Zsa Zsa Weerts

General discussion 245 10 serious adverse events. As treatment effects emerged towards the end of the eight- week treatment period, future studies should evaluate the efficacy and safety of longer treatment with small-intestinal release peppermint oil. It would also be of value to assess if longer treatment periods will be cost-effective, since we found that small-intestinal release peppermint oil is likely cost-effective on the short term. In addition, it may be interesting to explore the presence of pharmacogenetic effects on treatment response, as part of the mechanism of action of peppermint oil is via TRPM8 stimulation through its main constituent menthol. 29 Mutations in transient receptor potential channels are known from genetics analyses in pain research 30 and may affect treatment response. In chapter 5 , we investigated TRPM8 as the potential mechanism of action of peppermint oil, and postulated that activation of this receptor results in diminished release of inflammatory mediators which contribute to pain symptom generation. As this mechanistical study was small and preliminary, future research will need to elucidate these mechanisms further to optimize targeted treatments such as peppermint oil for IBS. We had hypothesized that the ileocolonic release would further increase efficacy, but this was not shown by our results. While reducing upper GI side effects, the ileocolonic release peppermint oil unexpectedly showed an increase in abdominal cramping. As ileocolonic-release peppermint oil also showed lower efficacy than small-intestinal release peppermint oil, we do not recommend its further development in the current form. Further insight into the differential intestinal expression of the receptor, i.e. expressional differences between duodenum, proximal colon and sigmoid, may lead to better understanding of the small-intestinal versus the ileocolonic release peppermint oil performance. Integrating mental health care In chapter 3 , we showed that a reduction in IBS symptom severity was not paralleled by improvement in quality of life and general life satisfaction in patients with IBS. Our data suggested that quality of life and general well-being were related to concurrent anxiety and depression risk scores, rather than GI symptom severity. Moreover, in the cost-effectiveness analysis of the PERSUADE study, we found that a large proportion of the total associated socioeconomic costs was driven by mental healthcare usage ( chapter 8 ). In patients with IBS, the prevalence of psychological co-morbidities is high and there is long-standing appreciation for a connection of anxiety and depression and altered stress responses and IBS. In view of the generally unsatisfactory results of