Title of project

Breaking Barriers: Decoding the Gut-Brain Axis in Obesity-Linked Neurodegeneration

Abstract

Emerging evidence suggests that metabolic dysregulation is associated with neurodegenerative processes; however, the underlying mechanisms remain unclear. This project will investigate whether barrier disruptions along the gut-liver-brain axis and microbial translocation contribute to this association. Under normal conditions, the intestinal barrier prevents luminal microbes and their components from entering the circulation. Diets high in fat and sugar, major drivers of the obesity pandemic, impair this barrier, and notably, lipopolysaccharide (LPS) is detected in the blood of obese, diabetic, and Alzheimer’s disease (AD) patients.

We hypothesize that diet-induced obesity compromises the intestinal barrier, allowing microbial components to transverse the gut barrier, reaching the liver via the portal vein and, ultimately, the brain. This may disrupt the blood-brain barrier (BBB), triggering neuroinflammation and neurodegeneration, thereby contributing to AD pathogenesis.

To explore this, we will use a customized, translational diet-induced obesity mouse model based on a fast food miciking diet (FFMD) that exacerbates liver pathology and impairs glucose homeostasis. Barrier integrity will be assessed using advanced imaging and molecular analyses, while behavioral testing will evaluate functional outcomes relevant to AD-pathogenesis. Microbial translocation will be examined through circulating measurements, tissue staining, cultivation, and sequencing approaches, and causality will be addressed using microbiota modulation. Human samples will be used to translate preclinical findings to clinical relevance.

This project integrates national and international expertise and includes collaborators at Danish hospitals. By elucidating the mechanisms linking obesity and type 2 diabetes (T2D) to neurodegeneration, we aim to uncover early biomarkers and therapeutic targets for prevention, early diagnosis, and treatment of AD in metabolically at-risk individuals.