A research team from Brigham and Women’s Hospital has discovered an astrocyte sub-population that serves an anti-inflammatory function in the brain based on signals regulated by gut bacteria.
A research team from Brigham and Women’s Hospital has discovered an astrocyte sub-population that serves an anti-inflammatory function in the brain based on signals regulated by gut bacteria. These findings, according to the researchers, may offer implications for the development of future therapies targeting various neurological diseases.
“Over the years, many labs, including mine, have identified important roles for astrocytes in promoting neurological diseases,” said corresponding study author Francisco Quintana, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham, in a statement. “This is the first case in which we’re showing that at least a subset of these cells (astrocytes) can prevent inflammation. The reason we haven’t seen this before was because we were studying these cells as if they were uniform, or one single cell type. But now we have the resolution to see the differences between these cells.”
In the study, which was published in a recent edition of Nature, Dr. Quintana and research colleagues identified the novel astrocyte subset using a set of refined gene- and protein-analysis tools. They discovered the astrocyte population close the membrane that encloses the brain and found it expresses LAMP1, a protein, in addition to another protein which induces cell death called TRAIL. The proteins assist the astrocyte sub-population, LAMP1+TRAIL+, in limiting inflammation in the central nervous system (CNS) via cell death in T-cells responsible for inflammation.
A series of tests were performed by the researchers using CRISPR-Cas9, a gene-editing technology, to identify the underlying mechanisms controlling LAMP1+TRAIL+ astrocytes in the brain. Interferon-gamma, a signaling molecule, was found to regulate TRAIL expression, while bacteria residing in the gut was found to induce expression of interferon-gamma in cells that reach the meninges, subsequently promoting astrocyte anti-inflammatory activities.
According to the investigators, deeper understanding of the underlying mechanisms responsible for the anti-inflammatory benefits of LAMP1+TRAIL+ astrocytes could facilitate the development of treatment approaches for neurological diseases, such as multiple sclerosis. In a statement, the researchers say they are looking into probiotic candidates that may be able to regulate the anti-inflammatory activity of the astrocytes.
Also, recent data from the study team suggests that certain brain tumors may exploit the newly discovered pathway to avoid the body’s normal immune response. Based on these data, the researchers are exploring the development of cancer immunotherapies to combat brain tumor attacks.
“Finding microbiome-controlled anti-inflammatory subsets of astrocytes is an important advance in our understanding of CNS inflammation and its regulation,” said Dr. Quintana. “This is a very novel mechanism by which the gut controls inflammation in the brain. It guides new therapies for neurological diseases, and we believe that this mechanism could contribute to the pathogenesis of brain tumors.”
Dr. Quintana added that his lab discovered the only other astrocyte subset known to be regulated by gut bacteria back in 2016, but the new study suggests there are likely others yet to be found. “It’s becoming clear that the gut flora are important in many diseases,” he said. “We’re lucky that we’ve been leading the charge to identify different subsets of astrocytes and the mechanisms that control them. We have a list of other populations of astrocytes, and we’re working to see how the gut flora may control them.”
The announcement of the findings from this study follows similar news of a study from Monash University, which identified specific molecules in the gut microbiome that may protect against asthma and certain aspects of COVID-19. These and other findings implicate the role of the gut microbiome in a series of diseases; many drug manufacturers are reaching to meet the demand for human microbiome products and research, but experts suggest a lack of uncertainty on the products’ efficacy may slow field growth.
