Investigating the gut-brain axis: immunological consequences of brain disease
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
Diseases of the central nervous system (CNS), including acute events (e.g. stroke) and chronic neurodegenerative diseases (e.g. Alzheimer's disease), represent a significant healthcare burden and leading cause of mortality worldwide. Many diseases of the CNS were historically considered distinct from those caused by infection or immune dysfunction. However, recent advances have highlighted a key role for inflammation in the pathology and progression of brain diseases. While local inflammation mediated by microglia and invading inflammatory immune cells are now appreciated to contribute to disease pathogenesis in the brain, an increasing body of evidence has begun to implicate signals from peripheral organs, in particular the intestine, as important determinants of brain disease severity.
The intestine has been termed "the second brain" due to the high density of nerves that line the gut. The intestine contains a plethora of immune cells and hosts trillions of commensal bacteria, which produce metabolites with the ability to modulate disease pathogenesis in a wide range of peripheral organs - including the brain. This has led to the proposal of a bidirectional "gut-brain" axis whereby signals from the intestine (e.g. from microbes and/or the immune system) can alter brain function and disease outcome. Conversely, nervous stimuli originating in the brain may modulate intestinal immune function through enteric nervous system feedback.
Interestingly recent evidence indicates that ischaemic stroke induces dramatic changes in intestinal barrier function, the intestinal immune system and the balance of bacterial species present in the intestine. These findings suggest a previously unappreciated link between the intestine and the brain in disease and suggest stroke may have long-term consequences beyond the CNS. This project will investigate the molecular and immunological mechanisms through which the "gut-brain axis" contributes to disease pathogenesis. An increased understanding of this previously unappreciated area of biology may result in identification of novel targets for the treatment of neurological diseases, such as stroke or Alzheimer's disease.
The successful student will receive a unique multidisciplinary training in neuroscience, immunology and microbiology by combining the expertise of the Hepworth (intestinal inflammation and immunology), Lawrence (stroke, Alzheimer's) and Brough labs (Alzheimer's, neuroinflammation). This project will utilize animal models of disease, immunological techniques and imaging, with the potential to incorporate next generation sequencing technologies.
The intestine has been termed "the second brain" due to the high density of nerves that line the gut. The intestine contains a plethora of immune cells and hosts trillions of commensal bacteria, which produce metabolites with the ability to modulate disease pathogenesis in a wide range of peripheral organs - including the brain. This has led to the proposal of a bidirectional "gut-brain" axis whereby signals from the intestine (e.g. from microbes and/or the immune system) can alter brain function and disease outcome. Conversely, nervous stimuli originating in the brain may modulate intestinal immune function through enteric nervous system feedback.
Interestingly recent evidence indicates that ischaemic stroke induces dramatic changes in intestinal barrier function, the intestinal immune system and the balance of bacterial species present in the intestine. These findings suggest a previously unappreciated link between the intestine and the brain in disease and suggest stroke may have long-term consequences beyond the CNS. This project will investigate the molecular and immunological mechanisms through which the "gut-brain axis" contributes to disease pathogenesis. An increased understanding of this previously unappreciated area of biology may result in identification of novel targets for the treatment of neurological diseases, such as stroke or Alzheimer's disease.
The successful student will receive a unique multidisciplinary training in neuroscience, immunology and microbiology by combining the expertise of the Hepworth (intestinal inflammation and immunology), Lawrence (stroke, Alzheimer's) and Brough labs (Alzheimer's, neuroinflammation). This project will utilize animal models of disease, immunological techniques and imaging, with the potential to incorporate next generation sequencing technologies.
