Postinjury Fecal Microbiome Transplant Decreases Lesion Size and Neuroinflammation in Traumatic Brain Injury

Abstract

Background: Traumatic brain injury (TBI) is an underrecognized public health threat. The constitutive activation of microglia after TBI has been linked to long-term neurocognitive deficits and the progression of neurodegenerative disease. Evolving evidence indicates a critical role for the gut-brain axis in this process. Specifically, TBI has been shown to induce the depletion of commensal gut bacteria. The resulting gut dysbiosis is associated with neuroinflammation and disease. Hypothesis: We hypothesized that fecal microbiota transplantation would attenuate microglial activation and improve neuropathology after TBI. Methods: C57Bl/6 mice were subjected to severe TBI (n = 10) or sham injury (n = 10) via an open-head controlled cortical impact. The mice underwent fecal microbiota transplantation (FMT) or vehicle alone via oral gavage once weekly for 4 weeks after injury. At 59 days after TBI, mice underwent three-dimensional, contrast-enhanced magnetic resonance imaging. Following imaging, mice were killed, brains harvested at 60 DPI, and CD45+ cells isolated via florescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3′ Reagent kit followed by sequencing on a HiSeq4000 instrument, and computational analysis was performed. Results: Fecal microbiota transplantation resulted in a >marked reduction of ventriculomegaly (P < 0.002) and preservation of white matter connectivity at 59 days after TBI (P < 0.0001). In addition, microglia from FMT-treated mice significantly reduced inflammatory gene expression and enriched pathways involving the heat-shock response compared with mice treated with vehicle alone. Conclusions: We hypothesized that restoring gut microbial community structure via FMT would attenuate microglial activation and reduce neuropathology after TBI. Our data demonstrated significant preservation of cortical volume and white matter connectivity after an injury compared with mice treated with vehicle alone. This preservation of neuroanatomy after TBI was associated with a marked reduction in inflammatory gene expression within the microglia of FMT-treated mice. Microglia from FMT-treated mice enriched pathways in the heat-shock response, which is known to play a neuroprotective role in TBI and other neurodegenerative disease processes.

Non-pharmacological interventions for traumatic brain injury

“…111 FMT in mice also reduced post-TBI inflammatory gene expression and T-cell infiltration into the brain, possibly by regulating the inflammatory signaling between the gut and brain. 111…”

“…110 In mice subjected to CCI injury, an FMT regimen that started 2 h after TBI and continued once weekly for 4 weeks resulted in a reduction in ventriculomegaly and lesion volume and preserved the white matter connectivity. 111 FMT in mice also reduced post-TBI inflammatory gene expression and T-cell infiltration into the brain, possibly by regulating the inflammatory signaling between the gut and brain. 111…”

Protective effects of fecal microbiota transplantation against ischemic stroke and other neurological disorders: an update

“…In the intestinal mucosa, activation (phosphorylation) of Stat3 serves as a master regulator of Th17 cell development by upregulating the production of IL-6, IL-17A, IL-22, and RAR-related orphan receptor gamma (RORγt) ( 125 ). FMT treatment reduces the activation of microglial cells and inflammatory gene expression in a mouse model of traumatic brain injury (TBI) ( 126 ). Another study found that FMT reduced the proliferative capacity of colonic mucosal T cells in colitic mice compared with animals who did not receive FMT.…”

The Intestinal Microbiome after Traumatic Injury

“…In addition, they found improved neurologic functional testing compared to untreated mice [ 99 ]. This same group studied the effects of daily fecal transplantation for four weeks in mice subjected to TBI and found that this resulted in reduced microglial inflammatory gene expression and even mitigated T-cell response postinjury compared to mice who were subject to TBI alone [ 100 ]. Du et al studied TBI in male rats and performed daily fecal transplantation for seven days, showing increased alpha-diversity, shifts in beta-diversity, and microbial composition differences along with improved neurological testing results and serum metabolite differences compared to rats who were subject to TBI alone after eight days [ 101 ].…”