Host-Microbiome Interactions Following NSAID Administration in Horses Goals and Objectives | Grant individual record
2018 - 2022
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently administeredpharmaceuticals in the world. Due to the frequency of use of this class of medications, they aregenerally considered very safe by both the public and prescribing veterinarians. There is strongevidence, however, in both people and animals that routine clinical usage of these drugs haveprofound deleterious effects on the gastrointestinal (GI) tract of both people and animals. Amajor contributor to the lack of appreciation for the negative effects of these drugs on the GItract is related to difficulties diagnosing their effects of the GI tract. Fulminant, severe NSAIDenteropathy in the horse has been well-described but the less severe effects of these drugs on theequine GI tract likely remain under-recognized similar to the "silent epidemic" of NSAIDenteropathy reported in people. Importantly, in both human and veterinary medicine there are noeffective treatment or prevention strategies to manage the deleterious effects of NSAIDs on thelower GI tract (i.e., NSAID enteropathy). In addition to lack of treatment very little is knownabout the pathophysiology of NSAID enteropathy in both people and animals. One aspect of thepathophysiology that is gaining increasing recognition is the role of the microbiota. Themicrobiota has been shown to influence NSAID enteropathy but exactly how this occurs remainsunclear. Thus, given the importance of the equine microbiota in both health and disease, there isa critical need to more thoroughly investigate the effects of NSAIDs on the equine GI tract andon the equine microbiota. In the absence of such information, a mechanistic frameworknecessary for the subsequent development of novel strategies to treating or preventing NSAID inducedenteropathy will remain elusive. Therefore, our long-term goals are to more completelyunderstand how NSAIDs injure the equine GI tract, and how the microbiota influences theseeffects, in order to derive more effective prevention and treatment strategies. We have strongpreliminary evidence suggesting routine use of NSAIDs does, in fact, result in both dysbiosis andmucosal injury to the equine GI tract. In addition, we have validated the use of a novel approachto non-invasively examine the intestinal transcriptome in the context of NSAID enteropathy.Based on the critical clinical need for such information and our strong preliminary data wepropose the following objectives.Objective 1: Characterize the gene expression profile (i.e., transcriptome) in exfoliatedintestinal epithelial cells from NSAID-treated horses as compared with control horses.Objective 2: Document NSAID-induced dysbiosis and link these changes to alterations inthe function of the microbiota as determined by alterations in the metagenome of themicrobiota and alterations in the fecal metabolome.This proposal involves a novel approach to non-invasively examining the intestinaltranscriptome of horses in the context of complications from one of the most commonlyadministered classes of medications in the world. Should we achieve our objectives then we willhave validated a technique to non-invasively examine the intestinal transcriptome of the horse.This approach will have broad application in equine intestinal disorders in terms of biomarkerdiscovery and potential diagnostic modality. Additionally, upon completion of this work we willhave described the metagenome and metabolome of the equine microbiota AND described howNSAIDs alter this critically important system. Documenting NSAID-induced alterations in thesesystems will be the foundation of identifying potential effective prevention and treatmentstrategies for NSAID enteropathy and other intestinal mucosal disorders of the horse.