Repetitive, mild traumatic brain injury results in a progressive white matter pathology, cognitive deterioration, and a transient gut microbiota dysbiosis

Abstract

traumatic brain injury (tBi) is often accompanied by gastrointestinal and metabolic disruptions. these systemic manifestations suggest possible involvement of the gut microbiota in head injury outcomes. Although gut dysbiosis after single, severe tBi has been documented, the majority of head injuries are mild, such as those that occur in athletes and military personnel exposed to repetitive head impacts. therefore, it is important to determine if repetitive, mild tBi (rmtBi) will also disrupt the gut microbiota. Male mice were exposed to mild head impacts daily for 20 days and assessed for cognitive behavior, neuropathology and disruptions in the gut microbiota at 0, 45 or 90 days after injury. Deficits in recognition memory were evident at the late post-injury points. Brains show an early increase in microglial activation at the 0-day time point that persisted until 90 days post-injury. This was compounded by substantial increases in astrocyte reactivity and phosphorylated tau at the 90day time point. in contrast, changes in the microbial community were minor and transient, and very few differences were observed in mice exposed to rmTBI compared to controls. While the progressive emergence of white matter damage and cognitive alterations after rmtBi resembles the alterations observed in athletes and military personnel exposed to rmtBi, these changes could not be linked to systematic modifications in the gut microbiota. Traumatic brain injury (TBI) results from a blow to the head and its severity can range along a continuum from mild (e.g., brief change in mental status or consciousness) to severe (e.g., extended unconsciousness, coma, prolonged amnesia) to fatal. TBI is one of the most common neurological diagnoses in the US 1 , with a CDC estimate of approximately 2.5 million people on an annual basis. About one-third of all injury deaths arise from TBI and roughly 90,000 persons experience long-term disability yearly as a result of brain injury 2. The cost of lifetime care for survivors of TBI has been estimated at $0.6-$1 million per individual with a total annual cost to the United States of ~$60 billion 3 , reflecting the severity of the dysfunction that results from this injury. Perhaps the form of TBI that has garnered the greatest scrutiny recently, in the public eye as well as within military, scientific and medical communities, is repetitive, mild TBI (rmTBI). Military operations in Iraq and Afghanistan are revealing that TBI accounts for about 28% of all combat casualties 4 approximately 85% of which are mild 4-6. More than 2.4 million US military personnel have served on multiple combat tours, and the US Defense and Veterans Brain Injury Center has estimated that ~413,000 military service members have been diagnosed with mTBI from 2001-2011 (https://dvbic.dcoe.mil/dod-worldwide-numbers-tbi). Besides the military,

Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature

“…Nevertheless, IgG staining was faint and restricted to the optic tract. Injury to the visual pathway including BBB-disruption and p-Tau accumulation in the optic tract has been shown after murine closed head injury [ 3 , 13 , 14 , 19 ]. Yet, we did not observe previously reported perivascular IgG staining in the cerebral cortex [ 69 ].…”

Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury

“…Indeed, neuroinflammation is exacerbated by systemic administration of LPS following experimental TBI (74), contributing to a more pronounced TBI-induced cognitive decline (75). Notably, depletion of the gut microbiota following experi-In preclinical TBI studies (145,146,(156)(157)(158), acute changes at the species and genus levels (158), as well as alterations in αdiversity with increased numbers of Proteobacteria and decreased Firmicutes, were correlated significantly with the severity of TBI (159). There is avid interest in the impact of changes in gut microbiota composition on neuroinflammation, neurological development, cognition, affect, and behavior (160)(161)(162)(163)(164)(165)).…”

Temporal patterns of microglial activation in white matter following experimental mild traumatic brain injury: a systematic literature review

“…Several studies report microglial activation at relatively chronic phases of the injury, ranging from 2 weeks post-final-injury to 1 year post-final-injury. These studies include groups 29a ([ 46 ]; 20 weight drop injuries to mice spaced 1 to 3 days apart; activation lasting at least 90 dpfi), 21b and 21c ([ 35 ]; 5 controlled piston-driven impacts to mice spaced 1 or 2 days apart; activation lasting at least 70 dpfi), 19a ([ 47 ]; 4 fluid pulse injuries to rats spaced 7 days apart; activation lasting at least 90 dpfi), 17a - c ([ 43 ]; 2 weight drop injuries to rats spaced 1 day apart; activation lasting at least 90 dpfi), 23a ([ 48 ]; 5 controlled piston-driven impacts to mice spaced 2 days apart; activation lasting at least 270 dpfi), 18a ([ 49 ]; 3 weight drop injuries to mice; activation lasting at least 60 dpfi), 20a and 20b ([ 50 ]; 4 controlled piston-driven impacts given to mice; activation lasting at least 180 dpfi), 25a and 25b ([ 51 ]; 1 or 5 controlled piston-driven impacts spaced 2 days apart; activation lasting at least 360 dpfi), 26a ([ 52 ]; 5 controlled piston-driven impacts to mice spaced 2 days apart; activation lasting at between 90 and 180 dpfi), 08a ([ 53 ]; 1 controlled piston-driven impact to ferrets; activation lasting at least 112 dpfi), 09a and 09b ([ 54 ]; 1 controlled piston-driven impact to mice; activation lasting at least 30 dpfi), 16a ([ 39 ]; 2 controlled piston-driven impacts to mice spaced 1 day apart; activation lasting at least 49 dpfi), 30a ([ 55 ]; 30 controlled piston-driven impacts to mice spaced 1 to 3 days apart; activation lasting at least 365 dpfi), and 27a ([ 41 ]; 5 controlled piston-driven impacts spaced 1 day apart; activation lasting at least 42 dpfi). For the groups in which the final timepoint assessed showed increased microglial activation in the white matter, it is unknown whether or not that activation will eventually resolve.…”

“…During the preparation of the results in this review, there was no difference in weighting for each of the experimental groups in a multi-group study (e.g., the 4 groups present in [ 57 ]) or a single experimental group from a single-group study (e.g., the 1 group present in [ 46 ]). Consequently, our findings have a bias towards multi-group studies, where a greater number of experimental groups results in a greater degree of bias.…”