Bacteroides fragilis modulates gut microbiome community composition, frontal cortex gene expression, and fecal and frontal cortex metabolites in a mouse model of Alzheimers disease pathologies

Abstract

Alzheimers disease (AD) is a neurodegenerative disease and the leading cause of dementia among elderly. Gut microbiome alterations precede pathogenesis and may affect disease outcomes. We evaluated the role of Bacteroides fragilis in triple transgenic mice modeling AD pathologies (3xTg-AD) and wild-type controls (WT). Subsets of 3xTg-AD and WT mice were longitudinally treated with B. fragilis or sterile vehicle control for five consecutive days at 8 weeks of age and then monthly up to 52-56 weeks. Fecal samples were collected fortnightly from 8 through 52-56 weeks of age. Mice were sacrificed at 8 (baseline), 24 (amyloid-{beta} plaques modeled), and 52-56 (amyloid-{beta} plaques and neurofibrillary tangles modeled) weeks of age. Expression of genes involved in neuroinflammation and neurotransmission were quantified using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Fecal bacterial microbiota were assessed by sequencing the V4 region of the 16S rRNA gene, and microbiome sequence data were analyzed using QIIME 2. Frontal cortex and fecal metabolomes were evaluated using LC-MS/MS. We observed that B. fragilis colonized the gut microbiota of 3xTg-AD mice earlier and more consistently than WT mice. 3xTg-AD mice treated with B. fragilis demonstrate lower gene expression of GFAP, SLC1A3, and FOXO3 in the frontal cortex. Consistent with this finding, treatment with B. fragilis restores levels of amino acid derivatives and neurotransmitters in 3xTg-AD mice to resemble levels in WT mice. These results highlight the role of the gut microbiome in AD-associated neuroinflammation and neurotransmission and the need for future studies to elucidate the mechanisms underlying these changes. ImportancePrevious studies in animals modeling Alzheimers disease pathologies and humans living with Alzheimers disease demonstrate shifts in the gut microbial community composition prior to and concomitant with pathological onset. The bacterial genus, Bacteroides, is commonly found differentially abundant in these studies but its effects on disease outcomes are poorly understood. In this study, we explore the effects of chronic exposure to Bacteroides fragilis in triple transgenic mice modeling Alzheimers disease pathologies and healthy, wild-type controls. We observed changes in microbial community composition in mice modeling Alzheimers disease when treated with B. fragilis, and associated changes in neuroinflammation, biomarkers of neurotransmission, and the brain metabolome. Taken together, these results suggest that Bacteroides fragilis exerts neuromodulatory effects that may be beneficial in Alzheimers disease.