Background: Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biologic mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition at the time of trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether baseline the gut microbiomes of trauma-exposed emergency department patients who later develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. Methods: We performed metagenomic analysis on stool samples (n=51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. Twelve-week post-trauma outcomes for post-traumatic stress disorder (PTSD) (PTSD checklist for DSM-5), normalized depression scores (PROMIS Depression Short Form 8b) and somatic symptom counts were collected. Generalized linear models were created for each outcome using microbial abundances and relevant demographics. Mixed-effect random forest machine learning models were used to identify associations between APNS outcomes and microbial features and metabolic pathways. Results: Microbial species, including Flavonifactor plautti and Ruminococcus gnavus, which are associated with inflammation and poor health outcomes, were found to be important in predicting worse APNS outcomes. Notably, worse APNS outcomes were highly predicted by decreased L-arginine related pathway genes and increased citrulline and ornithine pathways. Conclusions: Pro-inflammatory microbes that are enriched in individuals who develop APNS. More notably, we identified a biological mechanism through which the gut microbiome reduces global arginine bioavailability, which also has been demonstrated in patients with PTSD.  

The authors declare the following competing interests. Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Boehringer Ingelheim and Jazz Pharmaceuticals. Dr. Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, the Rett Research Foundation, and Samsung Research. Dr Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. Dr. Rauch reports grants from NIH during the conduct of the study; personal fees from SOBP (Society of Biological Psychiatry) paid role as secretary, other from Oxford University Press royalties, other from APP (American Psychiatric Publishing Inc.) royalties, other from VA (Veterans Administration) per diem for oversight committee, and other from Community Psychiatry/Mindpath Health paid board service, including equity outside the submitted work, other from National Association of Behavioral Healthcare for paid Board service, other from Springer Publishing royalties, and Leadership roles on Board or Council for SOBP, ADAA (Anxiety and Depression Association of America), and NNDC (National Network of Depression Centers). Dr. Sheikh has received funding from the Florida Medical Malpractice Joint Underwriters Association, Dr. Alvin E. Smith Safety of Healthcare Services Grant, the Allergan Foundation, the Jacksonville Aging Studies Center, the Substance Abuse and Mental Health Services Administration, and the Florida Blue Foundation. Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. Dr. McLean served as a consultant for Walter Reed Army Institute for Research and for Arbor Medical Innovations. Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. Dr. Koenen has been supported by the Robert Wood Johnson Foundation, the Kaiser Family Foundation, the Harvard Center on the Developing Child, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institutes of Health, One Mind, the Anonymous Foundation, and Cohen Veterans Bioscience. She has been a paid consultant for Baker Hostetler, Discovery Vitality, and the Department of Justice. She has been a paid external reviewer for the Chan Zuckerberg Foundation, the University of Cape Town, and Capita Ireland. She has had paid speaking engagements in the last three years with the American Psychological Association, European Central Bank. Sigmund Freud University in Milan, Cambridge Health Alliance, and Coverys. She receives royalties from Guilford Press and Oxford University Press. Dr. Bucci reports funding from the National Institute of Health, the Department of Defense, and the Bill & Melinda Gates Foundation for unrelated work. Dr. Bucci is also supported by a Sponsored Research Agreement from Vedanta Biosciences, Inc, which is unrelated to the present work.

This work was supported by R01 AG067483-01 to J.H. and partially by the CDMRP PRMP W81XWH2020013 to V.B. We would also like to thank Dr. Cindy Lai for her assistance with preparing and editing this manuscript. The AURORA (parent) study was supported by NIMH under U01MH110925, the US Army MRMC, One Mind, and The Mayday Fund. The content is solely responsibility of the authors and does not necessarily represent the official views of any of the funders. Data and/or research tools used in the preparation of this manuscript were obtained from the National Institute of Mental Health (NIMH) Data Archive (NDA). NDA is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in mental health. Dataset identifier(s): NIMH Data Archive Digital Object Identifier (DOI) 10.15154/1528593. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or of the Submitters submitting original data to NDA.

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