Influence of fecal microbiota transplantation on gut microbiota composition and neuroinflammation of 3xTg-AD mice.

Abstract

The gut microbiota, the aggregate of all microbial cells that inhabit the gut, bidirectionally communicates with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites via the gut-brain axis. The gut microbiota is thought to contribute to the development of Alzheimer's disease (AD), characterized by plaque deposition, neurofibrillary tangles, and neuroinflammation. We hypothesize that manipulation of the gut microbiota can alter development of AD pathologies and neuroinflammation via the gut microbiota-brain axis. To further elucidate the role of the gut-brain axis in AD, we performed fecal microbiota transplants (FMT) from aged (52-64 weeks) 3xTg-AD mice, modeling plaques and neurofibrillary tangles, to young 3xTg-AD (n=5) or wild-type mice (n=10). Phosphate buffered saline (PBS) was gavaged into 3xTg-AD (n=5) and wild-type mice (n=10) as a control. For FMT, a fecal slurry from aged 3xTg-AD mice was prepared and given to experimental mice via oral gavage. 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. Our results show a shift in microbiome composition in FMT-treated mice when compared to control (PBS-treated) mice. Bacteroides were increased in 3xTg-AD and wild-type mice receiving FMT. At 24 weeks of age, there was no difference in neuroinflammation between mice treated with FMT compared to control (PBS) in 3xTg-AD or wild type mice. We observed partial engraftment of the gut microbiota from aged 3xTg-AD mice in all FMT-treated mice. We demonstrate the ability to transplant an aged gut microbiome into young mice, however we did not observe changes in neuroinflammation at 24 weeks of age. Future studies will evaluate neuroinflammation and neuropathologies at later time points. These studies will contribute to our understanding of how features of the gut microbiota may contribute to AD development.