Anorectal function (ARF) disorders in patients with IBD cause disabling symptoms such as
fecal incontinence, increases in the stool frequency, urgency and tenesmus.
Patients with IBD in remission frequently experience diarrhea, fecal incontinence and lower
GI symptoms. However, ARF in IBD patients is underexplored.
Chronic mucosal inflammation may induce visceral hypersensitivity and rectal wall fibrosis,
but the casual relationship is hypothetical.
The absence of active inflammation and the presence of symptoms resemble IBS leading to the
speculation that an IBD diagnosis is a distressing event, and can induce mood disorders, and
an IBS-like condition.
Anorectal manometry detects abnormalities of sphincter function and rectoanal coordination.
Recently, a standardized HRAM protocol was published (The London consensus protocol) witch
also evaluates rectal sensitivity (RS) and rectal compliance (RC).
Earlier studies, using water-perfused AM, indicated that patients with active ulcerative
colitis (UC) may have increased RS, contractility and impaired RC whereas patients with
quiescent UC may have impaired RC, suggesting that chronic fibrotic changes of the rectal
wall may occur.[14, 15] IBS is characterized by abdominal pain and changes in stool pattern.
Its biological hallmark is increased visceral perception with disturbed bidirectional
brain-gut signaling, associated with serotonergic dysregulation, illustrated by the high
prevalence of mood disorders.
IBS is diagnosed using the Rome IV symptom criteria. Phenotyping IBS patients, as described
in a consensus paper by Boeckxstaens et al. in 2017, relies on GI symptom severity scales and
measurements of RS and RC using a barostat procedure. There is frequently overlap with other
functional GI disorders (FGIDs). Hence these should also be assessed, as well as
psychological comorbidities.
The gold standard for phenotyping is the use of validated questionnaires and a standardized
barostat protocol as described in a publication from the European COST action GENIEUR
group.[16] The level of agreement between the barostat protocol and the HRAM testing
procedure regarding sensory testing and measurement of rectal compliance is not established.
Progress in various types of -omics techniques has enhanced our possibilities to identify
markers of complex diseases such as IBD. Recent studies have associated gut microbiota,
genome, transcriptome and proteome-profiles with various aspects of the disease. Both
individual markers and panels of markers, so called "molecular signatures" are currently
tested for their predictive capacity and possible source for future biomarker identification.
Accumulating data indicate that some of this novel potential markers may reflect
non-inflammatory processes such as fibrosis.
The overarching aim of this study is to explore the anorectal function in symptomatic
patients with quiescent IBD compared to healthy volunteers and asymptomatic patients with
quiescent IBD, using both HRAM and a standardized barostat procedure. Symptom severity and
psychological parameters will be evaluated by validated questionnaires. Molecular
characterization will be performed by analyses of blood, faecal samples and mucosal biopsies.
Examination of single-layers of molecular data will be followed by integrated analyses of
several layers of
- - omics data and correlated to clinical and psychological phenotypes.
This
"multi-omics" approach requires development of bioinformatic methods, which currently are
underway.
The study goals are:
1. To determine the level of agreement and correlation of rectal sensitivity- and
compliance measurements between the HRAM method and the barostat method in healthy
volunteers and asymptomatic patients with IBD in remission. 2. To study ARF in symptomatic patients with IBD in remission and to compare the results
with data from healthy volunteers and asymptomatic patients with IBD in remission.
3. To measure parameters of brain-gut interaction in IBD patients using validated GI
symptom scales and psychometric questionnaires on anxiety, somatization, personality and
depression and to compare the results with data from healthy volunteers.
4. To analyse plasma, stool and rectal mucosa samples from symptomatic patients with IBD in
remission for proteomics, micro-RNA and microbial composition and to compare the results
with findings in healthy participants and asymptomatic patients with IBD in remission.
Part 1 and 2. Anorectal manometry, barostat assessment and validated questionnaires in
healthy volunteers and asymptomatic IBD patients.
Awareness of rectal filling is critical to normal bowel function. Abnormal visceral
sensitivity and/or biomechanical function (most commonly described by evaluation of rectal
compliance) is often found in fecal incontinence and evacuation disorders, providing the
rationale for measurement of anorectal sensory and motor function.
Aims:
To determine the correlation between sensitivity testing and the level-of-agreement of rectal
compliance testing between the HRAM and the barostat protocol.
To obtain normal values regarding anorectal function from healthy volunteers and asymptomatic
IBD patients which will be used for comparison with the values obtained from symptomatic
patients with IBD.
To obtain normal values regarding gastrointestinal symptoms and psychometric scales using
standardized questionnaires, which will be used for comparison with the values obtained from
symptomatic patients with IBD.
To obtain biological samples. Results of the analyses of these samples will be compared with
the results from the symptomatic IBD patients as outlined in the part 6 of the research plan.
Design: reliability and method comparison study but at the same time the participants will
constitute the control cases in the planed case control studies.
No data is available regarding normal values for rectal compliance using the HRAM method. In
a study comparing a rapid non-elastic barostat bag measurement with a standardized barostat
procedure, a total of 25 subjects was sufficient to detect a difference in sensitivity
threshold volumes.
The following validated questionnaires will be used:
ROME IV diagnostic criteria, IBS symptom severity index, Gastrointestinal symptom severity
scale, Bristol stool form scale, Nepean dyspepsia index, Depression Module (PHQ-9), Anxiety
module (GAD-7), Symptomatic severity module (PHQ-15), Visceral sensitivity index, Assessment
of disease-specific quality of life, Assessment of socioeconomic status of IBS patients,
Assessment of personality (NEO-FFI-3), Vaizey score for incontinence.
HRAM The investigation consists of a series of pressure measurements that assess resting
pressure of the anal canal, voluntary function during short and long squeeze, assessment of
the cough reflex, rectoanal inhibitory reflex during rectal distension and rectoanal
coordination and propulsive force during simulated defecation.
Rectal sensitivity testing and rectal compliance studies will be performed through inflation
of an elastic balloon connected to the HRAM catheter, placed within the rectum. During
inflation, perceived sensations are reported: first sensation, desire to defecate, urgency
and maximum toleration or pain.
The distending volume and pressure will be recorded and the rectal compliance after
correction for the internal compliance of the elastic balloon will be calculated (ΔV⁄ΔP).
Barostat protocol tests:
Ascending method of limits protocol: ramp inflation starting at 0 mmHg and increasing in
steps of 4 mmHg for 1 min per step to a maximum of 60 mmHg. Thresholds for first sensation,
first desire to defecate, urgency, discomfort and pain will be recorded and the rectal
compliance calculated.
Random order phasic distensions protocol: phasic distensions (60 sec) of 12, 24, 36 and 48
mmHg above basic operating pressure (BOP) will be each applied once in a random order. The
maximum pressure is limited by the pain threshold from the AML. The subjects will rate the
intensity of four different sensations during the last 30 sec of each distension (gas,
urgency, discomfort and pain).
Biological samples will be obtained during a separate visit to the gastroenterology
department.
Part 3 and 4. Assessment of symptoms and anorectal function in patients with quiescent
ulcerative colitis respective quiescent Crohns disease with anorectal involvement.
Aim To obtain values regarding anorectal function from patients with IBD in remission using
the HRAM protocol and the standardized barostat protocol.
To phenotype the patients by obtaining data regarding gastrointestinal symptoms and
psychometric values using standardized questionnaires, and to analyse these data together
with the anorectal function data.
To obtain biological samples from symptomatic patients with IBD in remission. There are no data available regarding normal values for rectal compliance and sensitivity
using the HRAM method in IBD patients. However, earlier studies, comparing healthy volunteers
with IBS patients using a similar standardized barostat protocol, demonstrated that a total
of 13 IBS patients and 13 healthy controls was sufficient to detect a difference in
sensitivity threshold volumes and rectal compliance. For this reason, 15 patients will be
included.
The same protocol as for part 1 will be applied.
Part 5. Assessment of IBS-like symptoms and psychological comorbidities in patients with UC
and Crohn's disease in remission.
Increased visceral perception (hypersensitivity) with disturbed bidirectional brain-gut
signaling is considered the biological hallmark of IBS.
Aim: to investigate whether patients with quiescent IBD meet the Rome IV criteria for IBS
with concomitant psychological comorbidity, or that these patients suffer from
gastrointestinal symptoms due to the effects of a long-lasting inflammatory process leading
to rectal fibrosis. This knowledge has consequences for the treatment of these patients.
The HRAM measurements will be used to establish the presence of an eventual rectal motor
dysfunction as the cause for symptoms. The barostat data will be used to establish whether
there is a decreased rectal compliance, suggestive for fibrosis, as well as to establish
whether the IBD patients show a visceral hypersensitivity, in comparison with healthy
controls.
The symptom and psychometric questionnaires will be used to establish whether the quiescent
IBD patients demonstrate a typical IBS phenotype with high comorbidities of anxiety,
depression, somatization and a personality treat with a high level of neuroticism.
Part 6. Molecular profile of symptomatic patients with quiescent IBD compared to healthy
volunteers and asymptomatic patients with quiescent IBD Aspects of gut microbiota, genome,
transcriptome and proteome-profiles will be compared between the study groups.
The microbiological data will be combined with proteomic data from plasma and rectal
biopsies, data from the mi-RNA analysis and correlated with data on the clinical and
psychological phenotype of the patients. This "multi-omics" approach requires development of
bioinformatics methods, which currently are underway in IBD studies.
