The Role of the Microbiome in Inter-Individual Variability in NSAID Disposition and Response

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of pain and inflammation. Mounting evidence indicates that rectal administration of NSAIDs is also effective in preventing pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) by an unknown mechanism. Alterations in the salivary and fecal microbiome have been observed in patients with pancreatitis compared to healthy subjects, suggesting that dysbiosis may contribute to the development and progression of pancreatitis. In addition, it has long been recognized that the intestinal microbiota can influence drug disposition, but few studies have directly investigated this effect in humans. We hypothesize that the microbiome is an important contributor to inter-individual variability in NSAID disposition and efficacy in preventing post-ERCP pancreatitis. In the proposed studies, we will investigate the bidirectional interaction between the oral and fecal microbiome and indomethacin treatment in healthy adults. In Part A stool, saliva, and oral swab samples will be collected after treatment with oral and rectal indomethacin and the corresponding controls to study the effect of NSAID and route of administration on the microbiome. In Part B indomethacin PK/PD profiles will be analyzed at baseline and following antibiotic treatment to study the effect of the gut microbiome on indomethacin disposition. The proposed studies will lay an important foundation for future investigation of whether alterations in the microbiome might represent a novel mechanism by which NSAIDs prevent post-ERCP pancreatitis. They will also evaluate the microbiome as a source of inter-individual variability in drug disposition.