, et al. The microbiome of uncontacted Amerindians. Sci Adv. 2015;1:1–12.
Maixner F, Krause-Kyora B, Turaev D, Herbig A, Hoopmann MR, Hallows JL, et al. The 5300-year-old Helicobacter pylori genome of the iceman. Science. 2016;351:162–5.
Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, et al. Helicobacter pylori infection prevents allergic asthma inmousemodels through the induction of regulatory Tcells. J Clin Invest. 2011;121:3088–93.
Arnold IC, Hitzler I, Muller A. The immunomodulatory properties of Helicobacter pylori confer protection against allergic and chronic inflammatory disorders. Front Cell Infect Microbiol. 2012;2:10.
Rook GAW, Raison CL, Lowry CA. Microbes and mood: a new approach to the therapy of depression? Microbiologist. 2011;32–6.
Gillespie L, Roosendahl P, Ng WC, Brooks AG, Reading PC, Londrigan SL. Endocytic function is critical for influenza Avirus infection via DC-SIGN and L-SIGN. Sci Rep. 2016;6:19428.
Vergne I, Gilleron M, Nigou J. Manipulation of the endocytic pathway and phagocyte functions by Mycobacterium tuberculosis lipoarabinomannan. Front Cell Infect Microbiol. 2014;4:187.
Smits HH, Hartgers FC, Yazdanbakhsh M. Helminth infections: protection from atopic disorders. Curr Allergy Asthma Rep. 2005;5:42–50.
van Kooyk Y, Geijtenbeek TB. DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol. 2003;3:697–709.
Bergman MP, Engering A, Smits HH, van Vliet SJ, van Bodegraven AA, Wirth HP, et al. Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J Exp Med. 2004;200:979–90.
Appelmelk BJ, van Die I, van Vliet SJ, Vandenbroucke-Grauls CM, Geijtenbeek TB, van Kooyk Y. Cutting edge: carbohydrate profiling identifies new pathogens that interact with dendritic cell-specific ICAM-3-grabbing nonintegrin on dendritic cells. J Immunol. 2003;170:1635–9.
Hunt JR, Martinelli R, Adams VC, Rook GA, Brunet LR. Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mousemodel. Clin Exp Allergy. 2005;35:685–90.
Moore MN. Do airborne biogenic chemicals interact with the PI3K/Akt/mTOR cell signalling pathway to benefit human health and wellbeing in rural and coastal environments? Environ Res. 2015;140:65–75.
Rook GA. Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. Proc Natl Acad Sci U S A. 2013;110:18360–7.
Rook GAW. Introduction: The changing microbial environment, Darwinian medicine and the hygiene hypothesis. In: Rook GAW, editor. The hygiene hypothesis and Darwinian medicine. Basel: Birkhäuser; 2009. p. 1–27.
Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med. 2002;8:625–9.
Holinger EP, Ross KA, Robertson CE, Stevens MJ, Harris JK, Pace NR. Molecular analysis of point-of-use municipal drinking water microbiology. Water Res. 2014;49:225–35.
Feazel LM, Baumgartner LK, Peterson KL, Frank DN, Harris JK, Pace NR. Opportunistic pathogens enriched in showerhead biofilms. Proc Natl Acad Sci U S A. 2009;106:16393–9.
Macovei L, McCafferty J, Chen T, Teles F, Hasturk H, Paster BJ, et al. The hidden ‘mycobacteriome’ of the human healthy oral cavity and upper respiratory tract. J Oral Microbiol. 2015;7:26094. This study documents abundant environmental microbes in themucosa of the oral cavity and upper airways of healthy human volunteers.
Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009;106:3698–703.
Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189:1363–72.
Nowak EC, de Vries VC, Wasiuk A, Ahonen C, Bennett KA, Le Mercier I, et al. Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med. 2012;209:2127–35.
Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487:477–81.
Farez MF, Mascanfroni ID, Mendez-Huergo SP, Yeste A, Murugaiyan G, Garo LP, et al. Melatonin contributes to the seasonality ofmultiple sclerosis relapses. Cell. 2015;162:1338–52.
Zhang YJ, Reddy MC, Ioerger TR, Rothchild AC, Dartois V, Schuster BM, et al. Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell. 2013;155:1296–308.
Zelante T, Iannitti RG, Cunha C, De LA, Giovannini G, Pieraccini G, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balancemucosal reactivity via interleukin-22. Immunity. 2013;39:372–85.
Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB, et al. Persistent organic pollutants modify gut microbiota-host metabolic homeostasis in mice through aryl hydrocarbon receptor activation. Environ Health Perspect. 2015;123:679–88.
Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453:65–71.
Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185:3190–8.
Qiu J, Zhou L. Aryl hydrocarbon receptor promotes RORgammat(+) group 3 ILCs and controls intestinal immunity and inflammation. Semin Immunopathol. 2013;35:657–70.
Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiotaaccessible carbohydrates. Cell Metab. 2014;20:779–86.
Cavaglieri CR, Nishiyama A, Fernandes LC, Curi R, Miles EA, Calder PC. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci. 2003;73:1683–90.
Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol. 2007;13:2826–32.
Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care. 2010;13:715–21.
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly Y, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73.
Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, de Roos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–5.
Zeng H, Chi H. Metabolic control of regulatory T cell development and function. Trends Immunol. 2015;36:3–12.
Zaccone P, Burton O, Miller N, Jones FM, Dunne DW, Cooke A. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention inNOD mice. Eur J Immunol. 2009;39:1098–107.
Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol. 2013;13:607–14.
Wang Y, Da'Dara AA, Thomas PG, Harn DA. Dendritic cells activated by an anti-inflammatory agent induce CD4(+) T helper type 2 responses without impairing CD8(+)memory and effector cytotoxic T-lymphocyte responses. Immunology. 2010;129:406–17.
Stahl B, Thurl S, Zeng J, Karas M, Hillenkamp F, Steup M, et al. Oligosaccharides from human milk as revealed by matrix-assisted laser desorption/ionization mass spectrometry. Anal Biochem. 1994;223:218–26.
Ko AI, Drager UC, Harn DA. A Schistosoma mansoni epitope recognized by a protective monoclonal antibody is identical to the stage-specific embryonic antigen 1. Proc Natl Acad Sci U S A. 1990;87:4159–63.
van Liempt E, Bank CM, Mehta P, Garcia-Vallejo JJ, Kawar ZS, Geyer R, et al. Specificity of DC-SIGN for mannose- and fucose-containing glycans. FEBS Lett. 2006;580:6123–31.
Adalid-Peralta L, Fragoso G, Fleury A, Sciutto E. Mechanisms underlying the induction of regulatory T cells and its relevance in the adaptive immune response in parasitic infections. Int J Biol Sci. 2011;7:1412–26.
Holt PG, Strickland DH, Wikstrom ME, Jahnsen FL. Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol. 2008;8:142–52.
Teitelbaum R, Schubert W, Gunther L, Kress Y, Macaluso F, Pollard JW, et al. The M cell as a portal of entry to the lung for the bacterial pathogen Mycobacterium tuberculosis. Immunity. 1999;10:641–50.
Fujimura Y. Functionalmorphology ofmicrofold cells (M cells) in Peyer’s patches—phagocytosis and transport of BCG by M cells into rabbit Peyer’s patches. Gastroenterol Jpn. 1986;21:325–35.
Belkaid Y, Segre JA. Dialogue between skin microbiota and immunity. Science. 2014;346:954–9.
Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, et al. Compartmentalized control of skin immunity by resident commensals. Science. 2012;337:1115–9.
Belkaid Y, Naik S. Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol. 2013;14:646–53.
Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701–12. This article provides a comprehensive review on the microbiota-gut-brain and behavior axis.
Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014;34:15490–6.
Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144:1394–401. This study provides the first evidence that probiotic administration in healthy humans modifies steady state activity of neural systems controlling cognitive and affective function.
Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105:755–64. Curr Envir Health Rpt.
Yang H, Zhao X, Tang S, Huang H, Zhao X, Ning Z, et al. Probiotics reduce psychological stress in patients before laryngeal cancer surgery. Asia Pac J Clin Oncol. 2016;12:e92–6.
Kato-Kataoka A, Nishida K, Takada M, Suda K, Kawai M, Shimizu K, et al. Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress. Benefic Microbes. 2016;7:153–6.
O'Brien ME, Anderson H, Kaukel E, O'Byrne K, Pawlicki M, von Pawel J, et al. SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results. Ann Oncol. 2004;15:906–14.
Reber SO, Siebler PH, Donner NC, Morton JT, Smith DG, Kopelman JM, et al. Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc Natl Acad Sci U S A. 2016. This study provides the first evidence that immunization with a heatkilled preparation of an environmental immunoregulatory microbe can prevent colitis and reduce anxiety-related behaviors in mice.
Kullberg MC, Ward JM, Gorelick PL, Caspar P, Hieny S, Cheever A, et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect Immun. 1998;66:5157–66.
Burich A, Hershberg R, Waggie K, Zeng W, Brabb T, Westrich G, et al. Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2001;281:G764–78.
Collins CH, Grange JM, Yates MD. Mycobacteria in water. J Appl Bacteriol. 1984;57:193–211.
Stanford JL, Paul RC. A preliminary report on some studies of environmental mycobacteria from Uganda. Ann Soc Belg Med Trop. 1973;53:389–93.
Primm TP, Lucero CA, Falkinham III JO. Health impacts of environmental mycobacteria. Clin Microbiol Rev. 2004;17:98–106.
Jin BW, Saito H, Yoshii Z. Environmental mycobacteria in Korea. I. Distribution of the organisms. Microbiol Immunol. 1984;28:667–77.
Pontiroli A, Khera TT, Oakley BB, Mason S, Dowd SE, Travis ER, et al. Prospecting environmental mycobacteria: combined molecular approaches reveal unprecedented diversity. PLoS One. 2013;8, e68648.
Gcebe N, Rutten V, van Pittius NC, Michel A. Prevalence and distribution of non-tuberculous mycobacteria (NTM) in cattle, African buffaloes (Syncerus caffer) and their environments in South Africa. Transbound Emerg Dis. 2013;60 Suppl 1:74–84.
Kamala T, Paramasivan CN, Herbert D, Venkatesan P, Prabhakar R. Isolation and identification of environmental mycobacteria in the Mycobacterium bovis BCG trial area of South India. Appl Environ Microbiol. 1994;60:2180–3.
Le Bert N, Chain BM, Rook G, Noursadeghi M. DC priming by M. vaccae inhibits Th2 responses in contrast to specific TLR2 priming and is associated with selective activation of the CREB pathway. PLoS One. 2011;6:e18346.
Lowry CA, Hollis JH, de Vries A, Pan B, Brunet LR, Hunt JR, et al. Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience. 2007;146:756–72.
Matthews DM, Jenks SM. Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav Process. 2013;96:27–35.
Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res. 2015;287:59–72.
Savignac HM, Kiely B, Dinan TG, Cryan JF. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil. 2014;26:1615–27.
Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 2010;170:1179–88.
Zuo L, Yuan KT, Yu L, Meng QH, Chung PC, Yang DH. Bifidobacterium infantis attenuates colitis by regulating T cell subset responses. World J Gastroenterol. 2014;20:18316–29.
Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2:256–61.
Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23:1132–9.
Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X, et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology. 2010;139:2102–12.
Lopez P, Gonzalez-Rodriguez I, Gueimonde M, Margolles A, Suarez A. Immune response to Bifidobacterium bifidum strains support Treg/Th17 plasticity. PLoS One. 2011;6, e24776.
Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7.
Castillo-Rojas G, Mazari-Hiriart M, de León Ponce S, Amieva-Fernández RI, Agis-Juárez RA, Huebner J, et al. Comparison of Enterococcus faecium and Enterococcus faecalis strains isolated from water and clinical samples: antimicrobial susceptibility and genetic relationships. PLoS One. 2013;8, e59491.
Divyashri G, Krishna G, Muralidhara M, Prapulla SG. Probiotic attributes, antioxidant, anti-inflammatory and neuromodulatory effects of probiotic Enterococcus faecium CFR 3003: in vitro and in vivo evidences. J Med Microbiol. 2015;64:1527–40.
Bernardeau M, Guguen M, Vernoux JP. Beneficial lactobacilli in food and feed: long-term use, biodiversity and proposals for specific and realistic safety assessments. FEMS Microbiol Rev. 2006;30:487–513.
Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009;1:6.
Benton D, Williams C, Brown A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr. 2007;61:355–61.
Vitali B, Minervini G, Rizzello CG, Spisni E, Maccaferri S, Brigidi P, et al. Novel probiotic candidates for humans isolated from raw fruits and vegetables. Food Microbiol. 2012;31:116–25. Curr Envir Health Rpt.
Hammes WP, Vogel RF. The genus Lactobacillus. In: Wood BJB, HolzapfelWH, editors. The genera of lactic acid bacteria. Chapman &Hall; 1995. p. 19–54.
Wang T, Hu X, Liang S, Li W,Wu X, Wang L, et al. Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rats. Benefic Microbes. 2015;1–11.
Perez-Cano FJ, Dong H, Yaqoob P. In vitro immunomodulatory activity of lactobacillus fermentum CECT5716 and Lactobacillus salivarius CECT5713: two probiotic strains isolated from human breast milk. Immunobiology. 2010;215:996–1004.
Chung YC, Jin HM, Cui Y, Kim DS, Jung JM, Park JI, et al. Fermented milk of Lactobacillus helveticus IDCC3801 improves cognitive functioning during cognitive fatigue tests in healthy older adults. J Funct Foods. 2014;10:465–74.
Jia L, Tao W, Shan L, Xu H, Wei L, Feng J. Ingestion of Lactobacillus strain reduces anxiety and improves cognitive function in the hyperammonemia rat. Sci China Life Sci. 2014;57:327–35.
Liang S, Wang T, Hu X, Luo J, Li W, Wu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience. 2015;310:561–77.
Ohland CL, Kish L, Bell H, Thiesen A, Hotte N, Pankiv E, et al. Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology. 2013;38:1738–47.
Smith CJ, Emge JR, Berzins K, Lung L, Khamishon R, Shah P, et al. Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice. Am J Physiol Gastrointest Liver Physiol. 2014;307:G793–802.
Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011;60:307–17.
Rodrigues DM, Sousa AJ, Johnson-Henry KC, Sherman PM, Gareau MG. Probiotics are effective for the prevention and treatment of Citrobacter rodentium-induced colitis in mice. J Infect Dis. 2012;206:99–109.
Woo JY, Gu W, Kim KA, Jang SE, Han MJ, Kim DH. Lactobacillus pentosus var. plantarum C29 ameliorates memory impairment and inflammaging in a D-galactose-induced accelerated aging mouse model. Anaerobe. 2014;27:22–6.
Tubelius P, Stan V, Zachrisson A. Increasing work-place healthiness with the probiotic Lactobacillus reuteri: a randomised, double-blind placebo-controlled study. Environ Health. 2005;4:25.
Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TM, et al. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol. 2005;115:1260–7.
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 U S A. 2011;108:16050–5.
Bloem K, Garcia-Vallejo JJ, Vuist IM, Cobb BA, van Vliet SJ, van Kooyk Y. Interaction of the capsular polysaccharide A from Bacteroides fragilis with DC-SIGN on human dendritic cells is necessary for its processing and presentation to T cells. Front Immunol. 2013;4:103.
Shen Y, Giardino Torchia ML, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe. 2012;12:509–20.
Konstantinov SR, Smidt H, de Vos WM, Bruijns SC, Singh SK, Valence F, et al. S layer protein A of Lactobacillus acidophilus NCFM regulates immature dendritic cell and T cell functions. Proc Natl Acad Sci U S A. 2008;105:19474–9.
Gilleron M, Jackson M, Nigou J, Puzo G. Structure, biosynthesis, and activities of the phosphatidyl-myo-inositol-based lipoglycans. In: DafféM, Rayrat J-M, editor. The mycobacterial cell envelope. Washington, DC: ASM Press; 2008. p. 75–105.
Ray A, Cot M, Puzo G, Gilleron M, Nigou J. Bacterial cell wall macroamphiphiles: pathogen-/microbe-associated molecular patterns detected by mammalian innate immune system. Biochimie. 2013;95:33–42.
Garg A, Barnes PF, Roy S, Quiroga MF, Wu S, Garcia VE, et al. Mannose-capped lipoarabinomannan- and prostaglandin E2-dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection. Eur J Immunol. 2008;38:459–69.
Carroll MV, Sim RB, Bigi F, Jakel A, Antrobus R, Mitchell DA. Identification of four novel DC-SIGN ligands on Mycobacterium bovis BCG. Protein Cell. 2010;1:859–70.
Quintana FJ, Cohen IR. The HSP60 immune system network. Trends Immunol. 2011;32:89–95.
Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest. 2006;116:2022–32.
Ohue R, Hashimoto K, Nakamoto M, Furukawa Y, Masuda T, Kitabatake N, et al. Bacterial heat shock protein 60, GroEL, can induce the conversion of naive T cells into a CD4 CD25(+) Foxp3-expressing phenotype. J Innate Immun. 2011;3:605–13.
van Eden W, van der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol. 2005;5:318–30.
Ercolani L, Florence B, Denaro M, Alexander M. Isolation and complete sequence of a functional human glyceraldehyde-3-phosphate dehydrogenase gene. J Biol Chem. 1988;263:15335–41.
Takaoka Y, Goto S, Nakano T, Tseng HP, Yang SM, Kawamoto S, et al. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) prevents lipopolysaccharide (LPS)-induced, sepsisrelated severe acute lung injury in mice. Sci Rep. 2014;4:5204.
Drage MG, Tsai HC, Pecora ND, Cheng TY, Arida AR, Shukla S, et al. Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of toll-like receptor2. Nat Struct Mol Biol. 2010;17:1088–95. Curr Envir Health Rpt.
Effort undertaken during the preparation of this review was sponsored by the Department of the Navy, Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award, Award No. N00014-15-1-2809.
Conflict of Interest
David G. Smith, Philip H. Siebler, Dominic Schmidt, Christopher E. Stamper, James E. Hassell Jr., Paula S. Yamashita, James H. Fox, Stefan O. Reber, Lisa A. Brenner, Andrew J. Hoisington, Teodor T. Postolache, Kerry A. Kinney, Dante Marciani, Mark Hernandez, Sian M.J. Hemmings, Stefanie Malan-Muller, Rob Knight, Charles L. Raison, and Graham A.W. Rook report that they have no conflict of interest. Christopher A. Lowry serves on the scientific advisory board of Immodulon Therapeutics Ltd. Kenneth P. Wright serves on the scientific advisory board of Torvec Inc., and has research grants from Torvec, Inc. and Philips Inc.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the topical collection on Early Life Environmental Health
About this article
Cite this article
Lowry, C.A., Smith, D.G., Siebler, P.H. et al. The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health. Curr Envir Health Rpt 3, 270–286 (2016). https://doi.org/10.1007/s40572-016-0100-5
- Posttraumatic stress disorder