Summary: Researchers examine the role gut bacteria plays in the development of neurological disorders. Using mouse models of multiple sclerosis, researchers found compounds generated from the breakdown of tryptophan can cross the blood-brain barrier and activate anti-inflammatory pathways that limit neurodegeneration. Activation of these pathway have also been linked to Alzheimer’s and brain cancers.
Source: Brigham and Women’s Hospital.
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 from Brigham and Women’s Hospital (BWH) 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. Their new publication defines a pathway that may help guide therapies for multiple sclerosis and other neurologic diseases.
“These findings provide a clear understanding of how the gut impacts central nervous system resident cells in the brain,” said corresponding author Francisco Quintana, PhD, 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.”
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.
Brigham 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.
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.
Activation of this same pathway has recently been linked to Alzheimer’s disease and glioblastoma. The Ann Romney Center for Neurologic Diseases, of which Quintana is a part, brings experts together to accelerate treatment for these diseases, as well as multiple sclerosis Parkinson’s disease and ALS (Lou Gehrig’s disease).
“It is likely the mechanisms we’ve uncovered are relevant for other neurologic diseases in addition to multiple sclerosis,” said Quintana. “These insights could guide us toward new therapies for MS and other diseases.”
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.
Funding: This work was supported by grants NS087867, ES02530, AI126880 and AI093903 from the National Institutes of Health; RSG-14-198-01-LIB from the American Cancer Society; RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society; a Collaborative Network Award from the International Progressive MS Alliance; an educational grant from Mallinkrodt Pharmaceuticals (A219074); fellowship from the German Research Foundation (DFG RO4866 1/1); the BMBF-funded competence network of multiple sclerosis (KKNMS); the Sobek-Stiftung; the DFG (SFB 992, SFB1140, SFB/TRR167, Reinhart-Koselleck-Grant); and the Ministry of Science, Research and the Arts, Baden-Wuerttemberg. The authors declare no competing financial interests.
Source: Haley Bridger – Brigham and Women’s Hospital
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Abstract for “Microglial control of astrocytes in response to microbial metabolites” by Veit Rothhammer, Davis M. Borucki, Emily C. Tjon, Maisa C. Takenaka, Chun-Cheih Chao, Alberto Ardura-Fabregat, Kalil Alves de Lima, Cristina Gutiérrez-Vázquez, Patrick Hewson, Ori Staszewski, Manon Blain, Luke Healy, Tradite Neziraj, Matilde Borio, Michael Wheeler, Loic Lionel Dragin, David A. Laplaud, Jack Antel, Jorge Ivan Alvarez, Marco Prinz & Francisco J. Quintana in Nature. Published May 16 2018.
Microglial control of astrocytes in response to microbial metabolites
Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1,2,3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of 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. 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. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.