• Lina Xian, Xiaochen Xu, Yongmeng Mai, Tongwu Guo, Zhen Chen, and Xiaoyan Deng.
• Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Intensive Care Unit, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, Hainan Province, PR China.
• Medicine (Baltimore). 2024 Sep 20; 103 (38): e39740e39740.

AbstractIncreasing literature has affirmed that changes in the gut microbiome (GM) composition were linked to distinct brain injury (BI) through the gut-brain axis, but it is uncertain if such links reflect causality. Further, the immune cell changes mediating the impact of GM on BI are not completely understood. We made use of the summary statistics of 211 GM (MiBioGen consortium), 731 immune cells, and 2 different BIs (FinnGen consortium), namely traumatic BI (TBI) and focal BI (FBI), from the extensive genome-wide association studies to date. We executed bidirectional Mendelian randomization (MR) analyses to ascertain the causal relationships between the GM and BI, and 2-step MR to validate possible mediating immune cells. Additionally, thorough sensitivity analyses verified the heterogeneity, robustness, as well as horizontal pleiotropy of the results. Based on the results of inverse-variance weighted (IVW) and sensitivity analyses, in MR analyses, 5 specific GM taxa and 6 specific GM taxa were causally associated with FBI and TBI, respectively; 27 immunophenotypes and 39 immunophenotypes were causally associated with FBI and TBI, respectively. Remarkably, Anaerofilum, LachnospiraceaeNC2004group, RuminococcaceaeUCG004, CCR2 on myeloid dendritic cell (DC), CD123 on CD62L+ plasmacytoid DC, and CD123 on plasmacytoid DC were causally associated with TBI and FBI (all P < .040). However, our reverse MR did not indicate any influence of TBI and FBI on the specific GM. In mediation analysis, we found that the associations between Escherichia.Shigella and FBI were mediated by CD123 on CD62L + plasmacytoid DC in addition to CD123 on plasmacytoid DC, each accounting for 4.21% and 4.21%; the association between FamilyXIIIAD3011group and TBI was mediated by CCR2 on myeloid DC, with mediated proportions of 5.07%. No remarkable horizontal pleiotropy or heterogeneity of instrumental variables was detected. Our comprehensive MR analysis first provides insight into potential causal links between several specific GM taxa with FBI/TBI. Additionally, CD123 on plasmacytoid DC in conjunction with CCR2 on myeloid DC may function in gut microbiota-host crosstalk in FBI and TBI, correspondingly. Further studies are critical to unravel the underlying mechanisms of the links between GM and BI.Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.

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