While no biomarkers have definitively met the diagnostic criteria for eosinophilic GI diseases, some biomarkers have been shown to be associated with disease activity.. Keywords Eosinoph
Trang 1https://doi.org/10.1007/s11882-024-01142-0
REVIEW
Minimally Invasive Approaches to Diagnose and Monitor Eosinophilic
GI Diseases
Accepted: 12 March 2024 / Published online: 27 March 2024
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024
Abstract
offer a unique and non-invasive approach to tracking EoE disease progression While no biomarkers have definitively met the diagnostic criteria for eosinophilic GI diseases, some biomarkers have been shown to be associated with disease activity Here, we examine the potential of recently studied biomarkers
include mRNA analyses, protein fingerprinting, amplicon sequence variants (ASVs), T cells and IgE receptors, eosinophilic cationic proteins, cytokines, and nitric oxide exhalation
representation of biopsy-based results, in contrast to biomarkers obtained from indirect or peripheral (blood, breath) methods However, this is based on limited clinical studies without sufficient numbers to evaluate true diagnostic accuracy Large-scale randomized trials are needed to fully ascertain both the optimal sampling technique and the specific biomarkers that reflect diagnostic status of the disease
Keywords Eosinophil · Eosinophilic oesophagitis · Eosinophilic esophagitis · Eosinophilic gastritis · Eosinophilic
enteritis · Eosinophilic gastroenteritis · Eosinophilic colitis · Biomarker
Introduction
Eosinophilic gastrointestinal diseases (EGIDs) are chronic
inflammatory diseases characterized histologically by
the dense intestinal eosinophilia Disease management
of EGIDs is challenging due to the lack of definitive
bio-markers outside of mucosal eosinophilia, which currently
require sedated endoscopy to obtain esophageal biopsies
This aspect of care greatly increases the cost and burden on
the patient, can diminish quality of life, and be associated with potential complications
Due to the negative effects surrounding multiple seda-tions, alternative methods for EGID management are necessary Biomarkers pose a promising alternative for disease management Biomarker retrieval can be non- or minimally invasive and can be obtained through a vari-ety of sampling techniques including blood draws, breath testing, luminal fluid sampling, mucosal surface brush-ing, and fecal testing Biomarker testing is less costly, faster, and minimally invasive, making it an important avenue of research However, currently, insufficient research has been done to determine diagnostic utility of these biomarkers, specifically for EGIDs Biomarkers can
be indicators of generalized inflammation, but may not show if inflammation is isolated to the intestinal tissue
As such, the need for a biomarker that is specific to the disease characteristics of EGIDs is necessary Currently, research in this area shows some advancement that will
be reviewed here
* Glenn T Furuta
glenn.furuta@childrenscolorado.org
1 Department of Public Health, University of Colorado School
of Medicine, Aurora, CO, USA
2 Digestive Health Institute, Children’s Hospital Colorado,
Aurora, CO, USA
3 Gastrointestinal Eosinophilic Diseases Program, University
of Colorado School of Medicine, Aurora, CO, USA
4 Department of Bioengineering, University of Colorado
Denver|Anschutz Medical Campus, Aurora, CO, USA
Trang 2What are Important Factors to Consider
When Measuring Biomarkers?
Biomarkers are measurable components of organisms or
biological processes that can have patterned, predictive
physi-ologic or pathophysiphysi-ologic events within the body, they
can serve to measure health, diagnose disease, or to
moni-tor the natural hismoni-tory of treated or untreated disease
When considering biomarkers as a way to understand
underlying biological processes, four items need to be
addressed First, what is the biomarker that will be
meas-ured? Selection relies on it providing a reliable,
repro-duceable, and validated reflection of the process to be
monitored For instance, hemoglobin A1c is a peripheral
biomarker that is a key component to detecting the body’s
ability to metabolize glucose properly and hence serves as
a screening for diabetes Another example pertaining to
the gastrointestinal (GI) tract relates to celiac disease Two
biomarkers used for celiac disease include the peripheral
measurement of tissue transglutaminase (ttg) that reflects
small intestinal damage and the histological assessment
of the small intestine for mucosal injury, specifically
vil-lous blunting and intraepithelial lymphocyte infiltration
Second, what sample needs to be collected to assay the
biomarker? This sample needs to reflect the biologic
pro-cess to be studied Some biological propro-cesses may express
biomarkers that circulate throughout the body and hence
blood samples may be adequate Diseases affecting the GI
tract may be reflected by peripheral biomarkers such as
blood or breath or may limit their release to local
microen-vironments In this case, stool, saliva, luminal fluids, and
tissue samples all have provided useful samples to
diag-nose or monitor diseases Furthermore, transport of the
biomarker from its emergent source to a peripheral
loca-tion may impact the utility of the sample for
understand-ing timunderstand-ing of disease progression For example, markers
found in the blood, sputum, or urine may not reflect early
disease if the source of the disease is separated from the
sampling milieu Regardless of source, the sample needs
to contain the biomarker of choice in quantity and quality
that reflects the process to be measured Third, what is
the best method to collect the biomarker? In this regard,
the two preceding questions will dictate the best
meth-odology Venipuncture is the best way to sample blood
and the natural expulsion is the easiest for breath, stool,
and urine Emerging methods such as luminal sampling
or epithelial cellular scraping may provide direct means
of obtaining esophageal samples that are still minimally
invasive More invasive measures may be needed to access
certain portions of the GI tract if that is the target Finally,
how will the biomarker be measured? Depending on the
biochemical properties, stability, and qualities of the bio-marker, any number of readily available techniques can be typically used for proteins including ELISA and point-of-care techniques such as lateral flow assays Conventional pathology may be used for cytology techniques In sum-mary, considerations for the analyses of biomarkers should address key questions of identification of the biomarker, targeting of the proper sample and determination of the best capture and analytical methods
What are Complexities of Assessing Biomarkers Relevant to Gastrointestinal Diseases?
With respect to the GI tract, several different anatomic and physiologic considerations need to be addressed when think-ing about biomarker detection The GI tract is a series of 4 luminal organs (esophagus; stomach; small intestine- duodenum, jejunum, ileum; and colon) that are connected to
2 solid organs (liver and pancreas) The esophagus carries food and secretions to the stomach where the mechanical and chemical process of digestion starts Chyme released into the small intestine is digested by the secretion of enzymes from the pancreas, liver, and gall bladder into the duodenal lumen As this process continues, selective absorption, along with mucous secretion, occurs thru the length of the duode-num, jejuduode-num, and ileum resulting in liters of effluent that are presented to the colon for desiccation and the eventual timely release of a small volume of fecal material Through-out this process, trillions of microbes reside in symbiosis and in varying distribution, providing key participants in the digestive process and when unbalanced, proposed contribu-tors to disease
Knowledge of this physiology is important to consider when thinking about the 4 key elements posed above to consider in biomarker selection In a GI disease, what bio-marker, where should it be measured, and how will it be collected to be reflective of health or disease in a specific organ? For instance, with respect to disaccharidase defi-ciency, lactase will be the relevant biomarker to assess as
it is key in sugar digestion and tissue samples should be collected from the small intestine since this is where the relevant underlying physiologic processes take place Given this information, it can be next ascertained that a method that directly samples small intestinal tissue would be opti-mal, which narrows the possible techniques to intestinal endoscopy Sampling of the gastric mucosa for lactase would not be helpful in this situation because it is not present in the stomach In another example, fecal calprotectin (FCP), a neutrophil enzyme that is a reliable biomarker for inflamma-tory bowel disease, can be assayed in the stool and collected
by naturally expelled samples In contrast, assay of the FCP
Trang 3in the saliva would not be reliable as the release of FCP in
IBD occurs more distally in the gut Finally, measuring the
microbiome in the stool of a patient with celiac disease may
or may not reflect the actual microbiome relevant to a
dis-ease that manifests primarily in the small intestine In this
regard, a method that samples mucosal microbiome locally
from the small intestine may be ideal This review will focus
on these elements of measuring biomarkers as they pertain
Presently, diagnostic criteria for EGIDs require a mucosal
As scientific investigation refines criteria and regulatory
requirements adjust, alternative biomarkers and sampling
will permit new diagnostic algorithms, but for now,
defini-tive diagnosis requires presence of symptoms, a mucosal
biopsy that identifies dense eosinophilia and exclusion of
alternative causes for these two findings With respect to
monitoring therapeutic responses to treatments,
histologi-cal measures of eosinophilia are still required for regulatory
approval To address some cumbersome elements related to
endoscopy, emerging technical advancements and scientific
discoveries are shaping new approaches to capture viable,
newly discovered biomarkers
What are Eosinophilic GI Diseases?
EGIDs are a broad term used to define a group of
com-plex GI diseases, characterized by GI symptoms and
dense mucosal eosinophilia, and include a series of
dis-eases identified by their predominant site of inflammation
diagnosis of EGID, other causes of symptoms and mucosal
eosinophilia need to be ruled out While studies are
defin-ing gene panels that may provide diagnostic platforms,
underlying mechanism of EGIDs is currently thought to
esophagitis (EoE) is characterized by swallowing
prob-lems and food impaction in adults and vague symptoms
related to reflux, abdominal pain, and feeding
difficul-ties in children Eosinophilic gastritis (EoG) patients can
present with a broad array of common symptoms
Eosinophilic enteritis (EoN) is the rarest of the EGIDs
and patients may present with similar symptoms as EoG
and diarrhea with or without profound laboratory
Importantly, these lab abnormalities can occur with
min-imal to no symptoms Eosinophilic colitis (EoC) is the
least well understood and characterized of the EGIDs and
can present with mild symptoms of abdominal pain and
the EGIDs is also characterized by mucosal abnormali-ties that include thickening of the mucosa, exudates and ulcerations that are specific to the diseased organ To date, EGIDs appear to be chronic and thus require ongo-ing treatment to prevent complications that include growth failure and partially obstructive luminal strictures Treat-ments include dietary restriction of food allergens, topical steroids, proton pump inhibitors and recently the anti-IL-4
inflammation can correlate with complications, assess-ment of relevant biomarkers on a timely basis is critical
to provide optimal care The bulk of the current literature
on this topic focusses on EoE; since the prevalence of EGIDs are increasing, and they affect the whole of the GI tract, this review will report data specific to EoE but also generalize findings when relevant, to include and discuss how they may pertain to EGIDs
Why is it Important to Measure Biomarkers Associated with Eosinophilic GI Diseases?
This topic is of particular importance for several reasons First, EGIDs are an increasing group of diseases that affect
EGID biomarkers that can diagnose or track disease activity have not been identified or sufficiently validated to be used
tissue inflammation Fourth, EGIDs are chronic diseases that require chronic treatment and disease activity needs to be
date, disease activity requires inspection and sampling of the intestinal mucosa with endoscopy that can be costly, associated with complication and diminished quality of life
of biomarker detection could be transformative for patients with EGIDs
What are Biomarkers Associated with EGIDs?
To date, biomarkers associated with EGIDs have been obtained from blood and intestinal tissue samples, but because of the inherent concerns about endoscopy, other sources have been assessed including saliva, intestinal flu-ids, and breath These biomarkers hold particular inter-est due to ease of retrieval and accuracy of measurement Below is a summary of the current biomarkers that have been measured, sample source, and methods used to ana-lyze and the samples
Trang 4Eosinophil‑Derived Granule Proteins
(Eosinophil cationic proteins (ECP), eosinophil-derived
neurotoxin (EDN), eosinophil peroxidase (EPO) and major
basic protein (MBP))-ECP, EDN, EPO, MBP are
cytoplas-mic eosinophil-associated granule proteins that reflect the
presence of eosinophils in any sample analyzed including
tissue, saliva, blood, and tissue effluent Regardless of the
tissue examined, EDGPs can be recognized in the sample
by their eosin-stained characteristic appearance Detection
can be in improved by specialized antibody staining for the
specific protein although measurements are subjective based
adults and children, an EPX scoring system was developed
leading to the ability to detect disease activity based on
meas-urement of EPX in oral secretions does not provide a reliable
Blood sampling of EDGPs as well as eosinophil counts
Elevated levels of ECPs have been shown consistently in
EDN levels have shown differing results, but two studies
found higher plasma levels to be shown in EoE patients
EPO levels were significantly lower in EoE patients once
controlled for eosinophils MBP levels are varied and do not
provide enough consistency for predictive outcomes While
elevated in some patients, the specificity of this
periph-eral marker is challenging because of fact that many EGID
patients also suffer from allergic diseases also characterized
by eosinophilia, and thus, measurements may be only
indi-cating presence of active allergic disease somewhere in the
body Finally, newer methods such as the string test allow
minimally invasive sampling of intestinal effluents including
intraluminal samples, which allow EDGPs capture that
sig-nificantly associates with esophageal mucosal inflammation
can also be tested via feces, offering a wide range of testing
options but the specificity of this sample with respect to GI
organ is lacking
Mast Cells
Mast cell infiltration has been associated with EGIDs and as
a result of increased expression of their inflammatory
mol-ecules and association with tissue fibrosis and injury may
tryptase serves as a reliable biomarker of mast cell presence
and activation that can be detected in tissue and blood
sam-ples and when analyzed alone or in combination with other
analytical results may be accelerated with recent artificial
Molecular‑Based Biomarker Panels
A number of studies have used broad molecular approaches
to characterize the inflammatory profiles of patients with
and shown patterns supportive of diagnostic panels and EoE subphenotypes along with some that change follow-ing treatments Most recently, an oral buccal mucosa scrap-ing sample study used publicly available RNA seq data and found differences of CDH26, KCNJ2, and PLD1 in EoE patients compared to controls yielding potentially supportive model for minimally invasive diagnostics In another study,
18 CpG methylation biomarkers were used to successfully
small patient numbers and more work will be needed to vali-date these approaches
Extracellular Matrix Molecules
Examining protein biomarker levels associated with myofi-broblast and inflammatory cell concentrations associated with EoE have been measured in blood by protein finger-printing to ascertain whether they were associated with increased eosinophil numbers in the tissue EoE can cause extracellular matrix changes due to myofibroblast and inflammatory disruption from proteases In a study of 29
patients, higher levels of biomarkers (PRO-C3, PC3X, C3M, CTX-II, PRO-C4, C4M, PRO-C5, PRO-C6, C6M, VICM, VIM, and CPa9-HNEs) were associated with an eosinophil
intriguing biomarker because of it proposed role in
intralu-minal analysis of periostin show it to be increased during active inflammation and a correlation with stenotic EoE
protein analytic capacity
MicroRNAs
MiRs are a short RNA fragment that control biologic pro-cesses including allergic responses Mechanistically, these molecules may participate in the generation of the associated
a study of 22 adults, measurements of MiR-4688 was found
can regulate TGF-β signaling, a molecule associated with EoE TGF-β activation can lead to a loss of epithelial barrier
by disruption of tight junctional molecules thus allowing elevated allergens and / or microbes with intimate contact with epithelial surfaces and the subepithelial immunomilieu
In another study of 56 adult saliva samples, miR-205-5p was
the exact mechanism that TGF-β signaling affects MiR-4688
Trang 5is unclear and the specificity of MiR-4688 for EoE is still not
certain, larger studies will be necessary to confirm EoE
phe-notypes as it relates to these specific MiRs will be needed
MiR testing can be completed using saliva or intraluminal
samples thus making it easy to collect but analysis will
require more sophisticated laboratory equipment
Microbiome Signals
A number of studies suggest alterations in the microbiome
are associated with EoE and may participate in the initiation
and perpetuation of esophageal inflammation and reflect
including RNA seq, have been used to analyze these
pat-terns from samples including saliva, tissue, and luminal
contents The advent of bioinformatics and
high-through-put sequencing will undoubtedly amplify this knowledge
non-invasive form of testing that in some circumstances my
Potential trigger bacteria include non-typeable H Flu,
Pro-teobacteria, and Pasturella with potential protection by H
pylori [58–60] A more recent study examined Amplicon
sequence variations, short, recovered DNA sequences from
genes of interest ASVs related to Streptococcus, Neisseria,
and Prevotella have been consistently higher among EoE
patients vs non EoE patients; the reasoning of elevated
lev-els is unknown and may be unrelated to disease effects and
Cytokines
T2 cytokines are synthesized and released in tissues affected
by EoE Assessment can be helpful to characterize the resident
immunomilieu but this may change rapidly Cytokine levels
(eotaxin-3, IL-4, IL-13, and IL-5) are shown to be elevated in
systemic allergic response can show similar cytokine levels
as EoE Most recently, peripheral analysis identified IL5RA
as a potential biomarker that can detect tissue inflammation
blood or saliva and are measured by ELISA
Cell Adhesion Molecules
CD41 is an integrin subunit that shows platelet
associa-tion specifically regarding the beta subunit of eosinophils
Increased levels of circulating CD41 proteins show increased
levels of eosinophils, a marker of EoE CD41 was shown to
CD41 can show increased eosinophil circulation in blood but
is unable to identify the origins of circulating eosinophils
This form of testing is non-predictive for EoE but could be confirmatory along with other factor Blood testing for CD41 offers a noninvasive form of testing
T Cells
T cells react to immune responses from IgE antibodies IgE antibodies can be elevated in EoE patients but it is unclear as
to whether or not this is related to the underlying esophageal eosinophilia Elevated and activated T cells may indicate food sensitization and thus support some therapeutic interventions but presently are not helpful for diagnosis or monitoring of
cells in the blood may be indicative of EoE disease activity due to an increased presence of allergy response
Exhaled Nitric Oxide
Fractionated exhaled nitric oxide (FeNO) is a byproduct of
examined the ability of breath measurements of FeNO to serve
with EoE, FENO was measured before and after treatment Despite histological response, no statistically significant
com-paring adults and children with EoE and not, after adjusting for other allergic diseases, FENO was found to be statistically
test-ing is an exhalation test that can be easily administered FeNO exhalation rates may provide insight into inflammation but are non-specific as to cause of inflammation or the location of inflammation, and thus, more studies are needed to eliminate confounding factors to use this as a biomarker or to utilize this
Plasma Urea Cycle Metabolites
Urea cycle metabolites can provide insight into the body’s energy expenditure, which may be upregulated with inflam-mation such as that in the esophagus associated with EoE Currently, no metabolomics have been identified as specific markers for EoE, but some have shown promising differ-ences in EoE patients vs controls such as dimethylarginine,
What are Current Advances in Capturing Biomarkers in EGIDs?
With respect to improving ways to capture EGID-related biomarkers, a number of different approaches have arisen that are designed to limit costs and complications related
to sedated endoscopy, reduce time to obtain results, target
Trang 6specific upper intestinal organs, and improve patient
expe-riences Four approaches have been developed to directly
analyze eosinophil associated biomarkers that includes
unse-dated transnasal endoscopy, the esophageal string test, the
Transnasal Endoscopy (TNE)
TNE is a relatively straightforward, well-established
tech-nique which takes advantage of a narrow caliber endoscopic
device that can be easily passed thru the anesthetized nasal
and pharyngeal passages without sedation It has been used
to previously assess for esophageal cancer and other
proxi-mal esophageal diseases The TNE has revitalized care for
patients with EoE in that this unsedated endoscopy can
efficiently procure esophageal samples to monitor disease
to traditional endoscopy, TNE is able to assess the visual
appearance of the esophageal mucosa, obtain biopsy
sam-ples of similar size and has a limited side effect profile
In addition, the TNE was preferred by patients who had
Since these initial studies, TNEs have now been adopted
by a number of pediatric centers to monitor EoE patient’s
esophageal mucosal eosinophilia and track response to
bleed-ing, infection, and perforation all of which are unusual and
are outweighed by the benefits that include reduced cost
and complication rates, less time to complete, and potential
improvement in quality of life for patients undergoing
mul-tiple inspections
Cytosponge
In order to eliminate risks associated with endoscopy, at
least 3 devices have emerged as innovative approaches
to assess for disease activity in patients with EoE The
is composed of a capsule containing a 30-mm
polyure-thane sponge that is attached to a retrieval string After
an unsedated patient swallows the capsule, the capsule
dissolves in the stomach and the sponge is retrieved thru
the esophageal lumen capturing superficial epithelial
frag-ments and luminal contents Re-assembly of the fragfrag-ments
can be accomplished from the sponge and staining of the
fragments developed an inflammatory score based on the
proce-dure in adults poses minimal risks, with the low possibility
of esophageal bleeding, gagging, and vomiting and
pro-vides an excellent approach to obtaining mucosal cellular
samples for analysis
EsoCheck
The EsoCheck is an ingestible plastic balloon attached to a
balloon is swallowed and inflated in the lower esophagus
It is withdrawn while inflated so the exterior of the balloon retrieves esophageal cells The cells are then harvested and sent for examination of eosinophils Similar to the Cyto-sponge, this procedure poses minimal risks, with the low possibility of gagging, esophageal bleeding, and vomiting
Esophageal String Test
The esophageal string capsule is a minimally invasive device designed to sample intraluminal GI inflammation The cap-sule is filled with a string and the proximal extruding end
of the string is taped to the cheek The capsule is then swal-lowed, and the string is taped to the cheek of the patient
for eosinophil-associated proteins by ELISA to develop an EoE Score that reflects whether the esophageal mucosa con-tains more or less than 15 eosinophils/HPF, the diagnostic threshold for EoE Risks of the procedure include gagging, bleeding, and vomiting which are minimal; this procedure
is preferred over endoscopy by patients as well as parents
of children
Other Testing Modalities‑EndoFLIP, Esophagram and pH Impedance
Three other approaches have been used to assess esopha-geal function and structure in patients with EoE The End-oFLIP is a catheter based device that is designed to sense esophageal distensibility as a metric of esophageal function
encased within a buffer filled balloon When inserted into the esophagus, the balloon is insufflated with buffer and when adjacent to the esophageal wall, pressure is sensed by the biosensors, leading to a manometric tracing This tracing can be translated into a numerical score of distensibility that can reflect esophageal flexibility and fibrosis in adults and children with EoE Testing in adult and pediatric patients provides a data not obtainable presently by other techniques that reflect esophageal structure and function, especially as
esophageal perforation or bleeding and cost is associated with the device and need to perform during endoscopic procedures The barium esophagram with pill ingestion is
a radiographic test in which patients swallow barium dye and a dissolvable barium coated pill to trace the esopha-geal diameter and monitor the ability of the esophagus to transfer an object from its top to bottom Image analysis provides an esophageal diameter and timed analysis of pill
Trang 7Facilities needs
Used in adults and c
Trang 8passage The value of this test lies in its ability to perform
a topographic analysis of the esophageal lumen and
real-life analysis of the esophageal function Studies in children
and adults identify esophageal narrowing or Schatzki rings
that may not be readily apparent at the time of endoscopy
indi-cating esophageal dysfunction or occult narrowing in EoE
Finally, pH impedance catheters have been used to assess
mucosal integrity in patients with EoE to analyze
epithe-lial barrier function Results are supportive in being able to
detect differences during eosinophilic inflammation
The above components represent important requirements
for developing diagnostic and monitoring tools for EGID
However, it is also important to consider the patient
perspec-tive when developing diagnostic tools Methods that are
bur-densome on patients and their families may not be adopted
in a timely manner Such burdens lie not only in the potential
cost but also in other factors such as needing to take time
off from school or work, risks of frequent, repeat testing,
and requirements for the facility and personnel—which may
increase cost, extent of pre-procedure fasting, and
many of these key factors for sample capture methods that
are either clinically available or are being evaluated for
diag-nosis or monitoring EGID These also represent important
requirements for developing new methods
Conclusion
Due to the complexities of repeat invasive procedures to
man-age EGIDs, minimally and non-invasive approaches to EGID
management are a worthwhile investment for further
investiga-tion Multiple endoscopies can have a negative effect on the
mental wellness of patients Biomarkers are a novel approach to
diagnosing and managing EGIDs Biomarkers can be examined
via the blood, luminal fluid, mucosal scraping, or from physical
properties of the esophageal mucous Some of this testing can
be administered in a primary care setting and thereby provide
more accessible methods for EGID management
Current research regarding EGID biomarkers has not
involved testing in medicated and unmedicated populations
of EGIDs Large-scale, randomized control trails using these
populations will provide more definitive results regarding
biomarkers that are specific to disease activity Further,
bio-marker research has yet to find an esophageal-specific
inflam-mation marker While these biomarkers are accurate
indica-tors for inflammation, they lack specificity for esophageal
inflammation, a key marker of EGIDs Further investigation
to identify a biomarker of esophageal inflammation would be
effective for EGID management Biomarker research presents
the opportunity to reduce the burden of testing and sedation administered to EGID patients Current methodologies provide promising advancements that should be further investigated
Author Contributions All authors contributed to the conception, writ-ing and reviewwrit-ing this manuscript
Funding This work was supported by the Silverman Chair in Pediatrics.
Compliance with Ethical Standards
Conflict of Interest EJMF declares no competing interests GTF is the Chief Medical Officer of EnteroTrack RS is the Chief Executive Of-ficer of EnteroTrack.
Human and Animal Rights and Informed Consent All reported stud-ies/experiments involving human or animal subjects performed by the authors were in accordance with the ethical standards of institutional and/or national research committee and with the 1964 Helsinki declara-tion and its later amendments or comparable ethical standards.
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