Microbiota-targeted approaches to resolve dysbiosis-induced AD neuropathology following brain injury.

Gut microbiota are an essential neuromodulator of gut-brain axis signaling and can impact brain inflammation and outcome after ischemic injury. Several studies have shown that microbiota composition, diversity, and richness can influence anxiety and depressive behaviors. The Villapol Lab has recently been focused on how TBI affects the function of peripheral systems and is studying how the brain injury alters the microbiome and the resultant impact on TBI-induced affective disorders.

We will investigate how gut dysbiosis after traumatic brain injury accelerates Alzheimer’s disease (AD) and whether microbiome restoration can blunt this trajectory. Building on evidence that the brain injury disrupts intestinal integrity and elevates toxic metabolites, we will define antibiotic effects on AD pathology and test microbiota-focused strategies to reduce neuroinflammation, lower Aβ, and rescue motor and cognitive function.

The Brain–Liver-gut Inflammatory axis in TBI: Mediators, and Acute-Phase response.

Traumatic brain injury (TBI) and cerebral ischemia cause focal loss of brain tissue followed by a robust neuroinflammatory response. Beyond the CNS, brain injury perturbs peripheral organ function and triggers systemic effects. Notably, focal brain lesions rapidly induce an acute-phase hepatic response, with liver-derived chemokines amplifying CNS inflammation and mediating bidirectional CNS–liver communication. Yet the specific inflammatory mediators, acute-phase proteins, and the breadth of peripheral organ injury, particularly in the liver, remain poorly defined.

Emerging evidence suggests that metabolic dysfunction–associated steatohepatitis (MASH) increases both the risk and severity of ischemic stroke, likely by driving systemic inflammation and vascular dysfunction. Our project will create a new mouse model that combines MASH and stroke to directly study this liver–brain inflammatory axis. Using this platform, we will test how S100A8/A9 contributes to systemic-to-brain immune signaling and worsened injury, and we will evaluate ALT-100 (a humanized antibody targeting extracellular NAMPT/eNAMPT) as a first-in-class therapy designed to dampen both liver inflammation and stroke-related neuroinflammation by disrupting key damage-associated pathways (including TLR4-related signaling).

 

Intranasal Delivery of Telomerase Reverse Transcriptase mRNA for Therapy of Traumatic Brain Injury.

Traumatic brain injury (TBI) disrupts neural function in nearly three million Americans each year, causing cognitive deficits and, in severe cases, death. Emerging evidence links TBI to accelerated telomere attrition, shortening of the chromosomal end-caps that protect genomic integrity. We propose to develop an mRNA-based therapeutic strategy to lengthen telomeres in brain cells, to restore motor and cognitive function after TBI.

Vagus Nerve Stimulation and the Gut–Brain Axis in Stroke Rehabilitation

Stroke leaves many survivors with long-term disability, and while rehabilitation can improve function, recovery is often incomplete. Vagus nerve stimulation (VNS) can enhance neuroplasticity when paired with therapy, but implanted devices are costly and less accessible, making non-invasive transcutaneous auricular VNS (taVNS) an appealing alternative. Our team is running a randomized, double-blind clinical trial delivering taVNS during motor training (with a home-based phase) to test whether it can safely boost functional recovery.

In parallel, our project will uncover how VNS works at a systems level by testing whether it reshapes the gut microbiome and reduces inflammation along the gut–brain axis, and whether microbiome/immune signatures can predict who benefits most. We will integrate stool and blood profiling (long-read sequencing and methylation, metabolomics, flow cytometry) with detailed neurological and cognitive outcomes to build a multisystem model of VNS-mediated stroke recovery and inform more precise, personalized rehabilitation.

CRISPR–Lipid Nanoparticle therapy for traumatic brain injury

Spaceflight profoundly reshapes the gut microbiome, with downstream effects on cognition and immune competence. In our animal model, we anticipate dysbiosis, gastrointestinal inflammation, and neuroendocrine perturbations. We will test whether spaceflight-relevant radiation drives cognitive deficits via disruption of the microbiome and evaluate how systemic inflammation modulates neuroendocrine signaling along the gut–brain axis.