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

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 CXCR4⁺ antibody-secreting cells are reduced in 5XFAD colons. This change corresponds with accumulating CXCR4⁺ B cells and gut-specific IgA⁺ cells 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 IgA⁺ cells, rescue peripheral T_reg levels, 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.