Peppermint Oil Pharmacokinetics/Dynamics and Novel Biological Signatures in Children with Functional Abdominal Pain

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 DESCRIPTION (provided by applicant): Functional abdominal pain (FAP) affects 10-15% of children and adults worldwide and is characterized by chronic, intermittent abdominal pain. Symptoms range from mild to severe and debilitating and result in reduced quality of life. Up to 66% of children go on to have similar symptoms as adults. There are few effective treatments because of poor understanding of their mechanism of action (biological signatures) and of the pathophysiology of what are phenotypically and arbitrarily defined disorders. This R21/R33 application proposes to investigate the pharmaco-dynamic/kinetics (PKD) of peppermint oil (PMO), a botanical with some evidence of efficacy in adults with irritable bowel syndrome – a condition similar to FAP. We propose to study the PKD-gastrointestinal (GI) function relationships in children with FAP to link GI responses to PMO PKD, providing bioavailability data to be used to optimize dosing for a particular biological signature response, ultimately benefiting treatment and management of this disorder. No matter the outcome, our proposed study will provide an innovative and significant opportunity to develop novel data about the pathophysiology of FAP by investigating a number of biomarkers simultaneously in the same individual using cutting edge methodology to characterize gut microbiome composition and gut function in FAP. Our Specific Aims are to: R21, Aim 1 - Determine the PKD of PMO (menthol) in children with FAP (n=30). Hypothesis - a relationship exists between intraluminal/systemic menthol exposure and GI function. Sub-Hypothesis – Systemic menthol exposure after PMO reflects a genotype-phenotype relationship in subjects with allelic variants of CYP2A6 and/or UGT2B7. Aim 2 – Determine effect of PMO administration on gut microbiome composition (16S RNA sequencing) and contractile activity/gut transit rate (using the SmartPill®). Hypothesis – PMO will increase gut diversity and decrease contractile activity and gut transit. R33, Aim 1 - Confirm the findings of the R21 in a larger sample size and adjust dosing if necessary to optimize tolerability/safety and beneficial effects on gut microbiome composition and motility. Hypothesis: The findings of the R21 will be confirmed in the larger sample size. Treatment will be given for 1 week. Aim 2 – Assess the effect of PMO on pain processing (conditioned pain modulation), gut inflammation (stool beta defensin and chromogranin concentrations), and barrier function (permeability). Hypothesis: PMO will reduce visceral hypersensitivity, gut inflammation, and/or improve gut barrier function. Aim 3 - Evaluate the effect of PMO on clinical symptoms, psychosocial distress/patient reported outcomes, and acceptability (abdominal pain and stooling pattern via validated diary, pediatric PROMIS measures, side effects questionnaire). Hypothesis: PMO treatment will reduce abdominal pain frequency and patient reported outcomes will reflect this improvement.