Dense, longitudinal sampling reveals key gut microbial communities associated with Alzheimer’s disease pathologies

Borsom, Emily Modrich (2022) Dense, longitudinal sampling reveals key gut microbial communities associated with Alzheimer’s disease pathologies. Doctoral thesis, Northern Arizona University.

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Abstract

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 as the gut-brain axis. The gut-brain axis is suspected to contribute to the development of Alzheimer’s disease (AD). We hypothesize that specific gut microbiota compositions contribute to the development of AD pathologies and neuroinflammation via the gut-brain axis. To 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, the V4 region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. We have identified changes in the gut microbiota and immune response that may be predictive of the development of AD pathologies. To explore the effect of modulation of the gut microbiota in mice modeling AD pathologies, we 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) with the sequencing methods described above. We observed a shift in microbiota composition of FMT-treated mice when compared to control (PBS-treated) mice with no effect on neuroinflammation. To investigate the gut microbiota composition with high resolution taxonomic assignments and include fungi, viruses, and other eukaryotic microbes, shallow shotgun metagenomic sequencing (SSMS) was run on select samples from the initial longitudinal and subsequent FMT study. Bacteroides, Lactobacillus, and Turicibacter, identified in the studies using 16S rRNA gene sequencing, were classified at species and strain level using SSMS. Finally, a meta-analysis of the gut microbiota composition in WT mice bred at NAU compared to WT mice bred at Jackson Laboratories using our available 16S rRNA gene sequencing data was performed. Beta diversity metrics reveal mice bred at Jackson Laboratories had an adjustment period of about 6 months, before more closely resembling mice bred at NAU. Taken together, our work shows that 3xTg-AD mice harbor a unique gut microbiota composition, associated with disease pathologies, early in life, that becomes more similar to WT mice by 52 weeks of age. The microbial communities associated with later stages of modeling AD pathologies are more transferrable to other 3xTg-AD mice than WT mice, but do not alter neuroinflammation. Finally, SSMS revealed the species and strain level classification of the microbial communities of interest from the 16S rRNA gene sequencing data. Future studies investigating the role of Bacteroides fragilis, Turicibacter H121, Lactobacillus murinis, and Lactobacillus animalis in the gut microbiome of 3xTg-AD mice are warranted to uncover potential therapeutic targets in the gut microbiota-brain axis for AD.

Item Type:	Thesis (Doctoral)
Publisher’s Statement:	© Copyright is held by the author. Digital access to this material is made possible by the Cline Library, Northern Arizona University. Further transmission, reproduction or presentation of protected items is prohibited except with permission of the author.
Keywords:	Alzheimer's disease; amyloid-beta; gut microbiome; gut microbiota; metagenomics; microglia
Subjects:	R Medicine > RC Internal medicine
MeSH Subjects:	C Diseases > C10 Nervous System Diseases
NAU Depositing Author Academic Status:	Student
Department/Unit:	Graduate College > Theses and Dissertations College of the Environment, Forestry, and Natural Sciences > Biological Sciences
Date Deposited:	08 Jun 2023 15:58
Last Modified:	04 Jan 2024 08:30
URI:	https://openknowledge.nau.edu/id/eprint/5987

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