Amyloid-β-driven Alzheimer's disease reshapes the colonic immune system in mice.

Abstract

The "gut-brain axis" is an emerging target in Alzheimer's disease (AD), although its immunological features remain poorly understood. Using single-cell RNA sequencing, coupled to extensive spectral-tuning flow cytometry validation of the colon immune compartment in the 5XFAD amyloid-β mouse model, we found several AD-associated changes including in B/plasma cell activity. Notably, levels of CXCR4antibody-secreting cells are reduced in 5XFAD colons. This change corresponds with accumulating CXCR4B cells and gut-specific IgAcells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, is expressed at higher levels in the 5XFAD brain and in in silico-analyzed human AD brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet could expand gut IgAcells, rescue peripheral Tlevels, reduce dysbiosis, improve serum microbial metabolite levels, and attenuate overall AD-associated frailty. Our study reveals key aspects of the gut-brain axis and highlights potential targets against AD.