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 (APOE4) 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 dev...