Predicting neurodegenerative disease using the unique gut microbiota composition of transgenic mice modeling amyloid‐β plaques and neurofibrillary tangles

Abstract

BackgroundThe gut microbiota, the aggregates of microbial cells that inhabit the gastrointestinal tract, communicates bidirectionally with the brain via immune, neural, metabolic, and endocrine pathways, known as the gut‐brain axis. The gut‐brain axis is suspected to contribute to the development of Alzheimer’s disease (AD). We hypothesize that altered gut microbiota composition contributes to the development of AD pathologies and neuroinflammation via the gut‐brain axis.MethodTo characterize the gut microbiota of 3xTg‐AD mice modeling plaque deposition and hyperphosphorylated tau, fecal samples were collected fortnightly from 4 to 52 weeks of age (n=57 3xTg‐AD mice, n=31 wild‐type). The V4 region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. Targeted reverse transcription qPCR assays were used to assess inflammation in the hippocampus and colon at 8, 24, and 52 weeks of age. Fold change was calculated using ΔΔCt.ResultOur results show altered microbial communities in 3xTg‐AD mice when compared to wild‐type [(PERMANOVA (8 weeks, p=0.001), (24 weeks, p=0.039), (52 weeks, p=0.058)]. Using q2‐longitudinal, we identified a temporal increase in Bacteroides acidifaciens and Turicibacter spp. in 3xTg‐AD mice (r‐squared = 0.658615). Using Random Forest, we successfully predicted strain in 3xTg‐AD mice 100% of the time, and in WT mice 92.85% of the time, improving accuracy over baseline assignment by 1.3 fold. Colonic expression of GFAP was increased at 24 week 3xTg‐AD mice compared to 52 week 3xTg‐AD mice (p=0.009, Mann‐Whitney). Colonic gene expression of IL‐6 was increased in 52 week 3xTg‐AD mice compared to 52 week WT mice (p=0.015, Mann‐Whitney). Hippocampal expression of GFAP was increased at 52 week 3xTg‐AD mice compared to 52 week WT (p=0.049, Mann‐Whitney). Finally, hippocampal expression of Mrc1 was elevated at 24 weeks in 3xTg‐AD mice compared to 52 weeks (p= 0.004, Mann‐Whitney).ConclusionWe have identified changes in the gut microbiota and immune response that may be predictive of the development of AD pathologies. Future shallow shotgun metagenomics sequencing will assess strain‐level features and functions of the gut microbiota in AD.