The Gut Microbiome Produces Metabolites that Affect Immune Cells in the Brain

Researchers here review the evidence for metabolites produced by the gut microbiome to influence the behavior of innate immune cells in the brain. The gut microbiome changes in composition with age, altering the production of metabolites and inflammatory signaling in ways that degrade tissue function throughout the body. Fixing the many resulting issues at the source by introducing a youthful mix of microbes to the aging gut is a tempting path forward, likely relatively straightforward to achieve via fecal microbiota transplantation from young individuals to old individuals. This short-cut would hopefully evade the onerous requirement to fully understand how exactly harms to the brain result from the aging of the gut microbiome, and thus improve late life health in the near term rather than requiring many more years of research.

There is now increasing evidence that metabolites produced in the gut can enter the brain and impact brain macrophages. The macrophages residing in the brain comprise parenchymal microglia and non-parenchymal macrophages located in the perivascular spaces, meninges, and the choroid plexus. It is important to better understand the underlying mechanisms of age-related dysbiosis, which causes changes in gut-derived metabolites and ultimately influence the central nervous system, as well as immune and endocrine responses of the host.

Several studies have found that microbial metabolites can affect gut-brain responses, affecting the morphology and function of brain macrophages. These changes include their polarization and phagocytic capacity, which, in turn, controls behavior and emotional processes. 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. 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.


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