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<sup>+</sup> antibody-secreting cells are reduced in 5XFAD colons. This change corresponds with accumulating CXCR4<sup>+</sup> B cells and gut-specific IgA<sup>+</sup> 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<sup>+</sup> cells, rescue peripheral T<sub>reg</sub> 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.
Authors
- Birgit Schilling (ORCID: https://orcid.org/0000-0001-9907-2749)
- Benjamin D Ambrose
- Jenny Hong Yu Ng
- Fei Wu (ORCID: https://orcid.org/0000-0002-8353-7676)
- A Kifle
- Daniel A. Winer (ORCID: https://orcid.org/0000-0002-8702-0957)
- Carlos Galicia Aguirre (ORCID: https://orcid.org/0009-0002-9257-9576)
- Priya Makhijani
- Arthur Mortha (ORCID: https://orcid.org/0000-0003-2673-0485)
- Kenneth A. Wilson (ORCID: https://orcid.org/0000-0003-3227-9977)
- Lisa Ellerby (ORCID: https://orcid.org/0000-0002-9050-7977)
- Saad Khan (ORCID: https://orcid.org/0000-0003-4686-4923)
- Olga Lucía Agudelo Rojas (ORCID: https://orcid.org/0000-0001-5250-2801)
- Anand Rane (ORCID: https://orcid.org/0000-0001-5886-5291)
- Rohini Emani
- Chao Wang (ORCID: https://orcid.org/0000-0003-3084-6093)
- David Furman (ORCID: https://orcid.org/0000-0002-3654-9519)
- Huixun Du (ORCID: https://orcid.org/0000-0001-9739-6774)
- Shawn Winer
- Wei‐Chieh Mu (ORCID: https://orcid.org/0000-0003-2669-7312)
- Julie K. Andersen (ORCID: https://orcid.org/0000-0003-1324-4875)
- Max Manwaring-Mueller
- Nan Chen (ORCID: https://orcid.org/0009-0008-0494-9789)
- Taylor R. Valentino (ORCID: https://orcid.org/0000-0003-3953-1194)
- Christopher Tan
- Prasanna Vadhana Ashok Kumaar
Institutions
- Mount Sinai Hospital (CA)
- Sunnybrook Health Science Centre (CA)
- University Health Network (CA)
- Buck Institute for Research on Aging (US)
- University of Toronto (CA)
- Toronto Rehabilitation Institute (CA)
- Ontario Brain Institute (CA)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-30
- DOI
- https://doi.org/10.1016/j.celrep.2025.116109
- Citations
- 2
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- Buck Institute for Research on Aging
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute on Aging