Potential causal association between gut microbiome and posttraumatic stress disorder
Authors: He Qiang , Wang Wenjing , Xu Dingkang , Xiong Yang , Tao Chuanyuan , You Chao , Ma Lu , Ma Junpeng ,   the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group, Nievergelt Caroline M. , Maihofer Adam X. , Klengel Torsten , Atkinson Elizabeth G. , Chen Chia-Yen , Choi Karmel W. , Coleman Jonathan R. I. , Dalvie Shareefa , Duncan Laramie E. , Logue Mark W. , Provost Allison C. , Ratanatharathorn Andrew , Stein Murray B. , Torres Katy , Aiello Allison E. , Almli Lynn M. , Amstadter Ananda B. , Andersen Søren B. , Andreassen Ole A. , Arbisi Paul A. , Ashley-Koch Allison E. , Austin S. Bryn , Avdibegovic Esmina , Babić Dragan , Bækvad-Hansen Marie , Baker Dewleen G. , Beckham Jean C. , Bierut Laura J. , Bisson Jonathan I. , Boks Marco P. , Bolger Elizabeth A. , Børglum Anders D. , Bradley Bekh , Brashear Megan , Breen Gerome , Bryant Richard A. , Bustamante Angela C. , Bybjerg-Grauholm Jonas , Calabrese Joseph R. , Caldas-de-Almeida José M. , Dale Anders M. , Daly Mark J. , Daskalakis Nikolaos P. , Deckert Jürgen , Delahanty Douglas L. , Dennis Michelle F. , Disner Seth G. , Domschke Katharina , Dzubur-Kulenovic Alma , Erbes Christopher R. , Evans Alexandra , Farrer Lindsay A. , Feeny Norah C. , Flory Janine D. , Forbes David , Franz Carol E. , Galea Sandro , Garrett Melanie E. , Gelaye Bizu , Gelernter Joel , Geuze Elbert , Gillespie Charles , Uka Aferdita Goci , Gordon Scott D. , Guffanti Guia , Hammamieh Rasha , Harnal Supriya , Hauser Michael A. , Heath Andrew C. , Hemmings Sian M. J. , Hougaard David Michael , Jakovljevic Miro , Jett Marti , Johnson Eric Otto , Jones Ian , Jovanovic Tanja , Qin Xue-Jun , Junglen Angela G. , Karstoft Karen-Inge , Kaufman Milissa L. , Kessler Ronald C. , Khan Alaptagin , Kimbrel Nathan A. , King Anthony P. , Koen Nastassja , Kranzler Henry R. , Kremen William S. , Lawford Bruce R. , Lebois Lauren A. M. , Lewis Catrin E. , Linnstaedt Sarah D. , Lori Adriana , Lugonja Bozo , Luykx Jurjen J. , Lyons Michael J. , Maples-Keller Jessica , Marmar Charles , Martin Alicia R. , Martin Nicholas G. , Maurer Douglas , Mavissakalian Matig R. , McFarlane Alexander , McGlinchey Regina E. , McLaughlin Katie A. , McLean Samuel A. , McLeay Sarah , Mehta Divya , Milberg William P. , Miller Mark W. , Morey Rajendra A. , Morris Charles Phillip , Mors Ole , Mortensen Preben B. , Neale Benjamin M. , Nelson Elliot C. , Nordentoft Merete , Norman Sonya B. , O’Donnell Meaghan , Orcutt Holly K. , Panizzon Matthew S. , Peters Edward S. , Peterson Alan L. , Peverill Matthew , Pietrzak Robert H. , Polusny Melissa A. , Rice John P. , Ripke Stephan , Risbrough Victoria B. , Roberts Andrea L. , Rothbaum Alex O. , Rothbaum Barbara O. , Roy-Byrne Peter , Ruggiero Ken , Rung Ariane , Rutten Bart P. F. , Saccone Nancy L. , Sanchez Sixto E. , Schijven Dick , Seedat Soraya , Seligowski Antonia V. , Seng Julia S. , Sheerin Christina M. , Silove Derrick , Smith Alicia K. , Smoller Jordan W. , Solovieff Nadia , Sponheim Scott R. , Stein Dan J. , Sumner Jennifer A. , Teicher Martin H. , Thompson Wesley K. , Trapido Edward , Uddin Monica , Ursano Robert J. , van den Heuvel Leigh Luella , van Hooff Miranda , Vermetten Eric , Vinkers Christiaan H. , Voisey Joanne , Wang Yunpeng , Wang Zhewu , Werge Thomas , Williams Michelle A. , Williamson Douglas E. , Winternitz Sherry , Wolf Christiane , Wolf Erika J. , Wolff Jonathan D. , Yehuda Rachel , Young Keith A. , Young Ross McD , Zhao Hongyu , Zoellner Lori A. , Liberzon Israel , Ressler Kerry J. , Haas Magali , Koenen Karestan C. 
Published: January 2024

Abstract
Background
The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR).

Methods
The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the MiBioGen consortium. As to PTSD, the Freeze 2 datasets were originated from the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD), and the replicated datasets were obtained from FinnGen consortium. Single nucleotide polymorphisms meeting MR assumptions were selected as instrumental variables. The inverse variance weighting (IVW) method was employed as the main approach, supplemented by sensitivity analyses to evaluate potential pleiotropy and heterogeneity and ensure the robustness of the MR results. We also performed reverse MR analyses to explore PTSD’s causal effects on the relative abundances of specific features of the gut microbiome.

Results
In Freeze 2 datasets from PGC-PTSD, eight bacterial traits revealed a potential causal association between gut microbiome and PTSD (IVW, all P < 0.05). In addition, Genus.Dorea and genus.Sellimonas were replicated in FinnGen datasets, in which eight bacterial traits revealed a potential causal association between gut microbiome and the occurrence of PTSD. The heterogeneity and pleiotropy analyses further supported the robustness of the IVW findings, providing additional evidence for their reliability.

Conclusion
Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms.