The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17
Sidhanth Chandra, … , Sangram S. Sisodia, Robert Vassar
Sidhanth Chandra, … , Sangram S. Sisodia, Robert Vassar
Published May 13, 2025
Citation Information: J Clin Invest. 2025;135(13):e180826. https://doi.org/10.1172/JCI180826.
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Research Article Immunology Microbiology Neuroscience

The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17

Abstract

Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer’s disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in a male APPPS1-21 AD mouse model. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (ABX) and identified a significant increase in plasma propionate, a gut-derived short-chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the ABX-induced phenotype. Astrocyte-specific RNA-Seq on ABX- and propionate-treated mice showed reduced expression of proinflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments, in which we found that ABX and propionate decreased peripheral RAR-related orphan receptor-γ+ (Rorγt+) CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Last, using an IL-17 mAb to deplete IL-17, we found that propionate reduced reactive astrocytosis and Aβ plaques in an IL-17–dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for the treatment of AD.

Authors

Sidhanth Chandra, Jelena Popovic, Naveen K. Singhal, Elyse A. Watkins, Hemraj B. Dodiya, Ian Q. Weigle, Miranda A. Salvo, Abhirami Ramakrishnan, Zhangying Chen, Thomas Watson, Aashutosh Shetti, Natalie Piehl, Xiaoqiong Zhang, Leah Cuddy, Katherine R. Sadleir, Steven J. Schwulst, Murali Prakriya, David Gate, Sangram S. Sisodia, Robert Vassar

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Figure 1

ABX-mediated GBM perturbation reduces GFAP+ astrocytes and Aβ plaques in the cortex of APPPS1-21 male mice.

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ABX-mediated GBM perturbation reduces GFAP+ astrocytes and Aβ plaques in...
(A) Schematic depicting the experimental paradigm. (B) Representative images of whole brain sections (original magnification, ×10) and high-magnification images of cortex (original magnification, ×40) stained for GFAP+ astrocytes and Aβ plaques in APPPS1-21 male mice treated with ABX or VHL control. Quantification of the cortical (C) GFAP+ astrocyte percentage area and (D) the Aβ plaque percentage area in VHL- and ABX-treated APPPS1-21 mice. (E) Pearson’s correlation analysis between GFAP+ astrocyte percentage area and Aβ plaque percentage area in VHL- and ABX-treated APPPS1-21 mice. Data are expressed as the mean ± SD. n = 11/group. Statistics were calculated using a 2-tailed, unpaired Student’s t test. n = 4 sections per animal. *P ≤ 0.05 and **P ≤ 0.01. Scale bars: 1,000 μm (×10 images) and 100 μm (×40 images). Dotted lines indicate the analyzed area of the cortex.