Effects of phenylbutazone alone or in combination with a nutritional therapeutic on gastric ulcers, intestinal permeability, and fecal microbiota in horses.

BACKGROUND: Gastrointestinal (GI) injury and dysbiosis are adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use in horses. Phenylbutazone has been shown to alter GI barrier function both in vitro and ex vivo, but its effects on barrier function have not been assessed in vivo. In addition, the ability of nutritional therapeutics to prevent these changes is not known. OBJECTIVE: Our objectives were to determine whether (a) phenylbutazone affected barrier function in vivo and (b) if phenylbutazone-induced GI injury could be ameliorated by the use of a nutritional therapeutic. ANIMALS: Thirty healthy horses were randomly assigned to 3 groups (n = 10 per group): control, phenylbutazone, or phenylbutazone plus nutritional therapeutic. METHODS: This study was conducted as a blinded, randomized block design. All horses were managed identically throughout the study period. Samples were collected throughout the study period to monitor fecal microbiota changes and gastric ulcers before and after treatment. Quantification of the bacterial 16S rRNA gene in blood was used as a marker of intestinal permeability. RESULTS: Phenylbutazone increased amounts of bacterial 16S rDNA in circulation 3.02-fold (95% confidence interval [CI], 0.1.89-4.17), increased gastric ulceration score by a mean of 1.1 grade (P = .02), and induced specific changes in the microbiota, including loss of Pseudobutyrivibrio of family Lachnospiraceae. These changes were attenuated by nutritional treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Collectively, these findings suggest that phenylbutazone induces GI injury, including impaired barrier function, and that nutritional treatment could attenuate these changes.

NSAIDs disrupt intestinal homeostasis by suppressing macroautophagy in intestinal epithelial cells.

Small intestinal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remains an under-recognized clinical disorder. The incomplete understanding of the pathophysiology has hampered the development of prevention and treatment strategies leading to the high morbidity and mortality rates. NSAIDs are known to modulate macroautophagy, a process indispensable for intestinal homeostasis. Whether NSAIDs stimulate or repress macroautophagy and how this correlates with the clinical manifestations of NSAID enteropathy, however, remains unknown. The objectives of this study were to determine whether NSAIDs impaired macroautophagy and how this affects macroautophagy-regulated intestinal epithelial cell (IEC) processes essential for intestinal homeostasis (i.e., clearance of invading pathogens, secretion and composition of mucus building blocks, and inflammatory response). We show that NSAID treatment of IECs inhibits macroautophagy in vitro and in vivo. This inhibition was likely attributed to a reduction in the area and/or distribution of lysosomes available for degradation of macroautophagy-targeted cargo. Importantly, IEC regulatory processes necessary for intestinal homeostasis and dependent on macroautophagy were dysfunctional in the presence of NSAIDs. Since macroautophagy is essential for gastrointestinal health, NSAID-induced inhibition of macroautophagy might contribute to the severity of intestinal injury by compromising the integrity of the mucosal barrier, preventing the clearance of invading microbes, and exacerbating the inflammatory response.