2015 James W. Freston Single Topic Conference – A
Renaissance in the Understanding and Management
of IBS
Full-Text Abstracts Selected for Poster Presentation
*Travel Awardees
*TITLE: Immunological and Psychological Abnormalities in Patients with Irritable
Bowel Syndrome
Author(s): S. Belous, I. Khalif
Affiliation(s): Scientific Centre for Coloproctology, Moscow, Russia
BODY:
Introduction: Irritable Bowel Syndrome (IBS) is a functional disorder in which abdominal
pain or discomfort is associated with changes in stool frequency and consistency, symptoms
are present at least 3 days a month for last 3 months for a total duration of complaints for at
least 6 months. Possible causes of IBS are inflammation, especially post-infectious,
immunologic factors, psychosomatic disorders and changes in intestinal microflora.
Aims: To determine characteristics of immune status, as well as psychosomatic, in patients
with various forms of IBS.
Methods: Study included 27 patients with IBS per Rome criteria III. Quntitative analysis of of
pro- and anti-inflammatory cytokines was performed with ELISA. Quality of life was assessed
via IBSQoL questionnaire, level of anxiety and depression was evaluated by Beck Depression
Scale (BDI), Hospital Anxiety and Depression Scale (HADS) and State-Trait Anxiety Inventory
(STAI). Statistical analysis was performed using SPSS Statistics 18.0.
Results: The group of patients was mostly represented by women (24(89%). Mean age was
48.19 +/- 15.69 years. In assessing dominant intestinal symptoms, patients were distributed
as follows: 17 (63%) – IBS-C, 7 (26%) - IBS-D, 1 (4%) – IBS-M, 2 (7%) - unclassified IBS. There
were no deviations from normal values while studying cytokine levels, but when assessing the
relationship with intestinal symptoms IL-6 levels were higher in IBS-C than in IBS-D (p =
0.043). According to BDI, the level of depression was 11.7 +/- 7.62, which corresponds to mild
depression. When assessing the level of anxiety on STAI level jet (42 +/- 9.93) corresponded
to moderate anxiety value, and the level of personal anxiety corresponded to high rate of
anxiety (46.42 +/- 12.13). On HADS anxiety level was 7.33 +/- 4.14, which can meet the
subclinical expressed dismay; level of depression corresponded to normal values (4.85 +/3.39). Assessing quality of life with IBS QoL questionnaire identified fairly high rate (90.78 +/10.18 at the maximum 100%).
Conclusion: In patients with IBS we may see variations in quality and quantity of cytokines.
There is also a tendency to anxiety and depressive states, which requires the selection of
adequate therapy.
*TITLE: The Role of the Glucocorticoid Receptor in the Regulation of StressInduced Nociception; Implications for Irritable Bowel Syndrome
Author(s): Rachel D. Moloney 1 and Beverley Greenwood-Van Meerveld 1,2,3
Affiliation(s): 1Oklahoma Center for Neuroscience,University of Oklahoma Health Sciences
Center,Oklahoma City,USA. 2Department of Physiology,University of Oklahoma Health
Sciences Center,Oklahoma City,USA. 3VA Medical Center,University of Oklahoma Health
Sciences Center
BODY:
Introduction: Irritable bowel syndrome (IBS) is a complex bio-psychosocial disorder typified
by abdominal pain, bloating and altered bowel habit. Current therapeutics for IBS mainly treat
aspects of constipation and diarrhea however limited pharmacological targets have been
approved for the treatment of visceral pain associated with IBS, due to a lack of detailed
understanding of the underlying molecular mechanisms. Stress has long been implicated in
the pathophysiology of IBS, both as a predisposing and an exacerbating factor.
Background: We have shown previously, using two different animal models of visceral
hypersensitivity, namely the amygdala corticosterone implant and the water avoidance stress
(WAS) models, that stress-induced visceral hypersensitivity was concomitant with reduced
glucocorticoid receptor (GR) expression in the central amygdala (CeA), a key brain nucleus
involved in the autonomic and neuroendocrine response to stress. Moreover, corticotrophin
releasing hormone (CRH) expression was markedly increased in both stress models, and upon
selective knockdown of CRH in the CeA, the stress-induced visceral hypersensitivity could be
reversed, thus indicating a critical pathway within the CeA mediating stress-induced visceral
pain.
Aims: Here we tested the hypothesis that knockdown of GR in the CeA in non-stressed
animals would recapitulate the nociceptive behaviors produced by WAS.
Methods: Bilateral cannulation of the CeA was performed for the delivery of
oligodeoxynucleotides (ODN) of antisense (ASO) or random (RSO) sequences targeting GR.
WAS or Sham WAS was performed for 1hr daily for 7days. Visceral sensitivity in response to
colorectal distension (CRD) was quantified as the number of abdominal contractions which
yielded the visceromotor response (VMR). Von Frey filaments assessed somatic sensitivity.
qRT-PCR was performed to assess changes in gene expression, specifically GR,
mineralocorticoid receptor (MR) and CRH expression within the CeA.
Results: Our data shows that WAS and GR knockdown increased VMR compared to controls at
40mmHg (20 vs 12, p<0.00001, 19 vs 12, p<0.00001) and 60mmHg (29 vs 18, p<0.00001, 28
vs 18, p<0.00001). Moreover, both WAS and GR knockdown decreased the withdrawal
threshold in the Von Frey test compared to controls (42g vs 76g, p<0.00001, 48g vs 76g,
p<0.0001). Gene expression analysis revealed that both WAS (p<0.001) and GR knockdown
(p<0.001) significantly reduced GR expression in the CeA. Furthermore, CRH expression was
significantly increased in both WAS (p<0.01) and GR knockdown animals (p<0.05). Finally MR
expression was reduced in the WAS group but not the GR knockdown group (p<0.05).
Conclusion: These studies highlights a pivotal role of stress pathways with the CeA in the
mediation of visceral hypersensitivity. GR and CRH communication appears critical to the
development of visceral pain which has significant implications for IBS patients where stress
is a key factor in the complex etiology and pathophysiology.
TITLE: A Novel Formulation Containing a L-Menthol and Peppermint Oil Blend (LPB) Reduces
Symptom Intensity and Frequency in Irritable Bowel Syndrome (IBS)
Author(s): Michael Epstein, MD, FACG(1); Syed Shah, PhD(2)
Affiliation(s): (1)Digestive Disorders Associates, Annapolis, Maryland; (2) Chief Innovation
Officer IM HealthScience, Boca Raton Florida
BODY:
Peppermint has been a popular digestive remedy for at least two centuries. Its use, as an
enteric-coated peppermint oil (PO) liquid dosage form, in treating IBS symptoms, was first
reported by Rees in 1979. In spite of the enteric coating in many of these older delivery
systems, these “single unit” systems sometimes caused heartburn by dumping the contents in
the stomach or caused anal burning by delaying the oral absorption well past the small
intestine . (Somerville 1984 ) (1) The new product, IBgard® LPB incorporates new site
specific technology consisting of microspheres of less than 3 mm in diameter, which can pass
relatively easily and reliably through the pylorus opening at the end of the stomach. These
microspheres can then, via their pH trigger, deliver PO across the small intestine. Thus, one
can avoid unreliable peppermint oil delivery, including dumping or delivery to the distal colon
and anus.
Introduction: There are limited options for IBS patients to obtain rapid relief of their
symptoms. Targeted delivery of ~ 41.5 mg L-menthol to the small intestine may provide relief
of these symptoms. We evaluated the delivery of 41.5 mg L-menthol per capsule (as L-menthol
[2 parts by weight] and PO [1 part by weight]/LPB), on symptom relief in a single arm trial
(IBSRRET) . The same level of L-menthol (41.5 mg/capsule) has been evaluated in a
completed randomized controlled trial of seventy-two patients.
Background: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder
that affects approximately 10% of the population worldwide. Patients with IBS experience
periodic exacerbations of 8 major symptoms, including abdominal pain or discomfort,
abdominal bloating, constipation, diarrhea, incomplete evacuation, pain at evacuation, passage
of gas or mucus, and urgency of bowel movement. (Cappello 2007)(2) The incidence of the
three primary sub-types of IBS has been reported as 61.0% for mixed IBS (IBS-M), 29.3% for
diarrhea-predominant IBS (IBS-D), and 9.7% for constipation predominant IBS (IBS-C).
(Drossman 2009)(3) While there are prescription options for IBS-C, there are no approved
products for IBS-M and limited options for IBS-D, representing an unmet need for patients
with IBS-M and IBS-D.
Aims: To assess IBgard® LPB, a L-menthol and Peppermint Oil Blend, which is prepared with
the equivalent level of L-menthol and containing a lower level of impurities than the IBgard®
formulation, was used in a prior randomized controlled study for the dietary management of
patients with Irritable Bowel Syndrome. This reduction in impurities is enabled by a
proprietary technology to create a L-menthol and PO blend or LPB.
Methods: We evaluated IBS patients who had met the enrollment criteria and had been
randomized to placebo in a previous double blind study. This single arm study (n=18), aged
18-61 years with mixed and diarrhea-predominate IBS (confirmed by Rome III criteria) took 2
capsules of LPB 3 times daily for 4 weeks. Patients rated the intensity frequency of 8 IBS
symptoms on a 5-point scale (IBS symptom questionnaire) and completed daily diaries
recording IBS symptoms, including bowel movement and Bristol stool form.
Results: Two patients were excluded from analysis due to non-compliance. For the 16
remaining patients, the mean Total IBS Symptom Score (TISS) decreased significantly from
baseline after 28 days (P=0.001) as well as the TISS frequency (P=0.017) and TISS intensity
(P=0.0005) scores. There was a statistically significant decrease from baseline in frequency of
3 out of 8 total symptoms and in intensity of 7 out of 8 total symptoms. (Table 1)
Conclusion: The single arm IBSRRET trial showed that the more purified LPB formulation
significantly reduced IBS symptoms within 4 weeks, versus baseline. This is the second trial to
show the benefit of targeted delivery of 41.5 mgs of L-menthol with site specific targeting
technology. The first clinical trial, a placebo-controlled randomized trial, had used the
identical coating system.
This single arm study confirms the utility of delivering 41.5 mgs of L-menthol via SST
technology, which was seen with the previous RCT trial. (Table1)
(1) Somerville KW, Richmond CR & Bell GD. Delayed release peppermint oil capsules
(Colpermin) for the spastic colon syndrome: a pharmacokinetic study. Br. J. Clin. Pharmac.
(1984), 18, 638-640
(2)Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint oil (Mintoil) in the
treatment of irritable bowel syndrome: a prospective double blind placebo-controlled
randomized trial. Dig.Liver Dis. 2007; 39: 530-536.
(3)Drossman DA, Morris CB, Schneck S, Hu YJ, Norton NJ, Norton WF, Weinland SR, Dalton C,
Leserman J, Bangdiwala SI. International survey of patients with IBS: symptom features and
their severity, health status, treatments, and risk taking to achieve clinical benefit. J
Clin.Gastroenterol. 2009; 43: 541-550.
Figure(s)/Table(s):
*TITLE: Cat Dander Sensitization - The Link Between IBS & Asthma
Author(s): Kewin Tien Ho Siah 1,2, Amelia Santosa 1,2, Hung Chew Wong 2, Reuben K Wong
1,2, Paul Lorenz Bigliardi 1,2
Affiliation(s): 1) University Medicine Cluster, National University Hospital 2) Yong Loo Lin
School of Medicine, National University of Singapore
BODY:
Introduction: Large epidemiological studies have shown that asthma and IBS frequently coexist.
Aims: Our aim was to elucidate the role of aeroallergen in IBS and its atopic relationship
through the review of: a) allergic symptoms b) food and aeroallergen sensitization and c)
possible occult parasitic infections.
Methods: Consecutive patients referred to the allergy clinic were invited to participate in the
study. Consenting subjects completed questionnaires, skin prick tests (SPT) and venipuncture
for: total serum IgE (Phadia® 100), specific IgE (ImmunoCAP ISAC®), IgG against Trichinella
sp, Toxocara sp, Echinococcus granulosus, Fasciola hepatica, Schistosoma sp, Filaria sp and
Strongyloides sp. Standard definition was used: IBS by ROME III criteria, asthma by ECRHS II
and allergic rhinitis by GA2LEN definition. Local institutional review board approved the
study. (NHG ROAM:2011/02188)
Results: A total of 87 (48F: 39M) subjects were recruited. 26.4% had asthma, 74.7% had
allergic rhinitis and 42.5% had atopic eczema. 3 subjects were non-atopic. Thirty-six (41.4%)
patients fulfilled ROME III IBS criteria (5 IBS-C, 11 IBS-D, 15 IBS-M and 5 IBS-U).
IBS was significantly (p<0.05) associated with cat sensitisation by two separate tests: positive
SPT to cat dander and specific IgE cat protein Fel d 1. The odds of having IBS were also
significantly higher for asthmatic patients, pet owners and positive SPT to dog allergens.
Allergic rhinitis, eczema and food allergy were not associated with IBS. One non-IBS subject
(out of 60 performed) was tested positive for Toxocara antigen.
Multivariate analyses revealed that asthma and cat sensitization (SPT) were independently
associated with IBS (OR (95% CI) = 7.2 (1.7-29.9), p=0.007 and 8.4 (1.7-41.3), p=0.009).
Conclusion: IBS subjects reported a high cat dander sensitization rate, suggesting a plausible
explanation of high asthma prevalence in IBS subjects. It is important to explore the
underlying pathophysiologic mechanisms and potential therapeutic options.
*TITLE: Physiological Correlates of Perceived Stress in Patients with IBS
Author(s): Weaver, K.R., Fourie, N.H., Sherwin, L.B., Abey, S., Melkus, G.D. & Henderson, W.A.
Affiliation(s): New York University, College of Nursing, National Institute of Nursing Research
(NINR), National Institutes of Health (NIH)
BODY:
Introduction: Irritable bowel syndrome (IBS) is a complex disorder characterized by
abdominal pain and alterations in bowel habits. Variations in the stress response system as
well as high rates of comorbid psychological disorders have been reported in this patient
population.
Background: Conflicting results permeate the literature regarding alterations of the
hypothalamic-pituitary adrenal (HPA) axis in patients with IBS. Correlating patients’
perceptions of stress with physiological indices, and evaluating the influence of patient
variables and perceived stress has not been routinely investigated.
Aims: To compare physiological markers of the stress response system in patients with IBS
and healthy controls (HC). To investigate correlations between IBS patients’ reports of stress
and corresponding stress-related physiological indices. To evaluate the influence of weight,
sex and IBS subtype upon these variables of interest.
Methods: Participants (IBS and HC) completed the 10-item Perceived Stress Scale (PSS) as a
subjective measure of their level of stress. Physiological indices were captured from fasting
peripheral whole blood. Specimens were collected in the morning to control for diurnal
variation, and female participants presented between days 3 and 10 of their menstrual cycle
to control for hormonal variation. Clinical and demographic data were analyzed with SPSS v22
and STATISTICA for descriptive statistics, Mann-Whitney tests, ANOVA, and Pearson’s
correlation coefficients. Significant values were set a priori as p < .05.
Results: Data from 106 participants were analyzed (IBS = 37, HC = 69). As a group, patients
with IBS were found to have significantly higher PSS total scores than HC (14.81 +/- 6.57
versus 10.84 +/- 6.23 respectively, p = 0.003). No differences in PSS scores were found when
grouping participants according to weight (normal weight versus overweight, p = 0.20), or by
sex (p = 0.95). The influence of IBS subtype upon PSS scores (diarrhea predominant,
constipation predominant or mixed) trended towards significance (p = .05). A significant
negative correlation was found between PSS scores and serum cortisol (r = - 0.23, p = 0.02).
Additional correlations between PSS scores with intra-abdominal fat (r = 0.18) and percent
body fat (r = 0.19) did not yield significant findings.
Conclusion: Patients with IBS have significantly higher perceived stress than healthy controls.
Peripheral indicators of the stress response system were found to be negatively correlated
with baseline values of self-reported perceived stress. Such findings lend support to
alterations of the stress response system in patients with IBS; subjects who reported
increased levels of perceived stress displayed diminished levels of cortisol in comparison to
their less stressed counterparts. Significant differences were found between patients with IBS
and healthy controls in baseline PSS scores, with the influence of IBS subgroup on PSS scores
approaching significance. Although an effect of body weight and sex upon PSS scores was not
found, trends were noted in the association of body fat percent and visceral adiposity. These
findings warrant further inquiry, as to the potential mechanism of increased stress among
subgroups of this patient population.
Figure(s)/Table(s):
35
PSS_TOTAL_SCORE_CORRECTED
30
Median
25%-75%
Min-Max
25
20
15
10
5
0
-5
0
1
IBS
Healthy control = 0; IBS =1
Serum Cortisol
24
PSS_TOTAL_SCORE_CORRECTED:Serum Cortisol: r = -0.2261, p = 0.0160; r2 = 0.0511
22
20
18
Serum Cortisol
16
14
12
10
8
6
4
2
0
-5
0
5
10
15
20
PSS_TOTAL_SCORE_CORRECTED
25
30
35
TITLE: Nutritional Management of Refractory IBS-D patients by the Medical Food SerumDerived Bovine Immunoglobulin (SBI) in a 28-Patient Cohort
Author(s): Ira Shafran, MD (1,2); Patricia Burgunder, ARNP (2); Hayley E. Young, PhD (3)
Affiliation(s): 1. University of Central Florida Medical School, Orlando, FL, United States 2.
Shafran Gastroenterology Center, Winter Park, FL, United States; 3. Entera Health, Inc.,
Medical Affairs, Cary, NC, United States.
BODY:
Introduction: Management of heterogeneous diarrhea-predominant irritable bowel
syndrome (IBS-D) can present a challenge: Many patients remain refractory to traditional
pharmaceutical (prescription or over-the-counter) interventions despite the numerous
therapies available. Serum-derived bovine immunoglobulin/protein isolate (SBI) is a
prescription medical food intended for the dietary management of intestinal disorders such as
IBS-D. Recent reports have illustrated the effects of the medical food in drug-refractory
patients; however these reports were mainly focused on endpoints between 4-6 weeks. Thus,
SBI was used in a community gastroenterology clinic setting to manage difficult-to-treat IBS-D
patients and their response was monitored for 16 weeks.
Aims: To determine the effect of SBI on the management of refractory IBS-D patients over the
course of 16 weeks of therapy.
Methods: A single-center, retrospective chart review of IBS-D patients meeting Rome III
criteria (N=28, 16 females, 12 males, average age 64 years) with limited to no response to
traditional therapies was performed after providing SBI (5 g/day) for nutritional support.
According to this practice’s standard of care, patients were contacted at least monthly to
assess symptom management measured by a Likert scale (0=none; 1=minimal; 2=moderate;
3=significant; 4=complete). Responses were reviewed after 16 weeks on therapy. Patients
reporting scores 2-4 were termed responders and 0-1 designated non-responders. A Chisquare test was used to determine the significance of the distribution of non-responders.
Results: Prior to SBI challenge, patients reported difficulty in managing the abdominal
discomfort, bloating, stool frequency, and stool consistency related to their conditions, despite
use of antidiarrheal, antispasmodics, serotonin 5-HT3 receptor antagonists, SSRIs, PPIs, and
antibiotics. Patients had suffered from longstanding IBS symptoms and struggled to find
successful therapy options. After 16 weeks of addition of SBI to their current therapy regimen,
patients reported an average Likert score of 2.4, representing moderate to significant
management of their IBS-D. Specifically, 4 patients reported none, 1 minimal, 8 moderate, 11
significant, and 4 complete. In total, 23 patients reported at least a moderate response while
only 5 patients reported minimal or no management with SBI. This is statistically significant
(Chi-squared=11.571; P=.0007) compared to a null hypothesis in which SBI administration
would have had no effect or minimal effect on patient response. Patients reported
improvement in stool frequency, stool consistency, cessation of fecal incontinence,
management of abdominal discomfort and bloating. These positive changes in patients’
conditions were noted around 2 to 4 weeks in the charts, and maintained to 16 weeks, as
evident by reported Likert score.
Conclusion: SBI afforded an effective option in managing difficult-to-treat IBS-D, allowing
significant management as reported by patients. This effect was observed at 16 weeks, longer
than previous analyses of SBI use in refractory patient populations. These outcomes support
use of SBI as a novel, effective nutritional management option for IBS-D.
Figure(s)/Table(s):
TITLE: Why Irritable Bowel Syndrome (IBS) and Functional dyspepsia (FD) are Immunoneuronal Disorders of Mucosal Cytokine Imbalances Reversible with Polymerized Cross-linked
Sucralfate?
Author(s): Ricky W. McCullough MD MSc
Affiliation(s): Translational Medicine Research Center, Mueller Medical International, Storrs
Connecticut USA;Department of Medicine & Emergency Medicine Veterans Administration
Medical Center, Teaching Hospital Warren Alpert Medical School of Brown University
Providence, Rhode Island 02908 USA; Department of Emergency Medicine Roger Williams
Medical Center Providence, Rhode Island 02908 USA Boston University School of Medicine
Teaching Hospital
BODY:
Background: This abstract is the culmination of a ten year inquiry of a two unexpected
outcomes. In a randomized placebo-controlled dyspepsia trial [1] patients with NERD
and comorbid IBS responded well to high potency polymerized cross-linked sucralfate
(HPPCLS). Comorbid IBS patient volunteered that their uncomfortable and irregular
bowel habits had resolved by the end of the 28 day trial. Since standard sucralfate has
no efficacy in patients with IBS and functional dyspepsia we were curious.
We found in clinical practice experience HPPCLS handily resolved symptoms and signs of IBS
and FD patients. Prospectively, six patients (2 with FD, 4 with IBS) were tested. All six
experienced rapid (2-4 day) resolution of symptoms and signs of FD and IBS. The large
magnitude of treatment effect (2-4 days vs expected 56-84 days response beyond placebo –
as required by FDA patient-reported outcomes guidelines) gave HPPCLS comparative rate
ratios and relative risk measures [2] that were far beyond any quantitative effects of
confounding biases. The clinical response was real, but why. HPPCLS like standard sucralfate
is a non-systemic, topically active agent. Though HPPCLS achieves and maintains surface
concentrations of sucralfate beyond that possible with standard (non-polymerized, noncross-linked) sucralfate (800% on normal lining, 2400% on ulcerated lining 3 hours postadministration), this did not explain why patients responded and, as important, why they
responded so rapidly.
Since HPPCLS is a non-systemic, topically active agent, it was reasoned that there had to be a
mucosa- mediated process engaged by HPPCLS. And if there is a mucosa-mediated process,
how could such a process give rise to the symptom and signs of IBS and FD. So began a
quest in 2005 that spanned nearly a decade.
In 2012 we published a manuscript entitled “IBS, NERD and functional dyspepsia are
immuno-neuronal disorders of mucosal cytokine imbalances clinical reversible with high
potency sucralfate” which disclosed most of our thoughts at the time [3]. This abstract
updates our model for IBS and FD with details not disclosed in 2013.The model appears to
fit most facts (known to author) regarding mucosal immunology and does not appear
inconsistent with newer findings regarding enteric mucosal immunology. One critical point
was identifying the tandem use of ‘TGF secretion paired with increased membrane
expression of GF receptor’ as a likely key feedback-mechanism of mucosal inflammation that
governs the rate of resolution. This point could only be proposed because of the observed
clinical outcomes of HPPCLS and the magnitude of the treatment effect – i.e., rapid resolution
of symptoms & signs. Not only in these 6 patients with IBS & FD but in patients with chemoradiation induced mucositis (oral, esophageal and intestinal) , the rapid response (2-3 days)
to HPPCLS [4] is also explained by the model offered in this abstract.
Structuring the Abstract as a question aided the communication of model to those interested
in a possible pathogenesis of IBS and FD. The question in the title is answered with three
‘Because’s’. I hope that the Abstract Committee find our submission suitable for the 2015
Conference. We believe that the model may provide a ‘roadmap’ to assist direction of future
investigations in IBS & FD.
Methods: Because there are mucosal and submucosal elements involved in a feedbackcontrolled mechanism to maintain integrity of the gastrointestinal lining – a GI
cytoprotection system – comprised of epithelial and subepithelial components (Figure 1)
Epithelial Components
(1.) Epithelial (EPI) and Enterochromaffin cells
(EEC) Key characteristics:
Responsive to upregulation by intra-epithelial lymphocytes (IEL) and provide
later feedback to IEL’s
(2.) At least 3 subpopulations of IEL’s: γδ-IEL / proximal GI αβ-IEL / distal GI
αβ-IEL Key characteristics:
• Fixed ratio of αβ-IEL to γδ-IEL (generally 3:1)
• αβ-IEL’s have regional immunogenicity divided according to their
anatomical location in the intestine: proximal first third, mid third
and distal (the colon).
• αβ-IEL initiate a tiered and measured immune response by
secreting pro-inflammatory cytokines that target epithelial &
submucosal cells
• γδ-IEL modulate & when prompted terminate the immunosignaling of αβ-IEL’s
• γδ-IEL are modulated by feedback immuno-signaling from
upregulated epithelial and enterochromaffin cells
Subepithelial Lamina Propria Components
(direct and indirect targets of αβ-IEL’s immune signaling)
(1.) Subepithelial αβ-T lymphocytes; (2.) Subepithelial Mast Cells; (3.)
Afferent/Efferent Neurons; (4.) monocytes; (5.) Recruited dendritic cells &
recruited neutrophils (6.) eosinophils in FD
Key characteristics:
• Upregulated αβ-T lymphocytes & mast cells stimulate afferent/efferent
neurons which in turn generate all symptoms and signs of IBS (mast cells
may target EEC)
• depending on the intensity of original αβ-IEL signal, epithelial tight
junctions loosens (increased permeability allow microbiota antigens
access to lamina propria resulting in recruitment of dendritic cells
and neutrophils
• all subepithelial cells are primarily subservient to immune signaling by αβ-IEL
• all are subservient to primary diminished signaling by αβ-IEL
• to lesser extent all are subservient to downregulating signals EPI & EEC
• in functional dyspepsia (FD), upregulated mast cells recruit esosinophils
and both cell types target and upregulate afferent/efferent neurons in duodenum
Critical Caveat: IEL do not increase in count nor do they differentiate. Most are positioned
within epithelial tight junctions. They are strictly surveillance cells with αβ-IEL identifying
perceived threats being ultimately subservient to any down-regulation by γδ-IEL which in
turn are responsive to downregulating by EPI that have been previously upregulated to
over-express growth factor receptors as part of a coordinated immune response to a
perceived threat initiated by αβ-IEL. It is our view that the variation in membrane
immunogenicity in αβ-IELs (with the lack of triggered downregulation by γδ-IEL) in the
colon is altered in patients with IBS-c and IBS-d; and for patients with IBS-mixed or postinfection IBS, this altered immunogenicity result in additional elaboration of cytokines
that result in loosen tight- junctions of EPI increasing permeability which in turn engage
recruited participation of submucosal dendritic cells and neutrophils. FD can be
conceptually regarded as ‘irritable bowel syndrome” of the duodenum and likely results
from altered immunogenicity of the αβ-IEL or γδ-IEL with submucosal targets of mast
cells, eosinophils (rather than monocytes) that themselves in turn target submucosal
afferent/efferent neurons which are responsible for all signs/symptoms of FD (whether in
the esophagus, stomach or duodenum). The activation of GF receptors over-expressed on
EPI and EEC (in the initial triggering of the immune reaction), send out downregulating
signal to γδ-IEL’s that in turn down regulated αβ-IEL’s erroneously upregulated by
antigenic threats perceived through their presumed altered immunogenicity.
Downregulated αβ-IEL’s in the colon, halt their secretion of pro-inflammatory cytokines
which then down regulate the submucosal immune response which had targeted the
afferent/efferent enteric neurons. Downregulated enteric neurons allow the rapid
cessation of all symptoms and signs of IBS and FD.
►Because high potency polymerized cross-linked sucralfate is a nonsystemic (HPPCLS), topically active agent that can only engage topically
accessible mucosal elements engaged in the signs and symptoms of IBS and
FD.
►Because a 6 patient cohort (IBS n=4, FD, n=2) with collective history of
120.5 years of symptomatic disease when given HPPCLS (1.5 grams) twice
daily experienced rapid resolution of all symptoms and signs in 2-4 days.
The magnitude of the HPPCLS treatment effect drives rate ratios and
relative risks beyond reach of confounding biases (p<0.05) and confirms
efficacy of HPPCLS for IBS & FD
Figure(s)/Table(s): The GICPS under down-regulation with HPPCLS is depicted in Figure 1.
Copyright  Mueller Medical 1995 in part/2001 in part/2006 in part used here by permission
A,B,C
Potency-enhanced poly-anionic saccharides, eg
HPPCLS, creating micro-environs that support efficient
activation of growth factor receptors, expressed on
EEC, and EPI enteric cells
Primary Attenuation of Inflammatory cytokines to
submucosal cells and neurons
D,E Primary Attenuation by enteric epithelium of stimulated
F
IELs with follow-on deactivation of other IELs,
intraepithelial lymphocytes (D,E) and by epithelial
receptors of chemosensitive neurons
Primary Attenuation by enteric epithelium of
stimulated epithelial receptors in
chemosensitive neurons
G,H,I Secondary attenuation of neuron-directed
inflammatory changes to mast cells, muscles, vessels
J,K,L Tertiary attenuation of mast cell stimulation of
vessels, muscles and other inflammatory cells
■
M
N,O
P,Q
R,S,T
Locally secreted Growth Factors (GF), fibroblast
growth factor, epidermal growth factor, and
transforming growth factor
Micro-environ surrounding newly expressed GF
receptors, known as tyrosine kinase receptors
Primary Attenuation by enteric cells of their
cytokine stimulation of submucosal sensory and
secretory neurons
Primary Attenuation by enterochramafin cells of
their cytokine stimulation of submucosal mast cells
(N) and sensory and secretory neurons (O)
Secondary Attenuation by IEL of their cytokine
stimulation of submucosal lymphocytes,
neutrophils, mast cells and sensory/secretory
neurons
Tertiary attenuation of cytokine secretion by downregulated submucosal lymphocytes, neutrophils,
and mast cells
TITLE: Context of Uncertainty Modulates Brain Activity during Rectal Distension in IBS
Author(s): 1,2,3Michiko Kano, 2Tomohiko Muratsubaki, 2Joe Morishita, 4Huynh Giao Ly,
5Patrick Dupont, 4Lukas Van Oudenhove, 2,3Shin Fukudo
Affiliation(s): 1Frontier Research Institute for Interdisciplinary Sciences, Tohoku University,
2Behavioral Medicine, Graduated School of Tohoku University, 3Psychosomatic Medicine,
Tohoku University Hospital Sendai. Japan, 4Translational Research Center for Gastrointestinal
BODY:
Introduction: Cognitive factor such as fear or anxiety in anticipation of pain may manipulate
pain experience and play an important role in pathophysiology of chronic pain disorders
including irritable bowel syndrome (IBS). IBS is characterized by chronic abdominal pain or
discomfort associated with change in bowel habit without organic alterations.
Aims: The present study sought to characterize difference in brain activity between IBS and
controls in the influence of anticipation, uncertainty of incoming aversive stimuli, on
processing of visceral sensation induced by colonic stimulation.
Methods: Twenty-six subjects with diarrhea-predominant or mixed IBS diagnosed by ROMEIII criteria (14 women, mean age 22.3) and 29 healthy controls (15 women, mean age 22.3)
participated in the study. Functional magnetic resonance imaging was used to acquire blood
oxygen level dependent contrast images. Data was collected whilst subjects received balloon
distensions to the rectum as well as during cued uncertain (50% chance of aversive
stimulation) and certain (100% chance of aversive stimulation) anticipation period. The
balloon volume eliciting 40-60% discomfort (severe discomfort) in each subject was recorded
beforehand and used for rectal stimulation during the scan. The participants rated level of
discomfort and anticipatory fear of stimuli using visual analogue scale. Whole-brain voxelbased analysis was conducted in SPM8 using a voxel-level threshold of uncorrected p < 0.01
combined with a cluster-level threshold at FWE-corrected p < 0.05 .
Results: Subjects with IBS showed significantly higher rating of discomfort and anticipatory
anxiety compared to controls. Brain response during certain anticipation were significantly
higher in controls compared to subjects with IBS in the precuneus, calcarine gyrus, mid
cingulate cortex, lingual gyrus, thalamus, superior temporal gyrus, and left rolandic
operculum. During uncertain anticipation, subjects with IBS demonstrated significantly higher
brain response in the right insula, postcentral gyrus, rolandic operculum inferior frontal gyrus
and superior temporal gyrus. Uncertain compared to certain anticipation induced higher brain
activity in the cerebellum, precuneus, linual gyrus, calcarine gyrus, supramarginal gyrus,
thalamus and superior temporal gyrus in subjects with IBS in comparison to controls. Rectal
distention after uncertain cue compared to that after certain cue induced higher brain
response in the mid cingulate cortex, precuneus, post erior cingulate cortex, paracentral
lobule and supplemetary motor area in subjects with IBS compared to controls.
Conclusion: Differences in anticipatory responses to discomfortable rectal distension
between IBS patients and healthy controls in pain- and anxiety related brain regions are
moderated by a context of uncertainty. The brain activity during anticipation was associated
with that during rectal distention differently between subjects with IBS and controls. These
findings suggest that context of uncertainty may produce different brain response during
anticipation and experience of aversive visceral stimuli in subjects with IBS compared to
controls.
*TITLE: 5-HT3 Receptor Signaling is a Rat Model of Sex Specific Visceral Hypersensitivity
Author(s): Nadine El-Ayache and James J Galligan
Affiliation(s): Michigan State University
BODY:
Background: The Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal
disorder characterized by altered bowel habits and visceral hypersensitivity, especially in
women. 5-Hydroxytryptamine (5-HT, serotonin) signaling is disrupted in some IBS patients
possibly due to polymorphic variations in the gene encoding the serotonin transporter (SERT)
which result in increased extracellular 5-HT availability. Female SERT knockout (KO) rats
exhibit visceral hypersensitivity to colonic distention that mimics colonic hypersensitivity
know to occur in female IBS patients. Alosetron, a 5-HT3 receptor antagonist is FDA approved
for the treatment of IBS in women suggesting that 5-HT signaling at 5-HT3 receptors plays a
role in the pathogenesis of IBS.
Aims: We tested the hypothesis that 5-HT action at 5-HT3 receptors contributes to visceral
hypersensitivity
Methods: We examined the effects of acute subcutaneous (s.c.) and intrathecal (i.t.)
administration of morphine and the 5-HT3 receptor antagonists alosetron, granisetron, and
ondansetron on visceral sensitivity in SERT KO and wild type (WT) rats. We measured the
visceromotor response (VMR) to colorectal distension (CRD)
Results: Ondansetron (0.1 mg/kg, s.c) did not affect visceral sensitivity, while alosetron (0.1
mg/kg, s.c.) increased the VMR to CRD in SERT KO female rats and WT male rats. Granisetron
(0.1 mg/kg, s.c.) increased VMR to CRD in SERT KO female rats only. Morphine (3 mg/kg s.c.)
suppressed the VMR to CRD in all rats. Ondansetron (25 nmol, i.t) and Granisetron (25 nmol,
i.t.) did not affect visceral sensitivity, while alosetron (25 nmol. i.t) increased the VMR to CRD
in SERT KO female. Morphine (10 µg, i.t.) suppressed the VMR to CRD in all rats
Conclusion: The 5-HT3 receptor antagonists used cross the blood brain barrier. Therefore,
the results suggests that global 5-HT3 receptor antagonism causes a paradoxical increase in
the VMR to CRD in SERT KO female rats and WT male rats. The increase in VMR to CRD
observed with inhibition of 5-HT3 receptors at the level of the spinal cord in SERT KO female
rats suggest that in the presence of altered serotonergic singling, ovarian hormones might
modulate this response. Supported by: 5R21NS075841
Figure(s)/Table(s): Additional figures will be added to poster ***
*TITLE: Anxiety Symptoms Mediate the Relationship Between Adverse Childhood
Experiences and Irritable Bowel Syndrome
Author(s): Elizabeth J. Videlock MD(1), Sarah H. Park MD(1), Wendy Shih MPH(2), Angela P.
Presson PhD(2,3), Emeran A Mayer MD PhD(1), Lin Chang MD(1)
Affiliation(s): 1. Oppenheimer Center for Neurobiology of Stress and 2. Dept of Biostatistics,
David Geffen School of Medicine at UCLA; 3. Div. of Epidemiology, Dept. of Medicine,
University of Utah
BODY:
Introduction: Adverse childhood experiences (ACEs) are associated with an increased risk of
irritable bowel syndrome (IBS). IBS patients with a history of abuse respond better to
psychological therapy (pharmacotherapy and CBT) than those without abuse.(Creed,
Psychosomatic Med 2005; Drossman, Gastro 2003)
Aims: To test the hypothesis that psychological symptoms mediate the relationship between
ACEs and IBS.
Methods: 148 Rome III+ IBS (73% women, mean age=31 years) and 156 healthy controls
(HCs, 60% women, mean age=30 years) completed the ACE Questionnaire, which measures
ACEs experienced before the age of 18.(Felitti, Am J Prev Med 1998) Exclusion criteria
included current diagnosis of a psychiatric disorder according to structured interview (DSM
MINI). The Hospital Anxiety and Depression (HAD) Scale measured current anxiety and
depression symptoms. The effect of ACE (as dichotomous measure and score (0-8)) on IBS
status was tested by logistic regression controlling for age, sex, BMI, race and education.
Mediation analysis was done with the “mediation” package in R version 3.2.0. Variance
inflation factor values were <5 for all variables, supporting the absence of multicolinearity.
Results: Participant characteristics are shown in Table 1. IBS patients had higher scores for
HAD anxiety and depression symptoms, though 75% and 96% of IBS patients scored within
the normal range for anxiety and depression, respectively (100% of HCs were in then normal
range for both). The presence of ACEs increased the odds of having IBS (odds ratio (OR)=2.05
[95% confidence interval (CI): 1.21-3.48], p=0.008). Compared to HCs, IBS subjects had
significantly higher ACE scores (2.07 vs. 1.28, p<0.001). Anxiety but not depression symptoms
mediated the effect of both the presence of ACEs and the ACE score on IBS status. The direct
and mediated effects of a history of ACE (yes vs. no) and ACE score on IBS status are shown in
Table 2.
Conclusion: A history of ACEs and the ACE score predict IBS status. While anxiety symptoms
mediated the effect of ACEs/ACE score on IBS, there was also a trend for a direct effect of ACE
score on IBS (p=0.08), which may have reached statistical significance in a larger sample. We
have previously shown a direct effect of early adverse life events on IBS controlling for anxiety
using the Early Trauma Inventory Self-Report Short Form.(Bradford, CGH 2012).
Figure(s)/Table(s):
Table 1: Participant Characteristics
Traits: Mean (SD)
HC (n=156)
Women (%)
93 (60%)
Age in years (SD)*
30.26 (10.92)
BMI (SD)*
26.56 (6.13)
IBS (n=148)
108 (73%)
31.05 (10.03)
24.64 (5.07)
Race (%)
Asian
41 (28%)
26 (19%)
African American
18 (12%)
12 (8%)
Caucasian
66 (45%)
77 (55%)
Other/Mixed
22 (15%)
25 (18%)
Education (%)
High School Graduate or Less
9 (6%)
5 (3%)
Some College
67 (45%)
57 (40%)
College Graduate
44 (30%)
42 (29%)
Any Post Graduate Work
29 (19%)
40 (28%)
HAD Anxiety (0-21)*
3.92 (2.86)
7.69 (4.45)
HAD Depression (0-21)*
1.59 (2.17)
3.44 (3.19)
*p<0.05. SD, standard deviation; HC, healthy control; IBS, irritable bowel syndrome; BMI, body
mass index; HAD, hospital anxiety and depression symptom scores
Table 2: Mediation Model Results
Total Effect
Predictor
Estimate
p-value
ACE Score
0.057
< 0.005
ACE (yes vs.
0.16
< 0.005
no)
ACE, adverse childhood experiences
Direct Effect
Estimate
0.028
0.036
p-value
0.08
0.52
Causal Mediation Effect
Estimate
p-value
0.029
< 0.005
0.13
< 0.005
*TITLE: Effects of Emotional Awareness and Expression Training Versus Relaxation
Training for People With Irritable Bowel Syndrome: A Randomized Trial
Author(s): Elyse R. Thakur1, Mark A. Lumley1, Hannah J. Holmes1, Nancy A. Lockhart1,
Jennifer N. Carty1, Maisa S. Ziadni1, Heather Doherty1, Jeffrey M. Lackner2, & Howard
Schubiner3
Affiliation(s): 1. Wayne State University, 2. University at Buffalo, SUNY, 3. St. John Providence
Health System
BODY:
Background: IBS is a common, disabling GI disorder, which in its more severe forms is
influenced by psychological factors such as negative emotions (e.g., anxiety, depression). In
the absence of a medical cure, a number of psychological treatments have been developed to
help patients control and reduce the daily burden of GI symptoms. Historically, psychological
interventions for IBS have emphasized suppressing negative emotions through
psychophysiological self-regulation strategies like relaxation training. Recent research
suggests that suppression of negative emotions may be counterproductive. This suggests that
emotional awareness and expression strategies designed to elicit negative emotions may have
therapeutic advantages over somatic control techniques like muscle relaxation.
Aims: We developed and tested a novel, brief psychological intervention—Emotional
Awareness and Expression Training (EAET), and compared it to a conceptually opposite
approach – relaxation training (RT) – and a treatment as usual (TAU) control condition.
Methods: 106 people (aged 18 – 70 years, M = 36.1; 80.2% female) with IBS were recruited
from the community and gastroenterological clinics. Participants completed self-report
measures of IBS symptom severity (IBS-SSS), psychological functioning (BSI), and quality of
life (IBS-QOL) at baseline and then were randomized to one of the three conditions (EAET, RT,
or TAU). Participants in EAET or RT had 3, weekly, 50-minute, individual therapy sessions. All
participants were re-assessed at 4-week and 12-week follow-ups.
Results: Treatment completion was 93% and 95% of participants provided follow-up data.
Intent-to-treat analyses compared the three conditions at each follow-up point, covarying
baseline levels of the outcome measure. At 4 weeks, EAET was associated with significantly
greater reduction in IBS symptom severity than TAU (ES = -0.65, p = .004), whereas RT did not
differ from EAET (ES = - 0.40, p = .13) or the controls (ES = -0.29, p = .15). Both EAET and RT
reduced anxiety (ES = -0.50, p = .003 and ES = -0.58, p = .001, respectively) and hostility (ES = 0.43, p = .01 and ES = -0.41, p = .03, respectively) compared to TAU at 4 weeks, and RT
reduced depression (ES = -0.60 p = .002). Although EAET and RT maintained these
improvements at 12 weeks, the conditions no longer differed because the controls improved.
For quality of life, however, both EAET and RT surpassed TAU at both 4 (ES = -0.90, p <.001
and ES = -0.92, p <.001, respectively) and 12 weeks (ES = -0.56, p =.004 and ES = -0.62, p =.02,
respectively).
Conclusion: A brief intervention that targeted unresolved stress and conflict by enhancing
emotional awareness and expression was as successful as relaxation training in improving
symptoms, distress, and quality of life in IBS. This suggests the potential value of emotional
processing interventions for this population. Future research should attempt to determine the
types of patients for whom this emotional intervention is best suited.
TITLE: Night Time Heart Rate Variability and its Relationship to Pain Sensitivity and
Gastrointestinal Symptoms Differ by Irritable Bowel Syndrome Bowel Pattern Group
Author(s): Monica E. Jarretta, PhD. Claire Jungyoun.Han, MSN. Kevin C. Cain, PhD. Robert L.
Burr, PhD. Margaret M. Heitkemper, PhD.
Affiliation(s): a Dept. of Biobehavioral Nursing and Health Systems, University of
Washington, Seattle, WA. b Dept. of Biostatistics and Office of Nursing Research, University of
Washington, Seattle, WA.
BODY:
Introduction: Irritable bowel syndrome (IBS) is a heterogeneous disorder characterized by
both the range of bowel alterations and dysfunctions in gastrointestinal (GI) motor activity,
visceral pain sensitivity, inflammation/permeability, dysbiosis, autonomic nervous system
(ANS) balance and/or processing of internal and external information by the central nervous
system. Of interest to us is the role of the ANS. One non-invasive approach to assessing an
individual’s ANS activity is to examine heart rate variability (HRV). A recent meta-analyses of
studies utilizing HRV measures found that, overall, patients with IBS have a low high
frequency (HF) band power when compared to healthy controls (HCs). However, the
differences of HRV between IBS and HC groups were primarily present when HRV was
measured in short intervals, but it was not consistently found with 24-hour HRV measures.
Thus, long-term protocols (e.g., 24 hr.) may have limitations due to chang es in body position
and uncontrolled stimuli that occur throughout the day.
Aims: The purpose of this study was first to compare nighttime HRV, upper GI visceral
sensitivity measured by water loading test (WLT), thermal pain sensitivity, and conditioned
pain modulation (CPM) efficiency score in a cohort of women with medically-diagnosed IBS to
HCs. Second, we explored the relationship of HRV indices (time domain and spectral analysis
variables) to daily abdominal pain, GI symptoms, upper GI visceral sensitivity, thermal pain
sensitivity, and CPM efficiency score. Based on the literature as well as our prior work, we
hypothesized that patients with constipation dominant and mixed-IBS (IBS-C+M) will have
reduced night-time HRV and increased sympathovagal balance, which is associated with
increased discomfort with the WLT, increased thermal sensitivity, and reduced CPM efficiency
relative to those with diarrhea dominant-IBS (IBS-D) and HCs.
Methods: We studied 55 women with IBS (IBS-C+M, n=25; IBS-D, n=30) and 38 age-matched
HCs. Participants completed questionnaires (e.g., Health History, Rome III questionnaires, and
Brief Symptom Inventory) and 4-week diaries and had night-time 12-hour Holter monitoring
performed. Time-domain HRV and spectral analyses for HF, low frequency (LF) and LF/HF
were assessed on data collected between 0200-0600 hr. In the morning a WLT (symptoms:
abdominal pain, bloating, fullness, and nausea over 30 minutes) and CPM test using a heat
stimulus were performed. Chi-square tests, t-tests and ANOVA were used to compare
demographic characteristics and outcome variables between IBS and HC women and across
subgroups of women with IBS; and Pearson correlation were used to test relationships among
the variables. Area under the curve (AUC) was used to compare differences in the WLT
symptoms. Due to the skewness of HRV measures, log transformation and means were used.
Add itional analyses were done to determine whether the results would have changed after
controlling for psychological distress, age and BMI.
Results: Women in the IBS-C+M group had lower HRV HF than HCs. Both IBS groups reported
more daily abdominal pain and GI symptoms than HCs. There was an overall increase in
symptoms on the WLT in the IBS groups compared to HCs (p = .037 to .007). The greatest
effect was between IBS-C+M and HCs (p = .010 - .004). LF/HF balance was positively
correlated with daily reports of GI symptoms in the IBS groups only (p <.05). Within the IBS
groups, IBS-C+M group exhibited greater (p < 0.05) thermal sensitivity at 46, 47, 48°C as
compared to IBS-D. The CPM effect was less in the IBS-C+M group (CPM = 0.7) as compared to
IBS-D (CPM = 1.1), but not significantly.
Conclusion: In women, ANS activity and its relationship to visceral and peripheral sensitivity
is dependent on predominant bowel type. Therapies directed at enhancing vagal activity may
be particularly beneficial for women with IBS-C+M group.
*TITLE: Feasibility of Measuring the Contractile Electrical Complex Over 72 Hours in a
Healthy Human Subject Using a Wearable, Wireless Electrode Patch.
Author(s): Anand Navalgund, PhD, (1) Steve Axelrod, PhD, (1) George Triadafilopoulos, MD
(2)
Affiliation(s): 1. G-Tech Medical, Mountain View, California, 94040, USA , 2. Gastroenterology
and Hepatology, Stanford University School of Medicine, Palo Alto, California 94304, USA
BODY:
Introduction: Dysfunction in the motility patterns of the gastrointestinal tract may play a role
in the pathogenesis of functional gastrointestinal disorders. The High Amplitude Propagating
Contraction (HAPC) observed manometrically, is a signature pattern seen in the colon [1-2].
Differences in the frequency and amplitude of the HAPC have been observed in functional
disorders, such as slow transit constipation [3] and IBS [4-6]. The HAPC is likely a
physiological equivalent to the Contractile Electrical Complex (CEC) that occurs in the 20-40
cycles per minute (cpm) range. [7-8]. Since the HAPCs/CECs typically occur 6-8 times over a
24 hour period in healthy humans [1-3], it becomes imperative to study the colonic function
for at least 24 hours, if not more. However, longitudinal studies have been limited due to the
difficulties associated with the invasive nature of available techniques, such as manometry
and/or the need for implantable electrodes. Recordi ngs of gastrointestinal myoelectrical
signals, such as the CEC on the abdominal surface could be a useful tool to understand and
characterize colonic motility, different functional disease states and potential pharmacological
influences. G-Tech Medical is developing a wireless, wearable disposable electrode patch for
the abdominal surface that would measure these gastrointestinal myoelectrical signals noninvasively over the course of several days. Herein, we present a 72-hour profile of the
electrical activity acquired in a healthy subject (male, 34 yrs., 155 lbs) using such wireless
“GutCheck” patch prototype.
Aims: To determine the feasibility of noninvasively measuring the contractile electrical
complex/colonic migrating motor complex over 72 hours in a healthy human subject
Methods: The G-Tech GutCheck patch, as shown in Figure 1A, consists of a flexible substrate
material approximately 2.5” diameter on which are printed Ag/AgCl electrodes, a medical
grade adhesive and electronics, to acquire, digitize and transmit electrical signals via
Bluetooth Low Energy (BLE) to a paired iPhone App (Figure 1B). The patch includes a 3 volt
watch battery to power its electronics. Periodically, the iPhone uploads the raw data onto a
cloud server that is accessed through an associated computer.
The subject cleaned and prepped the skin with isopropyl alcohol and NuPrep gel (Weaver and
Company, Aurora, Colorado, USA) before applying the GutCheck patch in the upper right
corner of the abdomen, as shown in Figure 2. The subject entered meals, bowel movements
(BM) and other activities through the app. Post-processing of the raw data was performed on
a notebook computer using a custom LabVIEW program that included removal of large
amplitude artifacts and band-pass filtering, followed by Fourier transformation to frequency
space over selected time subintervals.
Results: Peaks in the spectrum indicative of rhythmic activity were seen at frequencies across
the available spectral range throughout the 72-hour period. In particular, we focus here on
frequencies from 18 to 35 cpm as being related to colonic activity. On a majority of the
occasions when peaks occurred, an association with events such as meals and BMs was
observed. Figure 3A shows the “waterfall plot” of the frequency spectrum between 14 and 35
cpm (x-axis) computed every 4 minutes and staggered as a function of time (y-axis) for the
first 24 hours. The observed peaks are likely a result of the contractile electrical complexes.
Figure 3B shows the time dependence of the activity in the 18 to 35 cpm range, computed by
summing the spectral amplitude over that range for each 4 minute segment. Meals, BMs and
other activities such as sleep are noted. Figures 4 and 5 are similar plots for days 2 and 3,
respectively. The subject had four BMs on day 1, two BMs on day 2 and one BM on day 3. Dayto-day variability likely exists for colonic activity in general and that was observed for the
contractile electrical complex here. At the end of 73 hours the coin cell battery was drained;
the patch stopped acquiring and transmitting the data and the test concluded.
Conclusion: There is an intriguing level of agreement between the appearance of the peaks in
the 18-35 cpm frequency range and events, such as meals and bowel movements, to suggest
that G-Tech Medical’s “GutCheck” patch can record the contractile electrical complexes at the
abdominal surface. Further research is needed to study for intra- and inter-subject variability
and dietary or pharmacologic excitation or inhibition of HAPC.
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