In accordance with the Grant and Consortium Agreements, we have developed Project Management Guidelines and updated them according to the DISCOvERIE principles & progress of activities. The project boards and committees (Scientific Advisory Board, User Board, Internal Ethics Board and Steering Committee) ensure compliance with European and national ethical requirements and monitor the WPs and have been actively involved and informed about the project activities through the organization of meetings and timely communication on specific issues. Maintaining records of financial oversight and monitoring progress included submitting a request for change to the General Assembly due to the pandemic. A report including analyses of the retrospective IBS cohorts and data from the Hungarian national database was submitted. Prospective recruitment of IBS patients, disease controls and healthy controls was delayed due to COVID-19. This led the consortium to request a 6-month extension for recruitment, without affecting the overall project duration. Thanks to the implementation of contingency measures, the consortium was able to recruit a total of 826 subjects into the prospective study. Preliminary data show a trend towards more females in the IBS comorbid and multicomorbid groups, and a higher proportion of subjects with antidepressant use in the IBS multicomorbid group and in the disease control groups with mental disorders. In addition, preliminary analyses of the questionnaire data show a gradual increase in the severity of somatic symptoms, anxiety and depression in patients with increasing numbers of comorbid conditions. Standard operating procedures for collection, storage and distribution of all biological specimens (blood, feces, urine, colon biopsies) have been updated. For the assessment of small intestinal and colonic permeability, urine samples from all cohorts of patients and controls (n=775) are now being sent to the KUL partner. We have analyzed the first set of samples (n=208) in a blinded manner to avoid bias. Preliminary results show no differences in intestinal permeability. Other experiments are being performed in a small number of patients from those undergoing colonoscopy to obtain colon biopsies at KUL and VHIR to study intestinal barrier function in specially designed apparatus to measure electrophysiological parameters indicative of resistance to ions, electrolyte transport and water movement. Results from the KUL cohort of participants showed a trend toward reduced electrical resistance, indicating increased permeability throughout the 120 minutes of the study. In addition, two animal models are now underway to determine the directionality of brain-to-gut and gut-to-brain induced changes. To assess brain function and neuroinflammation, 3 centers are inducing psychosocial stress using the Montreal Imaging Stress Test, with a total of 67 subjects tested by 31/12/2022. The Maastricht Acute Stress Task will be used to assess stress axis function in the laboratory and in daily life. As of 31/12/2022, 107 subjects have been tested. In addition, deep analysis of human fecal samples, isolation and culture of candidate depression-associated bacteria, and transfer of these bacteria to animals models is underway to identify common biological pathways underpinning the pathophysiology of IBS with psychiatric comorbidity. We found a strong and positive genetic correlation between IBS and depression and IBS and anxiety and found dozens of independent hits indicating genetic overlap between IBS, anxiety and depression. We are performing similar analyses to identify causal genetic relationships between IBS and anxiety, depression, fibromyalgia and chronic fatigue. Isolation of genomic components from blood samples, and data analysis are severely delayed due to the pandemic. The central data repository will be maintained by Bytefactory. We have built a human protein functional interaction network around the protein data and built mathematical models to identify mechanistic links, rendering 320 proteins with suspected higher involvement in IBS and comorbidities. Using mathematical models, we identified 10 candidate biomarkers common to IBS and comorbidities in the search for mechanistic links. Validation of biomarkers in human samples that differentiate IBS from IBS with mental/somatic disorders & development of assays for those biomarkers for diagnosis, prognosis and disease/therapy monitoring is expected to start in the fourth year of the project. Up to 9 centers are using digital tools to monitor clinical responses and to obtain a personalized digital clinical phenotype. We have published 2 newsletters, launched 3 social media channels, individual communication streams of the project partners, seminars and conferences to start building a stakeholder network and raise awareness. A public website was developed:
https://discoverie.eu/. An exploitation plan was implemented and an Innovation and Exploitation Advisory Panel was created to raise awareness within the consortium.