Neurological disorders such as multiple sclerosis may be worsened by proinflammatory astrocyte neurotoxins, which may be more plentiful if astrocytes are exposed to certain microglia secretions, which may be promoted—or limited—by metabolites produced by gut microbes. This chain of events, which was uncovered by scientists based at Brigham and Women’s Hospital (BMH), contains links that could be weakened or reinforced. Perhaps the most intriguing link is near the start of the chain. This link, which consists of gut microbes capable of releasing inflammation-limiting metabolites, could lead to new therapies for multiple sclerosis and other neurological disorders.
The BWH team recently reported that it has identified “positive and negative regulators that mediate the microglial control of astrocytes.” Details appeared May 16 in the journal Nature, in an article entitled “Microglial Control of Astrocytes in Response to Microbial Metabolites.”
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 (CNS): 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.
BWH 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.
“TGFα [transforming growth factor-α] and VEGF-B [vascular endothelial growth factor B] produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis,” wrote the authors of the Nature article. “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.”
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.
“Expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage,” the article’s authors added. “Finally, 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.”
“These findings provide a clear understanding of how the gut impacts CNS resident cells in the brain,” explained the article’s corresponding author Francisco Quintana, Ph.D., of the Ann Romney Center for Neurologic Diseases at BWH. “Now that we have an idea of the players involved, we can begin to go after them to develop new therapies.”
“It is likely the mechanisms we've uncovered are relevant for other neurologic diseases in addition to multiple sclerosis,” Dr. Quintana added. “These insights could guide us toward new therapies for MS and other diseases.”
Dr. Quintana and his colleagues plan to further study the connections to neurologic diseases, and are also optimizing small molecules as well as probiotics to identify additional elements that participate in the pathway and new therapies.