The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17
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
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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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 6

ABX and propionate treatments reduce peripheral Th17 cells and IL-17 levels, which correlate positively with GFAP+ reactive astrocytosis in APPPS1-21 mice.

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ABX and propionate treatments reduce peripheral Th17 cells and IL-17 lev...
(A) Schematic depicting the experimental paradigm for ABX-treated APPPS1-21 male mice. (B) Th17 cell percentages by flow cytometry in LILN, SILN, and spleen in VHL- and ABX-treated APPPS1-21 mice. (C) IL-17 levels in the media of CD3/CD28 bead–restimulated T cells derived from the LILN, SILN, and spleen from VHL- and ABX-treated APPPS1-21 mice. (D) Schematic depicting the experimental paradigm for propionate-treated APPPS1-21 and NTG male mice. (E) Representative flow cytometry plot depicting a reduction in Th17 cells in the plasma of propionate-treated APPPS1-21 mice. Quantification of Th17 cell percentages by flow cytometry in the plasma of VHL- and propionate-treated (F) APPPS1-21 and (G) NTG mice. Quantification of IL-17 levels via ELISA in the large intestine of VHL- and ABX-treated (H) APPPS1-21 and (I) NTG mice. Quantification of IL-17 levels was done via ELISA in the plasma of VHL- and ABX-treated (J) APPPS1-21 and (K) NTG mice. (L) Pearson’s correlation analysis between LILN Th17 cells and LI IL-17 levels in VHL- and ABX-treated APPPS1-21 mice. (M) Pearson’s correlation analysis between plasma IL-17 and LI IL-17 levels in VHL- and ABX-treated APPPS1-21 mice. Quantification of IL-17 levels was done via ELISA in the large intestine of VHL- and propionate-treated (N) APPPS1-21 and (O) NTG mice. Pearson’s correlation analysis between GFAP+ astrocyte percentage area and LI IL-17 levels in (P) VHL- and ABX-treated APPPS1-21 mice and (Q) VHL- and propionate-treated APPPS1-21 mice. Data are expressed as the mean ± SD. n = 5–14/group. *P ≤ 0.05, by 2-tailed, unpaired Student’s t test. Males are denoted by triangles and females by circles.