Associations Between Blast Exposures and Intestinal Permeability and Neurotrauma Symptoms During Mortar Fire Military Tactical Training Operations.

Introduction: Military members are exposed in combat and training to recognized traumatic brain injury (TBI)-causing events and other sub-concussive events that result in physical, psychological, and physiological impacts. Studies by this team and others involving Service Members (SMs) engaged in tactical training operations with repeated exposure to low level blast (LLB) have shown associations with concussion-like symptomology as well as transient decrements in performance, blood-based neurotrauma biomarkers, and perturbations in epigenome and transcriptome profiles, as well as alterations in intestinal permeability (IP). The present study focused on SMs engaged in mortar fire tactical trainings, builds on our previous findings in breachers that identified associations between blast exposures and IP and neurotrauma symptoms following exposures to LLB.

Materials and methods: Self-report symptom data and blood specimens from 31 SMs were collected including 22 mortarmen who directly participated in tactical training operations and were exposed to LLB and 9 unexposed study controls. Symptom data and blood samples were collected at pre-, post, and follow-up time points, across 3 consecutive mortar fire training sessions. Blood samples were assessed across all sessions via enzyme-linked immunosorbent assay (ELISA) to measure levels of IP protein biomarkers (i.e., Zonulin, Lipopolysaccharide-Binding Protein (LBP), Claudin-3, Intestinal-Fatty Acid Biding Protein (I-FABP). Correlations between IP biomarker changes and magnitude of blast exposures in each training session were calculated and reported as effect sizes measured by Cohen's d using correlation to effect size conversion via R package effectsize. Impact of blast magnitude on IP biomarker changes across sessions were tested using a linear mixed effect model via R package lme4 and emmeans, with similar models used to investigate associations of IP biomarker changes following blast with physical and psychological symptoms or prior history of TBI.

Results: In mortarmen LLB exposure magnitudes were significantly associated with change in Intestinal-Fatty Acid Binding Protein (pre vs. post, P = .028) and Zonulin (pre vs. follow-up, P = .003) levels across training sessions. Associations with moderate to large effect sizes were observed between changes in LBP and CLDN3 levels and neurotrauma symptoms, including taking longer to think, dizziness, and concentration difficulties following exposures to LLB (Cohen's |d| > 0.5). Associations between TBI history and blast induced alterations in LBP and CLDN3 levels were identified with large effect sizes (|d| > 0.8).

Conclusions: The present study in mortarmen corroborates our prior findings showing that exposures to LLB can contribute to IP that is also associated with prior mild traumatic brain injury (mTBI) history, with concomitant decreases in self-reported cognitive functioning. These findings suggest a possible role of blast exposure in gut permeability and the importance of the gut-brain axis in blast injury, with significant clinical translational impact in how we target clinical symptoms associated with exposure to blast and long term sequalae. These results may lead to a paradigm shift in the manner by which the military can detect, mitigate, and treat blast-related sequelae.