The Microbiome in Posttraumatic Stress Disorder and Trauma-Exposed Controls: An Exploratory Study

Psychosomatic Medicine

Volumn 79, Issue 8, 2017, Pages 936-946

  Hemmings, Sian M J ^a,b   Malan Müller, Stefanie ^b   Van Den Heuvel, Leigh L ^b   Demmitt, Brittany A ^b   Stanislawski, Maggie A ^c   Smith, David G ^d   Bohr, Adam D ^d   Stamper, Christopher E ^b   Hyde, Embriette R ^b   Morton, James T ^e,f   Marotz, Clarisse A ^b,g   Siebler, Philip H ^b,h   Braspenning, Maarten ⁱ   Van Criekinge, Wim ^j   Hoisington, Andrew J ^k   Brenner, Lisa A ^l   Postolache, Teodor T ^m   McQueen, Matthew B ^a,b,c   Krauter, Kenneth S ^a,b   Knight, Rob ^b   Seedat, Soraya ^a,d   Lowry, Christopher A ^a,b,c,d   more..

^a UNIVERSITY OF STELLENBOSCH   (South Africa)

^b Cellular and Developmental Biology ^*  (United States)

^c Institute for Behavioral Genetics   (United States)

^d UNIVERSITY OF COLORADO   (United States)

^e Physical Medicine and Rehabilitation   (United States)

^f UNIVERSITY OF COLORADO   (United States)

^g DEPARTMENT OF VETERANS AFFAIRS   (United States)

^h UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

ⁱ NXT Dx   (United States)

^j GHENT UNIVERSITY   (Belgium)

^k UNITED STATES AIR FORCE ACADEMY   (United States)

^l Education and Clinical Center (MIRECC)   (United States)

^m UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

more..

Author keywords

C reactive protein; childhood trauma; immunoregulation; inflammation; microbiome; posttraumatic stress disorder

Indexed keywords

RNA 16S; BACTERIAL DNA; BACTERIAL RNA;

ADULT; AMPLICON; ARTICLE; CLINICAL ARTICLE; COMMUNITY STRUCTURE; CONTROLLED STUDY; DSM-5; EMOTIONAL STRESS; ENVIRONMENTAL EXPOSURE; FEMALE; HUMAN; INJURY; INTESTINE FLORA; MALE; MICROBIAL COMMUNITY; MICROBIAL DIVERSITY; PHYSICAL VIOLENCE; POSTTRAUMATIC STRESS DISORDER; PRIORITY JOURNAL; RANDOM FOREST; SEXUAL ASSAULT; SUDDEN DEATH; FECES; MICROBIOLOGY; MIDDLE AGED; PILOT STUDY; PSYCHOTRAUMA;

ADULT; DNA, BACTERIAL; FECES; FEMALE; GASTROINTESTINAL MICROBIOME; HUMANS; MALE; MIDDLE AGED; PILOT PROJECTS; PSYCHOLOGICAL TRAUMA; RNA, BACTERIAL; RNA, RIBOSOMAL, 16S; STRESS DISORDERS, POST-TRAUMATIC;

EID: 85023158450     PISSN: 00333174     EISSN: 15347796     Source Type: Journal    
DOI: 10.1097/PSY.0000000000000512     Document Type: Article

References (99)

1. Williams SL,WilliamsDR, Stein DJ, Seedat S, Jackson PB, Moomal H. Multiple traumatic events and psychological distress: the South Africa stress and health study. J Trauma Stress 2007;20:845-55
2. Kaminer D,Grimsrud A,Myer L, Stein DJ,Williams DR. Risk for post-traumatic stress disorder associated with different forms of interpersonal violence in South Africa. Soc Sci Med 2008;67:1589-95
3. World Health Organization. Violence Prevention. The Evidence. Available at: http://www.who.int/violence-injury-prevention/violence/4th-milestones- meeting/publications/en/.2009. Accessed April 3, 2016
4. Norman R, Matzopoulos R, Groenewald P, Bradshaw D. The high burden of injuries in South Africa. Bull World Health Organ 2007;85:695-702
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013
6. Bremner JD, Southwick SM, Darnell A, Charney DS. Chronic PTSD in Vietnam combat veterans: course of illness and substance abuse. Am J Psychiatry 1996; 153:369-75
7. Mendlowicz MV, Stein MB. Quality of life in individuals with anxiety disorders. Am J Psychiatry 2000;157:669-82
8. Zatzick DF, Marmar CR, Weiss DS, Browner WS, Metzler TJ, Golding JM, Stewart A, SchlengerWE,Wells KB. Posttraumatic stress disorder and functioning and quality of life outcomes in a nationally representative sample of male Vietnam veterans. Am J Psychiatry 1997;154:1690-5
9. Atwoli L, Stein DJ, Koenen KC, McLaughlin KA. Epidemiology of posttraumatic stress disorder: prevalence, correlates and consequences. Curr Opin Psychiatry 2015;28:307-11
10. Seedat SS. Post-traumatic stress disorder. S Afr J Psychiatry 2013:187-91
11. Morath J, Gola H, Sommershof A, Hamuni G, Kolassa S, Catani C, Adenauer H, Ruf-Leuschner M, Schauer M, Elbert T, Groettrup M, Kolassa IT. The effect of trauma-focused therapy on the altered T cell distribution in individuals with PTSD: evidence from a randomized controlled trial. J Psychiatr Res 2014;54:1-10
12. Sommershof A, Aichinger H, Engler H, Adenauer H, Catani C, Boneberg EM, Elbert T, Groettrup M, Kolassa IT. Substantial reduction of naïve and regulatory T cells following traumatic stress. Brain Behav Immun 2009;23:1117-24
13. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775-87
14. Freier E, Weber CS, Nowottne U, Horn C, Bartels K, Meyer S, Hildebrandt Y, Luetkens T, Cao Y, Pabst C, Muzzulini J, Schnee B, Brunner-Weinzierl MC, Marangolo M, Bokemeyer C, Deter HC, Atanackovic D. Decrease of CD4(+) FOXP3(+) T regulatory cells in the peripheral blood of human subjects undergoing a mental stressor. Psychoneuroendocrinology 2010;35:663-73
15. O'Donovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, Neylan TC. Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry 2014;77:365-74
16. Stein MB, Chen C-Y, Ursano RJ, Cai T, Gelernter J, Heeringa SG, Jain S, Jensen KP, Maihofer AX, Mitchell C, Nievergelt CM, Nock MK, Neale BM, Polimanti R, Ripke S, Sun X, Thomas ML, Wang Q,Ware EB, Borja S, Kessler RC, Smoller JW, Army Study to Assess Risk and Resilience in Servicemembers (STARRS) Collaborators. Genome-wide association studies of posttraumatic stress disorder in 2 cohorts of US Army soldiers. JAMA Psychiatry 2016;73:695-704
17. Lill CM, Schjeide BM, Graetz C, Liu T, Damotte V, Akkad DA, Blaschke P, Gerdes LA, Kroner A, Luessi F, Cournu-Rebeix I, Hoffjan S, Winkelmann A, Touze E, Pico F, Corcia P, Otaegui D, Antigüedad A, Alcina A, Comabella M, Montalban X, Olascoaga J, Matesanz F, Dörner T, Li SC, Steinhagen-Thiessen E, Lindenberger U, Chan A, Rieckmann P, Hartung HP, Aktas O, Lohse P, Buttmann M, Kümpfel T, Kubisch C, Zettl UK, Epplen JT, Fontaine B, Zipp F, Vandenbroeck K, BertramL. Genome-wide significant association of ANKRD55 rs6859219 and multiple sclerosis risk. J Med Genet 2013;50:140-3
18. Alloza I, Otaegui D, Lapuente AL, Antiguedad A, Varade J, Nunez C, Arroyo R, Urcelay E, Fernandez O, Leyva L, Fedetz M, Izquierdo G, Lucas M, Oliver-Martos B, Alcina A, Saiz A, Blanco Y, Comabella M, Montalban X, Olascoaga J, Matesanz F, Vandenbroeck K.ANKRD55 and DHCR7 are novelmultiple sclerosis risk loci. Genes Immun 2012;13:253-7
19. Harder MN, Ribel-Madsen R, Justesen JM, Sparsø T, Andersson EA, Grarup N, Jørgensen T, Linneberg A, Hansen T, Pedersen O. Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased ?-cell function whereas risk alleles nearANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort. J Clin Endocrinol Metab 2013;98:E801-6
20. Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, Westra HJ, Fehrmann RS, Kurreeman FA, Thomson B, Gupta N, Romanos J, McManus R, Ryan AW, Turner G, Brouwer E, Posthumus MD, Remmers EF, Tucci F, Toes R, Grandone E, Mazzilli MC, Rybak A, Cukrowska B, Coenen MJ, Radstake TR, van Riel PL, Li Y, Bakker PI, Gregersen PK, Worthington J, Siminovitch KA, Klareskog L, Huizinga TW, Wijmenga C, Plenge RM. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet 2011;7:e1002004
21. Viatte S, Plant D, Bowes J, Lunt M, Eyre S, Barton A, Worthington J. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann Rheum Dis 2012;71:1984-90
22. Jergovi? M, Bendelja K, Vidovi? A, Savi? A, Vojvoda V, Aberle N, Rabati? S, Jovanovic T, Sabioncello A. Patients with posttraumatic stress disorder exhibit an altered phenotype of regulatory Tcells. Allergy Asthma Clin Immunol 2014;10:43
23. Jergovi? M, Bendelja K, Savi? Mlakar A, Vojvoda V, Aberle N, Jovanovic T, Rabati? S, Sabioncello A, Vidovi? A. Circulating levels of hormones, lipids, and immune mediators in post-traumatic stress disorder-A 3-month follow-up study. Front Psychiatry 2015;6:49
24. Maes M, Lin AH, Delmeire L, Van GA, Kenis G, De JR, Bosmans E. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry 1999;45:833-9
25. Lindqvist D, Wolkowitz OM, Mellon S, Yehuda R, Flory JD, Henn-Haase C, Bierer LM, Abu-Amara D, Coy M, Neylan TC, Makotkine I, Reus VI, Yan X, Taylor NM, Marmar CR, Dhabhar FS. Proinflammatory milieu in combatrelated PTSD is independent of depression and early life stress. Brain Behav Immun 2014;42:81-8
26. Hoge EA, Brandstetter K, Moshier S, PollackMH,Wong KK, Simon NM. Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depress Anxiety 2009;26:447-55
27. Heath NM, Chesney SA, Gerhart JI, Goldsmith RE, Luborsky JL, Stevens NR, Hobfoll SE. Interpersonal violence, PTSD, and inflammation: potential psychogenic pathways to higher C-reactive protein levels. Cytokine 2013;63:172-8
28. Spitzer C, Barnow S, Völzke H,Wallaschofski H, John U, Freyberger HJ, Löwe B, Grabe HJ. 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
29. Plantinga L, Bremner JD, Miller AH, Jones DP, Veledar E, Goldberg J, Vaccarino V. Association between posttraumatic stress disorder and inflammation: a twin study. Brain Behav Immun 2013;30:125-32
30. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, O'Connor DT, Baker DG. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 2014;71:423-31
31. Pervanidou P, Kolaitis G, Charitaki S, Margeli A, Ferentinos S, Bakoula C, Lazaropoulou C, Papassotiriou I, Tsiantis J, Chrousos GP. Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuroendocrinology 2007;32:991-9
32. RookGA, Raison CL, LowryCA.Microbial 'old friends', immunoregulation and socioeconomic status. Clin Exp Immunol 2014;177:1-12
33. Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, LoberaM, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C. MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of ROR?+ regulatory T cells. Science 2015;349:993-7
34. Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, Busslinger M, Cerf-Bensussan N, Boneca IG, Voehringer D, Hase K, Honda K, Sakaguchi S, Eberl G. MUCOSAL IMMUNOLOGY. The microbiota regulates Type 2 immunity through ROR?t+ T cells. Science 2015;349:989-93
35. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007;449:804-10
36. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE.Metagenomic analysis of the human distal gut microbiome. Science 2006;312:1355-9
37. BranisteV, Al-Asmakh M, Kowal C,Anuar F, Abbaspour A, TóthM,Korecka A, Bakocevic N, Guan NL, Kundu P, Gulyas B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, Pettersson S. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 2014;6:263ra158
38. O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 2009;65:263-7
39. Cryan JF, Dinan TG.Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701-12
40. Reber SO, Siebler PH, Donner NC, Morton JT, Smith DG, Kopelman JM, Lowe KR, Wheeler KJ, Fox JH, Hassell JE Jr., Greenwood BN, Jansch C, Lechner A, Schmidt D, Uschold-Schmidt N, Füchsl AM, Langgartner D, Walker FR, Hale MW, Lopez Perez G, Van Treuren W, González A, Halweg-Edwards AL, Fleshner M, Raison CL, Rook GA, Peddada SD, Knight R, Lowry CA. 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; 113:3130-9
41. Reber SO, Langgartner D, Foertsch S, Postolache TT, Brenner LA, Guendel H, Lowry CA. Chronic subordinate colony housing paradigm: a mouse model for mechanisms of PTSD vulnerability, targeted prevention, and treatment-2016 Curt Richter Award Paper. Psychoneuroendocrinology 2016;74:221-30
42. Dinan TG, Borre YE, Cryan JF. Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry 2014;19:1252-7
43. Jørgensen B, Hansen JT, Krych L, Larsen C, Klein AB, Nielsen DS, Josefsen K, Hansen AK, Sørensen DB. A possible link between food and mood: dietary impact on gut microbiota and behavior in BALB/cmice. PLoS One 2014; 9:e103398
44. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013;36:305-12
45. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 2011;23:255-64, e119
46. Bercik P, Denou E, Collins J, JacksonW, 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 2011;141:599-609, 6091-3
47. Bercik P, Verdu EF, Foster JA,Macri J, PotterM, Huang X,Malinowski P, Jackson W, Blennerhassett P, Neufeld KA, Lu J, Khan WI, Corthesy-Theulaz I, Cherbut C, Bergonzelli GE, Collins SM. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 2010;139:2102-12
48. Heijtz RD,Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, HibberdML, Forssberg H, Pettersson S. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 2011;108:3047-52
49. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013; 18:666-73
50. 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 U S A 2011;108:16050-5
51. Barrett E, Ross RP, O'Toole PW, Fitzgerald GF, Stanton C. Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012;113:411-7
52. Higuchi T, Hayashi H,Abe K. Exchange of glutamate and gamma-aminobutyrate in a Lactobacillus strain. J Bacteriol 1997;179:3362-4
53. García-Ródenas CL, Bergonzelli GE, Nutten S, Schumann A, Cherbut C, Turini M, Ornstein K, Rochat F, Corthésy-Theulaz I. Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J Pediatr Gastroenterol Nutr 2006;43:16-24
54. Pace TW, HeimCM.A short reviewon the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun 2011;25:6-13
55. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;9:313-23
56. Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol 2011;23:473-80
57. Wang CM, Kaltenboeck B. Exacerbation of chronic inflammatory diseases by infectious agents: fact or fiction? World J Diabetes 2010;1:27-35
58. Guo G, JiaKR, ShiY, Liu XF, LiuKY, QiW, GuoY, ZhangWJ,Wang T, Xiao B, Zou QM. Psychological stress enhances the colonization of the stomach by Helicobacter pylori in the BALB/c mouse. Stress 2009;12:478-85
59. Burich A, Hershberg R, Waggie K, Zeng W, Brabb T, Westrich G, Viney JL, Maggio-Price L. Helicobacter-induced inflammatory bowel disease in IL-10-and T cell-deficient mice. Am J Physiol Gastrointest Liver Physiol 2001;281: G764-78
60. KullbergMC,Ward JM, Gorelick PL, Caspar P, Hieny S, Cheever A, Jankovic D, Sher A. 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
61. Yang I, EibachD, Kops F, Brenneke B,Woltemate S, Schulze J, BleichA,Gruber AD, Muthupalani S, Fox JG, Josenhans C, Suerbaum S. Intestinal microbiota composition of interleukin-10 deficient C57BL/6J mice and susceptibility to Helicobacter hepaticus-induced colitis. PLoS One 2013;8:e70783
62. Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G,Walker C. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002;8:625-9
63. Census 2011: Census in Brief Pretoria: Statistics South Africa; 2012
64. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J,Weiller E, Hergueta T, Baker R, Dunbar GC. TheMini-International Neuropsychiatric Interview (M.I.N.I): the development and validation of a structured diagnostic psychiatric interview for DSM-IVand ICD-10. J Clin Psychiatry 1998;59(suppl 20):22-33
65. Weathers FW, Litz BT, Kean TM, Palmieri PA,Marx BP, Schnurr PP. The PTSD Checklist for DSM-5 (PCL-5). 2013. Scale available from theNational Center for PTSD at www.ptsd.va.gov;https://www.ptsd.va.gov/professional/assessment/ adult-sr/ptsd-checklist.asp. Accessed August 2, 2017
66. Widom CS. Posttraumatic stress disorder in abused and neglected children grown up. Am J Psychiatry 1999;156:1223-9
67. Thayer Z, Barbosa-Leiker C, McDonell M, Nelson L, Buchwald D, Manson S. Early life trauma, post-traumatic stress disorder, and allostatic load in a sample of American Indian adults. Am J Hum Biol 2017;29
68. Bernstein D, Fink L. Manual for the Childhood Trauma Questionnaire. New York: The Psychological Corporation; 1998
69. Zijlmans MA, Korpela K, Riksen-Walraven JM, Vos WM, Weerth C. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology 2015;53:233-45
70. Klindworth A, Pruesse E, Schweer T, Peplies J, Quast C, HornM, Glöckner FO. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res 2013; 41:e1
71. Caporaso JG, Kuczynski J, Stombaugh J, BittingerK, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, WaltersWA,Widmann J, Yatsunenko T, Zaneveld J, Knight R. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010;7:335-6
72. DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, Huber T, Dalevi D, Hu P, Andersen GL. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol 2006; 72:5069-72
73. Genuer R, Poggi JM, Tuleau-Malot C. VSURF: An R package for variable selection using random forests. The R Journal 2015;7:19-33
74. Breiman L. Random forests. Machine Learning 2001;45:5-32
75. Ishwaran H, Kogalur UB. Package "randomForestSRC". Available at: http:// www.rdocumentat ion.org/packages/randomForestSRC/functions/ randomForestSRC-package.2016. Accessed December 7, 2016
76. Soo RM, Skennerton CT, Sekiguchi Y, Imelfort M, Paech SJ, Dennis PG, Steen JA, Parks DH, Tyson GW, Hugenholtz P. An expanded genomic representation of the phylum Cyanobacteria. Genome Biol Evol 2014;6:1031-45
77. Rienzi SC, Sharon I,Wrighton KC, Koren O, Hug LA, Thomas BC, Goodrich JK, Bell JT, Spector TD, Banfield JF, Ley RE. The human gut and groundwater harbor non-photosynthetic bacteria belonging to a new candidate phylum sibling to Cyanobacteria. Elife 2013;2:e01102
78. Hug LA, Baker BJ, Anantharaman K, Brown CT, Probst AJ, Castelle CJ, Butterfield CN, Hernsdorf AW, Amano Y, Ise K, Suzuki Y, Dudek N, Relman DA, FinstadKM, Amundson R, Thomas BC, Banfield JF. A new view of the tree of life. Nat Microbiol 2016;1:16048
79. Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Bio 2005;4:Article17
80. 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
81. Lowry CA, Smith DG, Siebler PH, Schmidt D, Stamper CE, Hassell JE Jr., Yamashita PS, Fox JH, Reber SO, Brenner LA, Hoisington AJ, Postolache TT, Kinney KA, Marciani D, Hernandez M, Hemmings SM, Malan-Müller S,Wright KP, Knight R, Raison CL, Rook GA. The microbiota, immunoregulation, and mental health: implications for public health. Curr Environ Health Rep 2016;3:270-86
82. Raison CL, Lowry CA, Rook GA. Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment ofmajor depression.ArchGen Psychiatry 2010;67:1211-24
83. Rook GA, Lowry CA. The hygiene hypothesis and psychiatric disorders. Trends Immunol 2008;29:150-8
84. Rook GA, Raison CL, Lowry CA. Can we vaccinate against depression? Drug Discov Today 2012;17:451-8
85. Rook GA, Raison CL, LowryCA.Microbiota, immunoregulatory old friends and psychiatric disorders. Adv Exp Med Biol 2014;817:319-56
86. RookGA, Lowry CA, Raison CL.Microbial 'old friends', immunoregulation and stress resilience. Evol Med Public Health 2013;2013:46-64
87. Rook GA, 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
88. Rook GA, Lowry CA. The hygiene hypothesis and affective and anxiety disorders. In: Rook GA, ed. The Hygiene Hypothesis and Darwinian Medicine, vol. 1. Basel: Birkhauser Publishing; 2009
89. Rook GAW, Raison CL, Lowry CA. Microbial "old friends", immunoregulation and psychiatric disorders. In:Heidt PJ,Midtvedt T, RuschV, Versalovic J, editors. Old Herborn University Monograph. Herborn: Old Herborn University Press; 2013:61-90
90. Shin NR, Lee JC, Lee HY, KimMS,Whon TW, Lee MS, Bae JW. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014;63:727-35
91. Gomez-Gallego C, Pohl S, Salminen S, de Vos WM, Kneifel W. Akkermansia muciniphila: a novel functional microbe with probiotic properties. Benef Microbes 2016;7:571-84
92. Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y,WangW, TangW, Tan Z, Shi J, Li L, Ruan B. Altered fecal microbiota composition in patientswithmajor depressive disorder. Brain Behav Immun 2015;48:186-94
93. Karl JP, Margolis LM, Madslien EH, Murphy NE, Castellani JW, Gundersen Y, Hoke AV, Levangie MW, Kumar R, Chakraborty N, Gautam A, Hammamieh R, Martini S, Montain SJ, Pasiakos SM. Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiological stress. Am J Physiol Gastrointest Liver Physiol 2017;31:G559-71
94. Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S,Consolandi C, Quercia S, ScurtiM,Monti D, CapriM, Brigidi P, CandelaM. Gut microbiota and extreme longevity. Curr Biol 2016;26:1480-5
95. BellisMD, Zisk A. The biological effects of childhood trauma. Child Adolesc Psychiatr Clin N Am 2014;23:185-222
96. LyteM.Microbial endocrinology in the microbiome-gut-brain axis: howbacterial production and utilization of neurochemicals influence behavior. PLoS Pathog 2013;9:e1003726
97. Hodes GE, PfauML, LeboeufM,Golden SA, ChristoffelDJ, Bregman D, Rebusi N, Heshmati M, Aleyasin H, Warren BL, Lebonte B, Horn S, Lapidus KA, Stelzhammer V, Wong EH, Bahn S, Krishnan V, Bolanos-Guzman CA, Murrough JW, Merad M, Russo SJ. 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
98. Alverdy J, Aoys E. The effect of glucocorticoid administration on bacterial translocation. Evidence for an acquired mucosal immunodeficient state. Ann Surg 1991;214:719-23
99. Tursich M, Neufeld RW, Frewen PA, Harricharan S, Kibler JL, Rhind SG, Lanius RA. Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis. Transl Psychiatry 2014;4:e413