title: The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health.
abstract: 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.
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA. christopher.lowry@colorado.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Smith
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Siebler
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: Dominic
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Stamper
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Hassell
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Yamashita
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Fox
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, D-89081, Ulm, Germany.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Reber
authors.affiliation: Departments of Psychiatry, Physical Medicine & Rehabilitation, University of Colorado, Anschutz School of Medicine, Aurora, CO, 80045, USA.|Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Denver, CO, 80220, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Brenner
authors.affiliation: Department of Civil and Environmental Engineering, United States Air Force Academy, Colorado Springs, CO, 80840, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoisington
authors.affiliation: University of Maryland School of Medicine, Baltimore, MD, USA.|Rocky Mountain MIRECC, Denver, CO, 80220, USA.|VISN 5 MIRECC, Baltimore, MD, 21201, USA.
authors.forename: Teodor T
authors.initials: TT
authors.lastname: Postolache
authors.affiliation: Civil, Architectural and Environmental Engineering, University of Texas Austin, Austin, TX, 78712, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Kinney
authors.affiliation: Qantu Therapeutics, Inc., Lewisville, TX, 75057, USA.
authors.forename: Dante
authors.initials: D
authors.lastname: Marciani
authors.affiliation: Department of Civil, Environmental and Architectural Engineering, University of Colorado Boulder, Boulder, CO, 80309, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, 7505, South Africa.
authors.forename: Sian M J
authors.initials: SM
authors.lastname: Hemmings
authors.affiliation: Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, 7505, South Africa.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Malan-Muller
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Wright
authors.affiliation: Departments of Pediatrics and Computer Science and Engineering, and Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Knight
authors.affiliation: School of Human Ecology and School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Raison
authors.affiliation: Center for Clinical Microbiology, UCL (University College London), WC1E 6BT, London, UK.
authors.forename: Graham A W
authors.initials: GA
authors.lastname: Rook
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D003863:Depression / Q000523:psychology; D006801:Humans; D056747:Immunomodulation / Q000502:physiology*; D007249:Inflammation / Q000150:complications / Q000523:psychology; D008603:Mental Health; D064307:Microbiota / Q000502:physiology*; D011634:Public Health
keywords: Anxiety; Depression; Lactobacilli; Microbiome; Mycobacteria; Posttraumatic stress disorder