Alterations to gut microbiota in mice lacking C5aR1 in Alzheimer’s mouse model do not account for protective effects in disease progression.

• Published in: Alzheimer's & Dementia
• Main Authors: Petrisko, Tiffany J, Chu, Shu‐Hui, Selvan, Purnika, Tenner, Andrea J
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2022
• Subjects: Arctic; Hernandez
• Online Access: http://dx.doi.org/10.1002/alz.065826; https://onlinelibrary.wiley.com/doi/pdf/10.1002/alz.065826

Abstract Background The complement (C’) system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies demonstrated that genetic ablation of downstream receptor C5aR1 provides protection from cognitive decline in AD animal models. C’ activation and associated cell‐signaling may influence the composition of the gut microbiome, modulating systemic inflammation, and ultimately inducing behavioral and cognitive changes. The objective of this study was to determine if deletion of C5aR1 (C5aR1KO) alters the fecal microbiome in the Arctic (Arc) model of AD which could contribute to the previously observed protection from cognitive decline (Hernandez et al., 2017). Method As the coprophagic nature of mice results in microbiome synchronization between cohoused mice, we sought to determine the impact on the microbiome when WT/Arc C5aR1KO and WT/Arc C5aR1‐sufficient (C5aR1+/+) animals were housed separately or together. Fecal samples were collected at 10 mo and subjected to microbial focused Illumina sequencing. Taxonomy was assigned using RDP18 followed by downstream analysis in R. Result When housed separately, WT C5aR1KO animals had a significantly reduced alpha‐diversity (ie. reduced number of species within their microbiome) compared to WT C5aR1+/+ mice, with a trending decrease observed in Arc C5aR1KO mice compared to Arc controls. Beta‐diversity indicated significant variation in species between the genotypes. Further analysis revealed alterations in the serotonin modulating bacteria. C5aR1+/+ mice had increased levels of Alistipes (serotonin‐increasing) compared to both WT and Arc C5aR1KO mice, while WT C5aR1KO had elevated levels of Turicibacter (serotonin‐decreasing) compared to WT and Arc C5aR1+/+ animals. In contrast, when cohoused, no difference in alpha‐ or beta‐ diversity, nor Alistipes and Turicibacter were observed. Conclusion While deletion of C5aR1 can influence the fecal microbiome these effects are overcome when C5aR1KO and C5aR1+/+ mice are cohoused. In ...