Post-traumatic stress disorder (PTSD) represents a global public health concern, affecting about 1 in 20 individuals. The symptoms of PTSD include intrusiveness (involuntary nightmares or flashbacks), avoidance of traumatic memories, negative alterations in cognition and mood (such as negative beliefs about oneself or social detachment), increased arousal and reactivity with irritable reckless behavior, concentration problems, and sleep disturbances. PTSD is also highly comorbid with anxiety, depression, and substance abuse. To advance the field from subjective, self-reported psychological measurements to objective molecular biomarkers while considering environmental influences, we examined a unique cohort of Israeli veterans who participated in the 1982 Lebanon war. Non-invasive oral 16S RNA sequencing was correlated with psychological phenotyping. Thus, a microbiota signature (i.e., decreased levels of the bacteria sp_HMT_914, 332 and 871 and Noxia) was correlated with PTSD severity, as exemplified by intrusiveness, arousal, and reactivity, as well as additional psychopathological symptoms, including anxiety, hostility, memory difficulties, and idiopathic pain. In contrast, education duration correlated with significantly increased levels of sp_HMT_871 and decreased levels of Bacteroidetes and Firmicutes, and presented an inverted correlation with adverse psychopathological measures. Air pollution was positively correlated with PTSD symptoms, psychopathological symptoms, and microbiota composition. Arousal and reactivity symptoms were correlated with reductions in transaldolase, an enzyme controlling a major cellular energy pathway, that potentially accelerates aging. In conclusion, the newly discovered bacterial signature, whether an outcome or a consequence of PTSD, could allow for objective soldier deployment and stratification according to decreases in sp_HMT_914, 332, 871, and Noxia levels, coupled with increases in Bacteroidetes levels. These findings also raise the possibility of microbiota pathway-related non-intrusive treatments for PTSD.
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Repository code: BioProject ID PRJNA844909 (web site link: https://github.com/shepp-hub/oral_microbiome_ptsd).
Koenen KC, Ratanatharathorn A, Ng L, McLaughlin KA, Bromet EJ, Stein DJ, et al. Posttraumatic stress disorder in the World Mental Health Surveys. Psychological Med. 2017;47:2260–74.
Association AP. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
Solomon Z, Shklar R, Singer Y, Mikulincer M. Reactions to combat stress in Israeli veterans twenty years after the 1982 Lebanon war. J Nerv Ment Dis. 2006;194:935–9.
Stein MB, Levey DF, Cheng Z, Wendt FR, Harrington K, Pathak GA, et al. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program. Nat Genet. 2021;53:174–84.
Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001;413:519–23.
Sragovich S, Gershovits M, Lam JCK, Li VOK, Gozes I. Putative blood somatic mutations in post-traumatic stress disorder-symptomatic soldiers: high impact of cytoskeletal and inflammatory proteins. J Alzheimers Dis. 2021;79:1723–34.
McEwan DG, Richter B, Claudi B, Wigge C, Wild P, Farhan H, et al. PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection. Cell Host Microbe. 2015;17:58–71.
Sragovich S, Ziv Y, Vaisvaser S, Shomron N, Hendler T, Gozes I. The autism-mutated ADNP plays a key role in stress response. Transl Psychiatry. 2019;9:235.
Kapitansky O, Giladi E, Jaljuli I, Bereswill S, Heimesaat MM, Gozes I. Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond. J Neural Transm. 2020;127:251–63.
Karmon G, Sragovich S, Hacohen-Kleiman G, Ben-Horin-Hazak I, Kasparek P, Schuster B, et al. Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and tau pathologies. Biol Psychiatry. 2022;92:81–95.
Zhu J, Li M, Shao D, Ma S, Wei W. Altered fecal microbiota signatures in patients with anxiety and depression in the gastrointestinal cancer screening: a case-control study. Front Psychiatry. 2021;12:757139.
Simpson CA, Adler C, du Plessis MR, Landau ER, Dashper SG, Reynolds EC, et al. Oral microbiome composition, but not diversity, is associated with adolescent anxiety and depression symptoms. Physiol Behav. 2020;226:113126.
Qing Y, Xu L, Cui G, Sun L, Hu X, Yang X, et al. Salivary microbiome profiling reveals a dysbiotic schizophrenia-associated microbiota. NPJ Schizophrenia. 2021;7:51.
Teng T, Clarke G, Maes M, Jiang Y, Wang J, Li X, et al. Biogeography of the large intestinal mucosal and luminal microbiome in cynomolgus macaques with depressive-like behavior. Mol Psychiatry. 2022;27:1059–67.
Shoubridge AP, Choo JM, Martin AM, Keating DJ, Wong ML, Licinio J, et al. The gut microbiome and mental health: advances in research and emerging priorities. Mol Psychiatry. 2022;27:1908–19.
Hemmings SMJ, Malan-Muller S, van den Heuvel LL, Demmitt BA, Stanislawski MA, Smith DG, et al. The microbiome in posttraumatic stress disorder and trauma-exposed controls: an exploratory study. Psychosom Med. 2017;79:936–46.
Polimanti R, Ratanatharathorn A, Maihofer AX, Choi KW, Stein MB, Morey RA, et al. Association of economic status and educational attainment with posttraumatic stress disorder: a Mendelian randomization study. JAMA Netw Open. 2019;2:e193447.
Lautrup S, Sinclair DA, Mattson MP, Fang EF. NAD(+) in brain aging and neurodegenerative disorders. Cell Metab. 2019;30:630–55.
Solomon Z, Horesh D, Ginzburg K. Trajectories of PTSD and secondary traumatization: a longitudinal study. J Psychiatr Res. 2021;138:354–9.
Solomon Z, Horesh D, Ein-Dor T, Ohry A. Predictors of PTSD trajectories following captivity: a 35-year longitudinal study. Psychiatry Res. 2012;199:188–94.
Derogatis LR, Savitz KL. The SCL-90-R, brief symptom inventory, and matching clinical rating scales. In: Maruish M E. editor. The use of psychological testing for treatment planning and outcomes assessment. New Jersey, USA: Lawrence Erlbaum Associates Publishers; 1999. p. 679–724.
Mueller DP. Social networks: a promising direction for research on the relationship of the social environment to psychiatric disorder. Soc Sci Med Med Psychol Med Socio. 1980;14A:147–61.
Spanier GB. Measuring dyadic adjustment: new scales for assessing the quality of marriage and similar dyads. J Marriage Fam. 1976;38:15–28.
Florian V, Drori Y. Mental Health Inventory (MHI): psychometric characteristics and normative data regarding the Israeli population. Psychology. 1990;1:26–35.
Fridman A, Bakermans-Kranenburg MJ, Sagi-Schwartz A, Van IJzendoorn MH. Genetic moderation of cortisol secretion in holocaust survivors: the role of ADRA2B. Int J Behav Dev. 2012;36:79–84.
Pavot W, Diener E. Review of the satisfaction with life scale. Psychological Assess. 1993;5:164–72.
Tedeschi RG, Calhoun LG. Posttraumatic growth: conceptual foundations and empirical evidence. Psychological Inq. 2004;15:1–18.
Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37:852–7.
Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–3.
Bokulich NA, Kaehler BD, Rideout JR, Dillon M, Bolyen E, Knight R, et al. Optimizing taxonomic classification of marker-gene amplicon sequences with QIIME 2’s q2-feature-classifier plugin. Microbiome. 2018;6:90.
Escapa IF, Chen T, Huang Y, Gajare P, Dewhirst FE, Lemon KP. New insights into human nostril microbiome from the Expanded Human Oral Microbiome Database (eHOMD): a resource for the microbiome of the human aerodigestive tract. mSystems. 2018;3:e00187–18.
Douglas GM, Maffei VJ, Zaneveld JR, Yurgel SN, Brown JR, Taylor CM, et al. PICRUSt2 for prediction of metagenome functions. Nat Biotechnol. 2020;38:685–8.
Callahan BJ, Sankaran K, Fukuyama JA, McMurdie PJ, Holmes SP. Bioconductor Workflow for Microbiome Data Analysis: from raw reads to community analyses. F1000Research. 2016;5:1492.
Lin H, Peddada SD. Analysis of compositions of microbiomes with bias correction. Nat Commun. 2020;11:3514.
Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847–9.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57:289–300.
Vaccarino V, Shah AJ, Moncayo V, Nye J, Piccinelli M, Ko YA, et al. Posttraumatic stress disorder, myocardial perfusion, and myocardial blood flow: a longitudinal twin study. Biol Psychiatry 2022;91:615–25.
Wu YR, Lee YC, Li WM, Hsu WC, Lin HH, Chang LL, et al. High Transaldolase 1 expression predicts poor survival of patients with upper tract urothelial carcinoma. Pathol Int. 2021;71:463–70.
Hao G, Zuo L, Xiong P, Chen L, Liang X, Jing C. Associations of PM2.5 and road traffic noise with mental health: evidence from UK Biobank. Environ Res. 2022;207:112221.
Jia YJ, Liao Y, He YQ, Zheng MQ, Tong XT, Xue WQ, et al. Association between oral microbiota and cigarette smoking in the chinese population. Front Cell Infect Microbiol. 2021;11:658203.
Gautam A, Kumar R, Chakraborty N, Muhie S, Hoke A, Hammamieh R, et al. Altered fecal microbiota composition in all male aggressor-exposed rodent model simulating features of post-traumatic stress disorder. J Neurosci Res. 2018;96:1311–23.
Liu M, Wang X, Wu F, Dai N, Chen M, Yu J, et al. Variations of oral microbiome in chronic insomnia patients with different tongue features. Am J Chin Med. 2020;48:923–44.
Sotozono M, Kuriki N, Asahi Y, Noiri Y, Hayashi M, Motooka D, et al. Impact of sleep on the microbiome of oral biofilms. PLoS One. 2021;16:e0259850.
Hjorth MF, Blaedel T, Bendtsen LQ, Lorenzen JK, Holm JB, Kiilerich P, et al. Prevotella-to-Bacteroides ratio predicts body weight and fat loss success on 24-week diets varying in macronutrient composition and dietary fiber: results from a post-hoc analysis. Int J Obes. 2019;43:149–57.
Heimesaat MM, Reifenberger G, Vicena V, Illes A, Horvath G, Tamas A, et al. Intestinal microbiota changes in mice lacking pituitary adenylate cyclase activating polypeptide (PACAP) – Bifidobacteria make the difference. Eur J Microbiol Immunol. 2017;7:187–99.
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011;470:492–7.
Nithichanon A, Gourlay LJ, Bancroft GJ, Ato M, Takahashi Y, Lertmemongkolchai G. Boosting of post-exposure human T-cell and B-cell recall responses in vivo by Burkholderia pseudomallei-related proteins. Immunology. 2017;151:98–109.
Teles FR, Teles RP, Sachdeo A, Uzel NG, Song XQ, Torresyap G, et al. Comparison of microbial changes in early redeveloping biofilms on natural teeth and dentures. J Periodontol. 2012;83:1139–48.
McDaniel J, McDaniel S, Samiano BJ, Marrujo M, Kingsley K, Howard KM. Microbial screening reveals oral site-specific locations of the periodontal pathogen Selenomonas noxia. Curr issues Mol Biol. 2021;43:353–64.
Schnaider L, Arnon ZA, Gazit E. Reevaluating the microbial infection link to Alzheimer’s disease. J Alzheimers Dis. 2020;73:59–62.
Bougea A, Anagnostouli M, Angelopoulou E, Spanou I, Chrousos G. Psychosocial and trauma-related stress and risk of dementia: a meta-analytic systematic review of longitudinal studies. J Geriatr Psychiatry Neurol. 2022;35:24–37.
Wang SC, Chen YC, Chen SJ, Lee CH, Cheng CM. Alcohol addiction, gut microbiota, and alcoholism treatment: a review. Int J Mol Sci. 2020;21:6413.
Armenta RF, Walter KH, Geronimo-Hara TR, Porter B, Stander VA, LeardMann CA, et al. Longitudinal trajectories of comorbid PTSD and depression symptoms among U.S. service members and veterans. BMC Psychiatry. 2019;19:396.
Gerasimenko M, Cherepanov SM, Furuhara K, Lopatina O, Salmina AB, Shabalova AA, et al. Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder. Sci Rep. 2020;10:10035.
Hadar A, Kapitansky O, Ganaiem M, Sragovich S, Lobyntseva A, Giladi E, et al. Introducing ADNP and SIRT1 as new partners regulating microtubules and histone methylation. Mol Psychiatry. 2021;26:6550–61.
Solomon Z, Levin Y, Crompton L, Ginzburg K. Is acute stress reaction a risk factor for early mortality? Health Psychol. 2019;38:606–12.
This work was supported in part by a MAF’AT grant to IG and ZS. EL-L’s doctoral research was supported by a Harry and Sadie Lasky Foundation Fellowship. SS was supported by an Eshkol fellowship from the Israel Ministry of Science and Technology, and The BioInnovation Fellowship and Mentorship by Teva. IG was further supported by ERA-NET neuron ADNPinMED, Holly and Jonathan Strelzik (American Friends of Tel Aviv University), and Drs. Ronith and Armand Stemmer (French Friends of Tel Aviv University). VOKL, JCKL, and IG were also supported by a Catalyst Award, US National Academy of Medicine. VOKL and JCKL are also supported in part by the Theme-based Research Scheme of the Research Grants Council of the Hong Kong SAR Government, under Grant No. T41-709/17-N. We acknowledge the assistance of Ruiqiao Bai, HKU-AI WiSe, The University of Hong Kong, in collecting the PM2.5 data.
The authors declare no competing interests.
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Levert-Levitt, E., Shapira, G., Sragovich, S. et al. Oral microbiota signatures in post-traumatic stress disorder (PTSD) veterans. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01704-6