Zsa Zsa Weerts

Summary 255 A anti-nociceptive and possibly anti-inflammatory effect. Peppermint oil, which has been used for decades to treat abdominal pain in IBS, has menthol as its main constituent. Interestingly, menthol is a TRPM8 agonist suggesting a possible effect through this TRP channel. In chapter 5 , we then investigated molecular mechanisms underlying the potential beneficial effect of TRPM8 agonism in IBS. As human data on intestinal TRPM8 was limited to a single study in Crohn’s disease and a brief report on polymorphisms in IBS, this was the first study investigating TRPM8 in intestinal tissue of IBS patients. In biopsies from both a London and Maastricht IBS cohort, we showed that TRPM8- immunoreactivity was colocalized with immune cells being predominantly of the dendritic cell lineage and in close approximation to nerve endings. In addition, we demonstrated that TRPM8 immunoreactivity and mRNA expression was increased in IBS patients as compared to controls. Ex vivo treatment of IBS patient biopsies with TRPM8 agonist icilin reduced the release of pro-inflammatory cytokines. These data indicate that TRPM8 may have important anti-inflammatory properties and by this virtue can impact neuro-immune disease mechanisms in IBS. Peppermint oil is one of the pharmacotherapeutic entities currently used for IBS and is also an agonist for TRPM8. Enteric-coated capsules that release peppermint oil in the small intestine are currently available as an over-the-counter drug in Europe. However, studies investigating the clinical efficacy of peppermint oil in IBS are hampered by methodological shortcomings that impede the ability to draw firm conclusions. In addition, the Rome diagnostic criteria have been updated and the European Medicines Agency (EMA) and Food and Drug Administration (FDA) have defined robust endpoints for clinical trials in IBS since then. Together, a methodologically well-designed trial to assess efficacy of peppermint oil in Rome IV diagnosed IBS patients was warranted. Although the mechanism of action of peppermint oil is multifactorial ( e.g. intestinal smooth muscle relaxation, inhibition of serotonin receptors, anti-microbial and anti- fungal), part of its effect is likely effectuated through TRPM8 stimulation via its main constituent, menthol. We hypothesized that an increased local colonic peppermint oil concentration would perhaps increase therapeutic efficacy and decrease burdensome upper GI adverse events from small-intestinal release peppermint oil, such as heartburn and belching, due to the more distal release. Therefore, an ileo-colonic release peppermint oil capsule was developed and its pharmacokinetic performance was assessed and compared to the already existing small-intestinal peppermint oil capsule in a crossover study, described in chapter 6 . We showed in eight healthy volunteers, that