Fecal Microbiota Transfer Attenuates Gut Dysbiosis and Functional Deficits After Traumatic Brain Injury

Abstract

Background: Traumatic brain injury (TBI) is an underrecognized public health threat. Survivors of TBI often suffer long-term neurocognitive deficits leading to the progressive onset of neurodegenerative disease. Recent data suggests that the gut-brain axis is complicit in this process. However, no study has specifically addressed whether fecal microbiota transfer (FMT) attenuates neurologic deficits after TBI. Hypothesis: We hypothesized that fecal microbiota transfer would attenuate neurocognitive, anatomic, and pathologic deficits after TBI. Methods: C57Bl/6 mice were subjected to severe TBI (n ¼ 20) or sham-injury (n ¼ 20) via an open-head controlled cortical impact. Post-injury, this cohort of mice underwent weekly oral gavage with a slurry of healthy mouse stool or vehicle alone beginning 1 h post-TBI followed by behavioral testing and neuropathologic analysis. 16S ribosomal RNA sequencing of fecal samples was performed to characterize gut microbial community structure pre-and post-injury. Zero maze and open field testing were used to evaluate post-traumatic anxiety, exploratory behavior, and generalized activity. 3D, contrast enhanced, magnetic resonance imaging was used to determine differences in cortical volume loss and white matter connectivity. Prior to euthanasia, brains were harvested for neuropathologic analysis. Results: Fecal microbiome analysis revealed a large variance between TBI, and sham animals treated with vehicle, while FMT treated TBI mice had restoration of gut dysbiosis back to levels of control mice. Neurocognitive testing demonstrated a rescue of normal anxiety-like and exploratory behavior in TBI mice treated with FMT. FMT treated TBI mice spent a greater percentage of time (22%, P ¼ 0.0001) in the center regions of the Open Field as compared to vehicle treated TBI mice (13%). Vehicle-treated TBI animals also spent less time (19%) in the open areas of zero maze than FMT treated TBI mice (30%, P ¼ 0.0001). Comparing in TBI mice treated with FMT, MRI demonstrated a marked attenuation in ventriculomegaly (P < 0.002) and a significant change in fractional anisotropy (i.e., loss of white matter connectivity) (P < 0.0001). Histologic analysis of brain sections revealed a FMT-injury dependent interaction in the microglia/macrophage-specific ionized calcium-binding protein, Iba1 (P ¼ 0.002). Conclusion: These data suggest that restoring a pre-injury gut microbial community structure may be a promising therapeutic intervention after TBI.

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

“…Quantitative MRI of TBI mice in our current and prior studies shows a marked reduction of cortical volume loss and significant preservation of white matter connectivity in mice treated postinjury with FMT (Fig. 1) (19). In addition, neuropathologic analysis of these FMT-treated brains demonstrated increased levels of Iba-1 staining, indicating increased activation and/or many MG in the FMT-treated groups compared with vehicle-treated mice.…”

“…In turn, gut dysbiosis can propel the index brain injury via neural, humoral, and metabolic mechanisms that are only beginning to be discovered (34). This bidirectional feedback loop between the gut microbial community and the brain then has the potential to either propel and propagate the index injury or set up a microenvironment facilitating repair and regeneration (11,(17)(18)(19). Our laboratory recently published that restoring a preinjury gut microbial community structure after TBI can mitigate or even ameliorate several cognitive, anatomic, and pathologic deficits seen after brain injury.…”

“…Using our controlled cortical impact TBI model, we linked differences in TBI pathology and neurocognition to a divergent microbial community structure with both injury and age (17,18). In a follow-up work, we hypothesized that replacing a healthy microbiome through FMT would attenuate neurocognitive deficits in TBI (19). We found that administering FMT in a clinically applicable postinjury model could restore gut microbial community structure.…”

Multicompartmental traumatic injury and the microbiome: Shift to a pathobiome

“…12,13 Preclinical studies have introduced fecal transplantation as a way to ameliorate dysbiosis in sepsis and traumatic brain injury, but this is not currently used in clinical practice. 14,15 Several preclinical studies have been performed on various levels of injury, including hemorrhagic shock and different organ injuries, which all demonstrate significant changes to the microbiome after trauma and a shift to the pathobiome. [16][17][18][19][20][21] However, few have studied severe and multicompartmental injuries; of these, only early changes in the microbiome, intestinal injury, and intestinal permeability have been investigated within 24 hours of injury.…”

“…Occludin, a transmembrane component of tight junctions, has been implicated as a plasma biomarker of intestinal permeability 12,13 . Preclinical studies have introduced fecal transplantation as a way to ameliorate dysbiosis in sepsis and traumatic brain injury, but this is not currently used in clinical practice 14,15 …”