The gut immune system is altered in mouse model of Alzheimer’s, providing a new target for therapeutics

(Press-News.org) The gut contains the largest collection of immune cells in the body. New research at the Buck Institute shows that some of those immune cells travel along the brain/gut axis in a mouse model of Alzheimer’s disease (AD) providing a potential new therapeutic pathway for the memory-robbing malady. The research, published in the August29, 2025 issue of Cell Reports, also shows that feeding the mice a high fiber diet reduces AD-related frailty, including tremor.

“This paper brings the gut immune system to the forefront of neurodegenerative disease pathology,” says Buck associate professor Daniel Winer, MD, an immunologist and co-senior author of the work. “Given its size and the cells’ ability to travel, it makes sense that those immune cells would have the ability to influence larger physiology.”  

Buck professor Julie Andersen, PhD, a neuroscientist and co-senior author adds, “As far as we know, this is the deepest investigation of the gut immune system in a model of neurodegenerative disease. We look forward to studying its impact in other diseases including Parkinson’s and multiple sclerosis.” 

The work was led by postdoctoral fellow Priya Makhijani, PhD, an immunologist who holds a joint appointment in the Winer and Andersen labs. She found that specific antibody-producing B cells, normally responsible for keeping the microbiome and the gut immune system in harmony, were reduced in the mice bred to develop AD. She also discovered that this cell type has a migratory signature; researchers found the gut-specific B cells and their migratory receptors in the brain and in its border region, the meningeal dura mater. “Remarkably, we found that these immune cells in the brain border which recognize bacteria living in the intestines were accumulating in the AD brain,” Makhijani says. 

Wanting to understand what was driving the loss of immune cells in the gut, Makhijani and team found that this gut immune cell receptor’s binding partner, a well-studied chemokine known for migration, was produced at higher levels in the glia, the inflammatory cells in the AD brain.  The migratory signature was also identified in human AD brains via data mining of previously conducted studies. Working with collaborators at the University Health Network, part of the University of Toronto, the team conducted blocking experiments in the axis using a small molecule drug, suggesting that a new long-range mechanism might be acting along the gut-brain axis. 

The benefits of a high fiber diet

Makhijani and team found that feeding the animals the anti-inflammatory pre-biotic fiber inulin restored balance in the gut of the AD mice.  “We found these migrating cells were replenished in the gut and that AD-related frailty, including the tremor trait, was reduced in the animals.”  Noting that inulin makes short chain fatty acids and other metabolites that concentrate in the gut and can also circulate systemically, she says the diet improved gut health and reduced chemokine signaling in the brain. “Again, this involved a bi-directional axis,” she says.

Winer notes that while the high fiber diet did not consistently reduce the levels of plaques in the mice’s brain, it did impact overall well-being. “We did an assay involving 31 metrics of aging in these mice. The diet definitely extended their healthspan, giving the animals a better quality of life,” he says, adding, “This project supports the ‘eat your fruits and vegetables’ advice that is featured in nearly every dietary recommendation.”   

The big picture

While the study provides a comprehensive characterization of gut immune system changes in a neurological disease, researchers say more work is needed to see if those changes are a response to brain alterations or whether they drive the disease itself. Winer says one possibility is that age-related insults might trigger AD-causing inflammation in the brain with chemokines signaling the gut immune system for help in dealing with the insult.  “In the beginning the process is likely protective, but over time the gut becomes compromised setting the stage for more dangerous types of bacteria to flourish which fuels inflammation throughout the body.”

Makhijani is eager to explore the potential of understanding and/or altering the gut microbiome in the context of disease.  “Maybe there is a microbiome that signals an increased risk of neurological disease. Perhaps we’ll be able to identify specific bacteria that set off immune system inflammation. What if we can inhibit the signaling chemokines early versus late in the disease process? Which would be protective for the whole system? This paper provides so many avenues for further exploration.”

Other Buck collaborators include Taylor R. Valentino, Max Manwaring-Mueller, Rohini Emani, Wei-Chieh Mu, Carlos Galicia Aguirre, Anand Rane, Kenneth A. Wilson, Alexander Kifle, Huixun Du, Fei Wu, Jenny Hong Yu Ng, Bejamin D. Ambrose, Prasanna Vadhana Ashok Kumaar, David Furman, Birgit Schilling, and Lisa M. Ellerby. Other coauthors include Christopher Ryan Tan, Saad Khan, Chao Wang, Arthur Mortha, and Olga L. Rojas, Department of Immunology, University of Toronto, Toronto Canada; Nan Chen, Division of Cellular & Molecular Biology, Toronto General Hospital Research Institute, Toronto, Canada and Shawn Winer, Department of Laboratory Medicine & Pathology, University of Toronto, Toronto, Canada.

 

Citation: Amyloid-B driven Alzheimer’s disease reshapes the colonic immune system in mice.

DOI: 10.1016/j.celrep.2025.116109.

Acknowledgments:
The work was funded by NIH grant 3RF! AG062280-01S1, NIA T32 AG000266, AG066591, PO1AG06659

COI disclosure: Daniel Winer is co-founder of Proprion Inc., a company that studies gut immune and related metabolite interventions for aging and related diseases.

About the Buck Institute for Research on Aging

At the Buck, we aim to end the threat of age-related diseases for this and future generations. We bring together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. Our goal is to increase human healthspan, or the healthy years of life. Located just north of San Francisco, we are globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Our success will ultimately change healthcare. Learn more at: https://buckinstitute.org

 

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