The “microbiome-gut-brain axis” in Alzheimer's disease and its role in neurocognitive decline

Alzheimer’s disease (AD) is a progressive neurocognitive disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation as well as immunosenescence and inflamm-aging seen in AD. Our own research has demonstrated a decreased abundance of anti-inflammatory taxa and an increased abundance of pro-inflammatory taxa in the gut microbiome of AD patients. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in serum, blood cytokine profiling, and cognitive assessments of AD older adults at 90-day intervals. In our early data collected from this ongoing study we have observed changes in B-cell populations with an increased abundance of class-switched B-cells in older adults with greater levels of cognitive impairment. We have further demonstrated that colonization of mice with the microbiome of AD older adults promotes B-cell class-switching when compared with cognitively impaired older adults without AD. Additionally, we have discovered a loss of phytoestrogen-metabolizing bacteria such as Adlercreutzia equolifaciens among AD older adults with rapidly progressing dementia. Phytoestrogens have been previously identified in protecting the intestinal epithelium from oxidative stress and epithelial permeability. Our preliminary studies have suggested that that the phytoestrogen (s)-equol, produced by A. equolifaciens, confers resistance to epithelial damage in the setting of bacterial lipopolysaccharide. Thus, we hypothesize that Adlercreutzia equolifaciens and similar phytoestrogen-metabolizing bacteria maintain epithelial homeostasis in the setting of inflammation while a gain of pro-inflammatory taxa in AD leads to intestinal barrier disruption, increased antigen presentation, immune cell dysregulation, and ultimately cognitive decline. This continuing work aims to further establish the connection between AD related neurocognitive decline, the microbiome, and immune system. This research was funded by grant numbers R01DK125407, R01AG067483, and 5T32A1007349-31 from the National Institutes of Health This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.