Development, dIagnostic and prevention of gender-related Somatic and mental COmorbitiEs in iRritable bowel syndrome In Europe

Irritable Bowel Syndrome (IBS) is extremely common in Europe: IBS is a
condition marked by altered defecation, abdominal pain, and/or bloating, being
the most frequent of the multiple recognized functional gastrointestinal
disorders (FGIDs). Current data indicate that IBS afflicts up to 85 million
European citizens.
IBS is characterized by several co-morbid diagnoses and complaints. For
example, patients with IBS have 40% to 80% higher prevalence odds of suffering
from chronic fatigue, fibromyalgia compared to control population without IBS.
Chronic fatigue syndrome and fibromyalgia are chronic pain/disabling
somatic/mental disorders that also afflict millions of people (17-24 million by
chronic fatigue syndrome and about 10 million fibromyalgia) across Europe.
Large cohort studies show that the prevalence of chronic fatigue syndrome in
IBS patients is 6-25% compared to 2.2% in healthy controls3 and of 32.5% for
fibromyalgia (28%-65%).
Epidemiological evidence has also consistently demonstrated a link between IBS
and mood and anxiety disorders, as adult patients with IBS display a nearly
3.6-fold increased risk of developing psychiatric disorders. Specifically, in
studies that have administered structured clinical interviews to establish the
rate of psychiatric comorbidity per criteria as specified in the American
Psychiatric Association*s Diagnostic and Statistical Manual of Mental
Disorders, approximately 60% of treatments seeking IBS patients have a
diagnosable psychiatric condition, such as generalized anxiety disorder and
depression, being the most common disorders affecting 25 to 44% of IBS. Mood
and anxiety disorders also represent the most prevalent psychiatric conditions
in the EU, affecting over 60 million people and this is expected to nearly
double by 2030.

Despite these alarming figures, to date, comorbidities in IBS are treated
mostly as a separate condition by a variety of drugs, mainly analgesics and
antidepressants, on a *trial-and error* basis because prediction of treatment
response is currently not possible. This strategy often renders poor results
and has failed to a large extent, as it does not consider in full the potential
role of brain- gut interactions in symptom generation. Consequently, treatments
are unsatisfactory for patients and doctors. For instance, with current
antidepressant treatments, only half of the patients achieve a 50% reduction in
depressive symptoms, remission is achieved in around 20-30% of patients, and
many patients inadequately respond to any therapy and develop
treatment-resistant depression. Similarly, the majority of IBS patients
categorized their healthcare as unsatisfactory (73.3%) and this was partially
related to the coexistence of psychological traits and psychological disorders
and to an average therapeutic gain over placebo of only 5% to 15% for most
available treatments. For chronic fatigue syndrome sufferers, available
therapies only provide moderate satisfaction, and same applies to fibromyalgia
patients.


Different patients with IBS may show resiliency or susceptibility to develop
mental and somatic comorbidities. The reasons and mechanisms explaining the
association of IBS with mental and somatic comorbidities are, unfortunately,
far from being established. Therefore, the overarching aim of the multicentre
DISCOvERIE trial is to understand similarities and differences among patients
with IBS with and without comorbidities, and to demonstrate mechanisms
underlying these differences and similarities . In order to achieve this,
patients with IBS with and without these comorbidities, as well as a small
group of healthy control patients without these conditions, and a group of
patients with the comorbid conditions but without IBS, will be included in this
pan-European project, with the aim to compare the following measures within and
between the groups:

· Demographic, clinical and psychosocial characteristics, as well as
lifestyle factors (e.g. sleep, physical activity, nutrition, stress and social
interaction)
· Mechanisms of intestinal and central nervous system function, and
their interaction with the peripheral microbiota-gut-brain axis. Specifically,
we will look at epithelial barrier function and neuro-immune function in the
intestine and in the neuroendocrine stress system, as well as the function of
nociceptive and affective-cognitive neuro-circuits in the brain.
· Disease-specific genetic and epigenetic signatures.

This approach should allow us to identify specific-disease diagnostic
biomarkers for comorbid IBS and to further develop novel and efficient
predictive and therapeutic strategies. Within this multicentre study, the
Radboudumc will not contribute to the IBS patient group (and its control group)
but will recruit patient control groups: patients with depression or anxiety,
chronic fatigue syndrome or fibromyalgia, or both a mental and somatic
diagnosis.

Primary Objective: The overarching goal of the multicentre trial is to
characterize the overlap between mental and non-mental comorbid conditions of
IBS. In IBS and patient control groups we will characterize depression,
anxiety, fibromyalgia and chronic fatigue syndrome with a particular focus on
age and gender-related differences, infections, life style and nutrition.

Secondary Objective(s): Locally, three patient control groups 1) patients with
a depression or anxiety diagnosis, 2) patients with chronic fatigue syndrome or
fibromyalgia, or 3) patients with both a mental and somatic diagnosis will be
assessed. For these patient groups, three objectives are determined:

1. A thorough clinical and psychosocial characterization. We will look for
depression, anxiety, fibromyalgia and chronic fatigue syndrome.
2. Assessment of epithelial barrier function via sugar excretion in urine,
bacterial products in blood and gut microbial profile through sequencing of
bacterial DNA in faecal sample.
3. Determining the influence of lifestyle (sleep, physical activity, nutrition,
stress and social interaction) on disease symptoms through eHealth monitoring
tools.

This is a prospective, cross-sectional, longitudinal cohort study lasting 24
months in a regular care setting. This cross-sectional cohort will be followed
up for a maximum of 3 years. During this time we will record clinical symptoms
using a digital platform and collect blood (annually) and urine and faeces
(twice) to unravel shared mechanisms of brain-gut-microbiota axis dysfunction.

The data collection in the DISCOvERIE study at the Radboudumc/StMaartenskliniek
is part of a large multi-centre effort characterizing the overlap between
gastrointestinal and mental and non-mental comorbid conditions. In other
centres, IBS patients, with and without mental and non-mental comorbidities, as
well as different combinations of disease controls and health will be
recruited. At the Radboudumc/StMaartenskliniek we will recruit patients with a
psychiatric and/or somatic diagnosis, though no IBD patients and no healthy
controls. To assess the study objectives data will be pooled across centres.

The frequency of the blood draws has been reduced to minimise burden. Blood
samples will be collected by experienced members of the study team. Local
anaesthetics (e.g. Emla band-aid) can be provided for minimising pain. If the
participant will report resistance or discomfort, the procedure will be stopped
immediately. No examination will be performed against the will of the
participant or the caregiver. Where needed, appropriate therapeutic care will
be provided in the best interest of the participant.
Faeces and urine donation are non-invasive and have a low burden on the
participant.

The participant may benefit directly from participation by receiving detailed
characterization of their symptoms, both mental and somatic, as well as the
ecological measures. On the long term patient care will improve by increased
understanding of co-morbidity in IBS and generally the underlying mechanisms
driving somatic complaints in mental disorders and vice versa.