Age-dependent effects of gut microbiota metabolites on brain resident macrophages

In recent years, development of age-related diseases, such as Alzheimer's and Parkinson's disease, as well as other brain disorders, including anxiety, depression, and schizophrenia have been shown to be associated with changes in the gut microbiome. Several factors can induce an alteration in the bacterial composition of the host‘s gastrointestinal tract. Besides dietary changes and frequent use of antibiotics, the microbiome is also profoundly affected by aging. Levels of microbiota-derived metabolites are elevated in older individuals with age-associated diseases and cognitive defects compared to younger, healthy age groups. The identified metabolites with higher concentration in aged hosts, which include choline and trimethylamine, are known risk factors for age-related diseases. While the underlying mechanisms and pathways remain elusive for the most part, it has been shown, that these metabolites are able to trigger the innate immunity in the central nervous system by influencing development and activation status of brain-resident macrophages. The macrophages residing in the brain comprise parenchymal microglia and non-parenchymal macrophages located in the perivascular spaces, meninges, and the choroid plexus. In this review, we highlight the impact of age on the composition of the microbiome and microbiota-derived metabolites and their influence on age-associated diseases caused by dysfunctional brain-resident macrophages.