Pyridostigmine Bromide, the Enteric Nervous System, and Functional Gastrointestinal Disorders in Gulf War Illness
Abstract
Gastrointestinal problems are common and debilitating in Veterans afflicted with Gulf War illness. Yet the trigger that initiated these gut problems and the mechanisms that maintain them remain unknown. The objective of this proposal is to understand how the anti-nerve gas drug pyridostigmine bromide contributes to the development of gastrointestinal disorders in Gulf War illness. Our central hypothesis is that pyridostigmine bromide disrupts gut functions by creating inflammation within the branch of the nervous system that coordinates gut functions. Our specific hypothesis is that the detrimental effects of pyridostigmine bromide are mediated by its effects on a type of supporting cells, called enteric glia, that surround gut neurons. We propose that controlling the pro-inflammatory actions of enteric glia will improve gut functions and the overall well-being of Gulf War Veterans. Our proposal has two specific aims that are directly applicable for understanding the pathogenesis of Gulf War illness and improving its treatment. The individual experiments within these aims use detailed physiological tests to understand how pyridostigmine bromide promotes gut dysfunction by analyzing its effects on individual cells and the integrated functions of the organ. Further, our experiments will test the therapeutic benefit of decreasing gut inflammation on gastrointestinal-specific functions and systemic inflammation. The main benefit of our study will be for Gulf War Veterans who predominantly exhibit gastrointestinal symptoms of Gulf War illness. We anticipate that our study will identify specific therapeutic targets that will improve gastrointestinal functions in these individuals. The gastrointestinal tract also has a major influence on behavior, metabolism, and immunity. Therefore, it is highly likely that controlling inflammation in the intestine will be broadly beneficial for all individuals suffering from Gulf War illness by controlling the systemic effects of gut inflammation. Therapies developed from our proposed work will be directly translatable to the clinical treatment of gut dysfunction in Gulf War illness. However, as stated above, this strategy could also have indirect clinical benefits on multiple systemic aspects of Gulf War illness including the cognitive, metabolic, and immunological symptoms. Thus, the potential benefits of our study are very high. Our therapeutic strategy also presents little risk for patients because we will utilize an endogenous anti-inflammatory compound to control gut inflammation. This strategy is particularly useful for rapidly translating our findings to a patient-related outcome because this compound is already in clinical use for other inflammatory conditions. In all, we anticipate that our study will be a major advance in the understanding of the pathogenesis of Gulf War illness. Virtually nothing is known about how gastrointestinal symptoms arise in Gulf War illness despite the key role of the gastrointestinal tract in all other aspects of the syndrome. Our proposed study will identify the specific mechanisms that link exposure to Gulf War illness inducing drugs to gut dysfunction. This detailed, mechanistic understanding is essential for the development of more effective therapies for the gastrointestinal and systemic aspects of Gulf War illness.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610631
Entities
People
- Brian D Gulbransen
Organizations
- Michigan State University
- United States Army