A longitudinal study of the unique gut microbiota of 3xTg-AD mice modeling key AD pathologies.

Abstract

The collective microbes and their genomes that inhabit the gastrointestinal tract, known as the gut microbiome, contribute to a myriad of host functions including digestion, vitamin synthesis, and immune function. Individuals differ widely in the composition of their gut microbiome. This can be attributed to the effects of environment, genetics, and diet. The gut microbiota, the aggregate of microbial cells that inhabit the gastrointestinal tract, communicates bidirectionally with the brain via immune, neural, metabolic, and endocrine pathways, known collectively as the gut-brain axis. The gut-brain axis is suspected to contribute to the development of Alzheimer's disease (AD), characterized by plaque deposition, neurofibrillary tangles, and neuroinflammation. We hypothesize that altered gut microbiota composition contributes to the development of AD pathologies and neuroinflammation via the gut-brain axis. To elucidate the role of the gut-brain axis in AD, we characterized the gut microbiota of triple transgenic (3xTg-AD) mice that model plaque deposition and neurofibrillary tangles. Fecal samples were collected fortnightly from 4 to 52 weeks of age (n=57 3xTg-AD mice, n=71 wild-type). DNA was extracted, the V4 region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq. Taxonomic profiling, and alpha- and beta-diversity were analyzed using QIIME 2. A custom reverse transcription qPCR assay will be used to assess microgliosis, astrogliosis, and Th1/Th2 inflammation in the hippocampus and colon at 8, 24, and 52 weeks of age. Our results show altered microbial communities in 3xTg-AD mice when compared to wild-type (p=0.001, pairwise PERMANOVA at 4, 24, and 50 weeks). Alpha diversity decreased in 3xTg-AD compared to their wild-type strains at each timepoint [(4 weeks(p=0.00083), 24 weeks (p=0.0131), and 50 weeks (p=0.0037), Kuskal Wallis)]. Using q2-longitudinal, we determined Bacteroides and Turicibacter relative abundance increased over time while Lactobacillus abundance did not significantly change over time in 3xTg-AD mice. We have identified changes in the gut microbiota that may be predictive of the development of AD pathologies. Future studies using a multi-omic approach will assess strain-level features and functions of the gut microbiota in AD.