Linking multi-barrier permeability with cognitive dysfunction in Borrelia infection-associated chronic illness 2257467

Abstract Introduction Infection-Associated Chronic Illnesses (IACI), such as Post-Treatment Lyme Disease (PTLD), are a significant public health crisis. Despite antibiotic treatment, at least 10% of patients develop debilitating, long-term symptoms like severe cognitive dysfunction, or “brain fog”. Progress in understanding and treating IACI is hindered by a critical lack of objective, mechanism-based biomarkers for diagnosis and predicting disease course. The current diagnostic model, relying on symptom-based criteria, is often inadequate. Our central hypothesis is that a breakdown in the body’s barriers is a foundational mechanism in IACI that drives systemic inflammation and neurocognitive dysfunction. Methods We analyzed preliminary data from the MAESTRO study, assessing human PTLD patients across cognitive tasks involving processing speed and oculomotor control. We measured plasma biomarkers for neural injury, astrogliosis, and multi-barrier disruption. This was complemented by an animal model of Lyme disease in C3H mice. In the animal model, we used an Evan’s blue dye assay to visualize gut barrier permeability and observed mouse behavior. Results Individuals with PTLD demonstrated measurable cognitive deficits that co-occurred with elevated plasma levels of biomarkers for neural injury (NfL), astrogliosis (GFAP), and multi-barrier disruption (occludin, sCD14). This link was supported by our animal model, in which infected C3H mice showed severe gut barrier compromise. Additionally, infected mice displayed a profound “frozen,” immobile behavior, providing a compelling animal correlate for the functional decline and malaise experienced by human patients. Conclusion Our findings suggest that therapies aimed at restoring barrier function could have broad utility for patients. These approaches should be investigated for their potential impact on some of the most debilitating IACI symptoms, including impaired neurocognitive function. Funding Source Emily and Malcolm Fairbairn donor advised fund, Massachusetts life sciences, NIH NIAID RO1 AI 178713-01 Topic Categories Immune Mechanisms of Human Disease (HUM)