Periodic Reporting for period 3 - DISCOvERIE (Development, dIagnostic and prevention of gender-related Somatic and mental COmorbitiEs in iRritable bowel syndrome In Europe)
Berichtszeitraum: 2023-01-01 bis 2024-06-30
DISCOvERIE aims to provide a better understanding on irritable bowel syndrome (IBS) and associated comorbidities and their risk factors to support a better diagnostic approach in clinical practice and to facilitate the development of evidence-based medicine clinical guidelines leading to early and improved management and personalized medicine. The project is leaded by a multidisciplinary team of experts in the field of neurogastroenterology, psychiatric disorders and somatic pain disorders in association with small and medium-sized technology companies. The progress of the project and the financial oversight is monitored by internal and external committees of experts in science, ethics and European regulations and by the EC itself and involves also an end-users committee.
We have prospectively recruited a total of 852 participants, including IBS, alone or with somatic and/or mental comorbidities, and disease and healthy controls. The analysis of demographic and clinical data highlights the cumulative effect of comorbiditidies and female gender on the severity of clinical course, the association with trauma, its impact on work absenteeism, and differences in alcohol intake, diet and education levels. Comorbidities also impacted on frequency of allergies, history of COVID-19 and medication use. Biological samples (blood, colonic biopsies, faeces and urine) have been collected, distributed across the project partners and partially analyzed. Unexpectedly, intestinal permeability in vivo did not differ between IBS and healthy, though striking differences were found in IBS patients across recruiting centers. Conversely, brain-to-gut rodent’s preclinical models showed altered intestinal permeability, both paracellular and transcellular. Transcriptomics and proteomics of colonic that some proteins such as TSZH3, MCMBP may be good IBS comorbid diagnostic biomarkers but need further validation. Other proteins and genes, including CDH11 and CXCL11may be useful to differentiate IBS subtypes. Histological analysis of colon biopsies revealed that nerve sprouting, indicated by GAP43, was increased in the IBS comorbid and multicomorbid groups compared to healthy and detected histological and ultrastructural signs of enhanced mast cell activation. Moreover, supernatants from IBS patients induced changes in permeability and in the structure of tight junctions. Patients with higher extraintestinal symptom severity gave significantly higher negative affect ratings in typical tests of brain function and augmented right amygdala stress response that was related to pain and fatigue. Comorbid IBS patients also had higher depressive, anxiety, and fatigue symptoms as compared to non-comorbid IBS patients. Pain severity was highest in those with somatic comorbidities and also higher in patients with mental comorbidities compared to those with IBS alone. Anticipatory stress and cortisol, but not sex or gender played a role in determining stress responses in certain IBS subgroups. Pain was related in these patients with the neural circuits involved in stress susceptibility and stress resilience. Unfortunately, based only on brain response to stress is not useful as a reliable signature for comorbidity severity. Gut-to-brain animal models support the association of enhanced epithelial and brain barrier permeability in the development of neuroinflammation and anxiety behaviour. It resulted that gut microbiota faecal transplants from an animal model of IBS transferred visceral hypersensitivity only from donor male comorbid animals and depression-like behaviour only transferred from donor male depression cluster animals to recipient animals. Recipient animals in receipt of a FMT from humans with IBS exhibited visceral hypersensitivity compared to those in receipt of a FMT from healthy controls in both male and female animals.Notably there was a sex-specific alteration in the stress axis and in the expression of tight junction proteins in these animals. Furthermore, the cohort showed a significant increase in the dysbiotic Bacteroides 2 enterotype, previously associated with inflammatory bowel disease, depression, and obesity, a decrease in commensal bacteria and butyrate producers, and an increase in other dysbiotic communities. Some specific bacterial taxa were altered, like Dialister in the IBS comorbid somatic group or Streptococcus or Senegalimassilia in the IBS multicomorbid group. Changes in certain bacterial metabolites were also detected in IBS groups, such as tiropramide or glutarate. We described a strong and positive genetic correlation between IBS and depression and anxiety and found 28 independent hits indicative of genetic overlap between them. Initial analysis of genetic data has not disclosed major differences in terms of microRNAs, with the exception of miR-22-3p, but found significant methylation differences between IBS patients and healthy controls. However, the majority of genetic analysis is still pending. We are running causality and mechanistic analyses to identify causal genetic/epigenetic relationships between IBS and anxiety, depression, fibromyalgia and chronic fatigue from a systems biology perspective. We are working on the obtention of an individual differential expression gene signature for each patient and also in defining the underlying molecular mechanisms and the protein interactions. The proteins that are more promising as pathogenic biomarkers for the differential diagnosis of IBS comorbid groups include peroxisome proliferator-activated receptor alpha, caudal type homeobox 2, and transcription factor PU.1 although validation is needed. In parallel, we have been working in the feasibility development of several potential candidates for immunoassays, like S100B and BDNF. Results from digital health platforms reveal to date that real-time abdominal pain and lower gastrointestinal symptoms in IBS patients are significantly associated with affect and environmental triggers, and vary across IBS subgroups. We have issued many dissemination activities, including some open access publications that can be found in the project website. An exploitation plan has been implemented under the supervision of the Innovation and Exploitation Advisory Panel. A questionnaire to evaluate the socio-economic impact of IBS has been developed and distributed online.
In RP4 DISCOvERIE will deliver valuable sex/age patient-centered clinical guidelines to improve disease management and to increase quality of life of patients. Results of DISCOVERIE will also facilitate the strengthening of existing connections and expansion of a European network of medical specialists and researchers in the area of diseases related to the microbiota-brain-gut axis to promote research and teaching. All this should enable professionals to develop novel and efficient diagnostic, predictive and therapeutic disease-specific biomarkers for IBS, associated comorbidities and other microbiota-brain-gut axis disorders in the future. The knowledge gained will provide new opportunities for various sectors of industry and stakeholders and remain of interest to apply patents or intellectual property. Policy makers and National & Regional Health Bodies in Europe can benefit from our findings to help design future public-health policies. Finally, we expect that the benefit will reach soon patients and their families in the form of earlier diagnosis and personalized medicine approaches.