Bidirectional Brain-Gut interactions, chronic neuroinflammation and neurodegeneration after traumatic brain injury

University Of Maryland Baltimore, Baltimore MD

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Abstract

Traumatic brain injury (TBI) causes chronic neuroinflammation with progressive neurodegeneration and may ultimately lead to Alzheimer’s disease and/or Alzheimer’s Disease-related dementia and long-term neurocognitive dysfunctions. Emerging evidence suggests that bi-directional brain-systemic interactions contribute to these neuropathological changes. Notably, TBI causes gastrointestinal (GI) tract pathology and GI diseases are associated with neurological dysfunctions. We hypothesize that brain trauma and colitis interact to promote a persistent microglia dysregulation/neuroinflammation that drives the development of Alzheimer’s disease-type neuropathology with progressive tissue loss and cognitive decline. TBI-induced GI damage is common, correlates with injury severity and may include mucosal injury, intestinal barrier disruption and dysmotility. The enteric nervous system (ENS) and enteric glial cells (EGCs) regulate mucosal barrier homeostasis. We reported that moderate controlled cortical impact (CCI) in mice, a well-characterized experimental TBI model, induces increased EGCs gliogenesis/reactivity and causes delayed, chronic mucosal barrier dysfunction in the colon. These changes may explain the increased risk for enteric infections in brain trauma patients. Moreover, an enteric infection during the chronic period after TBI resulted in increased colonic mucosal barrier impairment compared to infections in non-injured animals. Importantly, the enteric infection positively interacted with TBI secondary injury mechanisms and significantly exacerbated posttraumatic neuroinflammation and related neurodegeneration. Late-onset Alzheimer’s Disease is the most common human neurodegenerative disease; however, a proper understanding of the underlaying processes as well as the availability and efficacy of disease-modifying interventions is lacking. Alzheimer’s Disease is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes. The strongest genetic risk factors include the 4 allele of apolipoprotein E (APOE4) and point mutations in triggering receptor expressed on myeloid cells 2 (TREM2) locus. Clinical studies have found that traumatic brain injury (TBI) is associated with an increased risk for subsequent development of Alzheimer’s Disease. Furthermore, our preliminary data show that microglia, the principal TREM2 expressing cell population in the brain, undergo a persistent shift toward activated phenotypes following TBI that are characterized by both TREM2 and ApoE overexpression. Intriguingly, increasing evidence suggests that reciprocal communication between the enteric and the central nervous system, termed the brain-gut axis, plays a key role in neurodegenerative disease. Thus, population-based cohort studies demonstrate a significant association between inflammatory bowel diseases (IBD) and subsequent development of dementia. Importantly, among dementia types, the risk of developing Alzheimer’s dementia demonstrated the greatest increase in IBD patients compared to controls. We propose that, mild-TBI and colitis synergize to promote the development of chronic neurodegenerative processes, causing delayed central inflammation, hippocampal neuronal loss and neurobehavioral dysfunctions and manifesting as Alzheimer’s disease-type neuropathology. A critical question is what underlying mechanisms drive the brain-gut pathological interactions after TBI and lead to chronic neuroinflammation, neurodegeneration and neurocognitive deficits that result in an Alzheimer’s disease and/or Alzheimer’s Disease-related dementia. The proposed studies will probe the novel concept that therapeutic strategies that target GI tract mechanisms may limit brain disease processes, including neurodegeneration, and thus attenuate chronic cognitive decline and the development of Alzheimer’s disease-type neuropathology after TBI. Our central hypotheses are: 1) TBI causes chronic dysfunctions in brain-gut axis, priming increased pathological responses after late enteric challenges including activation in microglia of molecular responses such as Trem2 and ApoE, which are known to play important roles in the progression of Alzheimer’s disease; 2) Targeting ENS/EGCs or microglial activity promotes brain-gut homeostasis, attenuating brain neuroinflammation and specific microglial mechanisms that may drive Alzheimer’s disease-like processes, thus reducing dementia, neurodegeneration and neurocognitive deficits. AIM1: Elucidate the mechanisms of chronic EGCs changes after mouse TBI and demonstrate that EGC modulators attenuate enteric pathology and neuropathology in the chronic phase after TBI. AIM2: Examine the ability of ECGs activity modulators to limit colon injury and neurodegeneration after combined mild-TBI+colitis. AIM3: Show that mild-TBI primes central microglia to develop a dysfunctional pro-inflammatory response to a later enteric challenge.