A study published this week in Nature sheds new light on the connection between the gut and the brain, untangling the complex interplay that allows the byproducts of microorganisms living in the gut to influence the progression of neurodegenerative diseases. Investigators have been using both animal models and human cells from patients to tease out the key players involved in the gut-brain connection as well as in the crosstalk between immune cells and brain cells.

The new research focuses on the influence of gut microbes on two types of cells that play a major role in the central nervous system: microglia and astrocytes. Microglia are an integral part of the body's immune system, responsible for scavenging the CNS and getting rid of plaques, damaged cells and other materials that need to be cleared. But microglia can also secrete compounds that induce neurotoxic properties on the star-shaped brain cells known as astrocytes. This damage is thought to contribute to many neurologic diseases, including multiple sclerosis.

Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14⁺ cells correlates with the multiple sclerosis lesion stage.

The researchers have previously explored the gut-brain connection to gain insights into multiple sclerosis. Although some studies have examined how byproducts from organisms living in the gut may promote inflammation in the brain, the current study is the first to report on how microbial products may act directly on microglia to prevent inflammation. The team reports that the byproducts that microbes produce when they break down dietary tryptophan - an amino acid found in turkey and other foods - may limit inflammation in the brain through their influence on microglia.

Authors show that metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. 

To conduct their study, the research team examined gut microbes and the influence of changes in diet in a mouse model of multiple sclerosis. They found that compounds resulting from the breakdown of tryptophan can cross the blood-brain barrier, activating an anti-inflammatory pathway that limits neurodegeneration. The researchers also studied human multiple sclerosis brain samples, finding evidence of the same pathway and players.

"It is likely the mechanisms we've uncovered are relevant for other neurologic diseases in addition to multiple sclerosis," said the seniroa uthor. "These insights could guide us toward new therapies for MS and other diseases."

https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=3018

https://www.nature.com/articles/s41586-018-0119-x