Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis, and reactive microglia in a dose- and sex-specific manner

肠道菌群 失调 小胶质细胞 淀粉样变性 微生物群 生物 基因组 淀粉样蛋白(真菌学) 生理学 免疫学 内分泌学 内科学 遗传学 医学 炎症 基因 植物
作者
Megan E. Bosch,Hemraj B. Dodiya,Julia Michalkiewicz,Choonghee Lee,Shabana Mehtab,Ian Q. Weigle,Can Zhang,John Osborn,Aishwarya Nambiar,Priyam Patel,Samira Parhizkar,Xiaoqiong Zhang,Marie L. Laury,Prasenjit Mondal,Ashley Gomm,Matthew J. Schipma,Oleg Butovsky,Dania Mallah,Eugene B. Chang,Rudolph R Tanzi,Jack A. Gilbert,Sangram S. Sisodia,David M. Holtzman
出处
期刊:Research Square - Research Square
标识
DOI:10.21203/rs.3.rs-3394003/v1
摘要

Abstract It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in mouse models. METHODS: To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. Initially, male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8 to 12 weeks of age. Additionally, to corroborate existing published studies and further investigate sex-related differences, 5XFAD male and female mice were treated daily with 100mg/kg of GV-971 from 7 to 9 months of age. Subsequently, the studies assessed amyloid-β accumulation, metagenomic analysis, metabolic analysis, and neuroinflammatory profiles. RESULTS: These studies showed that cerebral amyloidosis was reduced dose-dependently only in males in both the APPPS1-21 and 5XFAD mice across independent investigations. We observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered similar bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses. CONCLUSIONS : In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer’s disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner.
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