Influence of fecal microbiota transplantation on gut microbiota composition in transgenic mice modeling amyloid‐β plaques and neurofibrillary tangles

Abstract

BackgroundThe gut microbiota, the aggregates of all microbial cells that inhabit the gut, bidirectionally communicates with the brain through cytokines, hormones, metabolites, and neurotransmitters via the gut microbiota‐brain axis. The gut microbiota is thought to contribute to the development of Alzheimer’s disease (AD), which is characterized by plaque deposition, neurofibrillary tangles, and neuroinflammation. We hypothesize that manipulation of the gut microbiota will alter development of AD pathologies and neuroinflammation via the gut microbiota‐brain axis.MethodWe performed fecal microbiota transplants (FMT) from aged (52‐64 weeks) 3xTg‐AD mice, which are modeling plaques and neurofibrillary tangles, to young 3xTg‐AD (n=5) or wild‐type mice (n=10) via oral gavage. Phosphate buffered saline (PBS) was gavaged into 3xTg‐AD (n=5) and wild‐type mice (n=10) as a control. At 8 weeks, mice were gavaged with FMT or PBS for 5 consecutive days, followed by fortnightly maintenance transplants for 24 weeks. The V4 region of the 16S rRNA gene was sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. Reverse transcriptase qPCR was used to assess microgliosis, astrocytosis, and Th1/Th2 inflammation in the hippocampus of the FMT cohort at 24 weeks of age.ResultWe observed a shift in microbiota composition of FMT‐treated mice when compared to control (PBS‐treated) mice. Bacteroides acidifaciens was increased in 3xTg‐AD and wild‐type mice receiving FMT. We demonstrate partial engraftment of the gut microbiota from aged 3xTg‐AD mice in all FMT‐treated mice, demonstrated by a Random Forest model, which correctly predicts treatment groups based on gut microbiota composition (Accuracy Ratio over baseline assignment: 2.6).ConclusionWe demonstrate the ability to transplant an aged gut microbiome into young mice. Future shallow shotgun metagenomic sequencing will be used to determine the species‐ and strains‐ that engraft in the GI tract. Additionally, targeted reverse transcription RT‐qPCR and immunostaining for plaques and hyperphosphorylated tau in the hippocampus will be used to assess how FMTs alter AD pathologies. These studies will contribute to our understanding of how features of the gut microbiota may contribute to AD development.