Multiple sclerosis (MS) is an inflammatory disease that causes demyelination and axonal degeneration of central nervous system (CNS) axons. Characteristic symptoms include visual, motor and sensory disturbances in addition to fatigue. Bowel dysfunction, such as constipation, is common in many MS patients but the etiology of this symptom is poorly understood. Dysfunction of the pelvic floor muscles can occur in MS, but cannot account for all aspects of the constipation. Instead, there is evidence of enteric nervous system (ENS) involvement as demonstrated by instances of delayed transit in the proximal colon and the presence of delayed colonic migrating myoelectric complexes in MS patients. Further, the blood of some MS patients contains circulating antibodies directed against antigens that are found in both the CNS and the ENS, including neurofilaments, found in enteric neurons, and S100B, found in enteric glia. This leads us to the hypothesis that constipation in MS is caused by serum antibodies that target the ENS itself. We will collect serum samples from patients with MS, and from mice with experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. We will test whether the sera contain antibodies against the ENS (Aim 1) by indirect and direct immunostaining methods. We will then administer these antibodies to mice and isolated mouse colons to determine if the antibodies elicit a change in gut physiology. Next, we will characterize the gastrointestinal (GI) dysfunction that occurs in EAE mice (Aim 2). We will test whether the GI dysfunction can be ameliorated when EAE is induced in mice with certain immunological deficiencies, including B-lymphocyte deficient mice.
These aims will be completed in the context of a training plan sponsored by Gary Mawe, Ph.D., an enteric neurobiologist, and co-sponsored by Cory Teuscher, Ph.D., an immunologist with extensive MS mouse model experience, and Angela Applebee, M.D., a neurologist who specializes in MS. The training plan will include research, coursework, and professional development experiences to train Estelle (Stellie) Spear as an independent translational neuroscientist. The scientific training plan will focus on the neurological control of GI motility in health and in response to inflammation under MS and EAE disease states. Coursework will supplement the education that Stellie gains from her co-sponsors; classes will include those offered by the UVM medical and graduate schools in anatomy, physiology, immunology, and relevant techniques. Career development training will include oral/poster conference presentations and skills workshops. Monthly discussions between Stellie and her sponsors and formation of an individualized development plan (IDP) will ensure that she receives the training necessary to pursue her objective as an independent academic researcher.
Patients with multiple sclerosis (MS) suffer from visual abnormalities, motor and sensory symptoms, and fatigue; constipation is a debilitating symptom that causes extraordinary discomfort and distress. Here, we investigate gastrointestinal dysmotility in MS by replicating the symptoms in a mouse model and determining whether circulating antibodies in either the mouse model or in human MS target the nervous system of the gut. Understanding the pathogenesis of constipation in MS will not only contribute to the knowledge of the disease mechanisms, but could also lead to the development of therapies for better symptom management
| Spear, E T; Holt, E A; Joyce, E J et al. (2018) Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil 30:e13349 |
