Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used classes of medications in the world, yet they induce an enteropathy that is associated with high morbidity and mortality. A major limitation to better understanding the pathophysiology and diagnosis of this enteropathy is the difficulty of obtaining information about the primary site of injury, namely the distal small intestine. We investigated the utility of using mRNA from exfoliated cells in stool as a means to surveil the distal small intestine in a murine model of NSAID enteropathy. Specifically, we performed RNA-Seq on exfoliated cells found in feces and compared these data to RNA-Seq from both the small intestinal mucosa and colonic mucosa of healthy control mice or those exhibiting NSAID-induced enteropathy. Global gene expression analysis, data intersection, pathway analysis, and computational approaches including linear discriminant analysis (LDA) and sparse canonical correlation analysis (CCA) were used to assess the inter-relatedness of tissue (invasive) and stool (noninvasive) datasets. These analyses revealed that the exfoliated cell transcriptome closely mirrored the transcriptome of the small intestinal mucosa. Thus, the exfoliome may serve as a non-invasive means of detecting and monitoring NSAID enteropathy (and possibly other gastrointestinal mucosal inflammatory diseases).