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

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.