Interestingly, the gut microbiome has emerged as a regulator of microglial function. The Holtzman group has shown that this microglial regulation not only coincides with tau-induced brain cell death, but it is, in fact, required for tau to cause neurodegeneration. These findings suggest that targeting the gut microbiota to alter microglial behavior may be a novel therapeutic strategy for Alzheimer’s disease (AD).
During the first Microbiome consortium funding cycle, the Holtzman team disrupted the gut microbiome of older mice to replicate the gut changes associated with AD that occur later in life. They observed reduced brain volume and increased inflammation, suggesting that a loss of the gut microbiome later in life may exacerbate tau-related neurodegeneration.
In this study, Dr. Holtzman’s team will test the hypothesis that the worsened tau pathology observed in the previous experiment stems from metabolic changes caused by disruption of the gut microbiome. When gut microbes break down food, they produce various byproducts, called metabolites, that can influence how the body functions. When Holtzman’s lab disrupted the microbiome of older mice, they found that metabolites from the breakdown of tryptophan—an essential amino acid involved in immune function—decreased. Their next step is to determine whether tryptophan-derived metabolites can provide neuroprotective benefits in mouse models of tau pathology. Additionally, they will continue to investigate how human microbiome samples influence tau progression in mice. As part of this, they will explore how different gut bacterial communities, called enterotypes, influence these effects. They will also explore the influence of diet on gut microbiome composition and tau progression, similar to experiments conducted by the Cox lab, which focused on amyloid pathology.
