As one of the most common medications, it is reasonable to assume that the adverse effects from nonsteroidal anti-inflammatory drugs (NSAIDs) are well understood. While this is the case for NSAID-induced gastropathy, NSAID-induced enteropathy is often clinically overlooked and has a pathogenesis that is incompletely understood. The goal of this study was to determine how alterations in the microbiota impact NSAID-induced intestinal injury. Initial studies explore how gastric acid secretion suppression substantially decreases Bifidobacteria in the small intestine, and emphasize how replenishment of these bacteria results in an amelioration of NSAID-induced enteropathy. Follow-up studies involved pretreating rats with specific bacteria that have conferred protection in other models of small intestinal injury. We examined the role that acetate may play in reducing the damage by evaluating bacteria that had an acetate production gene knocked out via homologous recombination. Protection levels were similar between wildtype and knockout bacteria, and it did not appear that acetate had a key role in damage reduction. Moreover, we found that changes in intestinal damage were dependent not only on the strain of bacteria used but also on the NSAID administered. None of the bacterial pretreatments tested protected against indomethacin- or diclofenac-induced small intestinal injury, and pretreatment with one specific bacterial strain resulted in a significant worsening of damage. To gain further insight as to the potential role of the microbiota in exacerbation of injury, we conducted studies using single antibiotics and antibiotic cocktails. No single antibiotic treatment conferred protection against naproxen-induced small intestinal injury, but an antibiotic cocktail decreased damage scores by ~46%. Furthermore we explored the effects of L-lactic acid supplementation of drinking water but this was unable to reduce naproxen-induced intestinal damage. Collectively, the work presented in this thesis provides novel insights on the relationship between alterations in the microbiota and susceptibility to NSAID-induced enteropathy. / Dissertation / Doctor of Philosophy (Medical Science)