Applying Manuka Honey in Gastroenterology

Honey is a substance with a long tradition of use in medicine going back to
ancient Egypt. Research shows wide therapeutic potential, demonstrating An
anti-oxidant, bacteriostatic, andt-inflammatory and antimicrobrial properties.
It is a carbodydrate rich syrope produced by bees, primarliy from floral
nectars. The major components are fructose and glucose, however a large number
of other chemical components are present in small amounts, varying depending on
the type of honey.

The therapeutic mechanism of honey has not yet been fully elucidated. However,
an antibacterial effect has been attributed to osmolarity, hydrogen peroxide
generation and unidentified additional phytochemical components3. Furthermore,
as well as antibacterial activity, honey has been shown to have an
anti-inflammatory function5. The anti-inflammatory effects may be due to
antioxidant components.

Numerous studies have demonstrated that unprocessed honeys have antibacterial
activity against a range of pathogens. The investigated pathogens include
isolates of diarrhoea causing bacteria, isolates from infected community,
nosocomial wounds and burns, bacterial infections of the conjunctiva and other
ocular surface diseases. Our research team1, as well as other clinical
researchers2 have performed in vitro studies demonstrating that unprocessed
honeys have antibacterial activity against a range of pathogens, including
Clostridium difficile.

Clostridium difficile (CD) associated disease is an increasingly common health
problem. C. difficile is a causative agent of antibiotic associated
pseudomembranous colitis, antibiotic associated colitis and antibiotic
associated diarrhea4. CD overgrowth usually occurs during antibiotic therapy,
as the normal gastrointestinal flora is disrupted. Discontinuation of
antibiotics does not lead to symptomatic improvement and new strains of the
pathogen have a substantial failure rate after therapy cessation5.

Microscopic colitis (MC) is an umbrella term for chronic watery diarrhea with a
normal macroscopic appearance of the colonic mucosa by endoscopy though with
typical histological inflammatory changes. MC includes two main subtypes, i.e.
collagenous colitis (CC) and lymphocytic colitis (LC). Over 80% of MC patients
respond well on induction therapy with oral budesonide6. However, approximately
60-80% of all patients experience symptom relapse after cessation of treatment
(after 3-6 months) and require additional low dose budesonide maintenance
therapy7,8,9. A considerable proportion of the relapsing patients (10-20%) will
finally turn out to be non-responder to oral budesonide9. Risk-factors for
primary non-response are unknown. Unfortunately, an alternative evidence based
treatment is not yet available. The exact pathophysiological mechanisms of
chronic diarrhea in MC are not clarified. A clear association between MC and
concomitant autoimmune disorders like rheumatic disease, celiac disease and
thyroid disease is described10,11, suggesting MC to be an auto-immune mediated
disorder. Furthermore, drug-induced inflammation, bile-salt malabsorption and
changes in the epithelial barrier function (e.g. increased permeability) due to
luminal factors12 are considered as contributing factors to MC development.
However, the exact mechanisms remain to be elucidated.

Functional gastro-intestinal disorders (FGID) are common disorders which
present with persistent and recurring GI symptoms. More than 20 FGID have been
identified, the most commonly known being Irritable Bowel Syndrome (IBS)13.
FGID are thought to have a multifactorial pathophysiology including
gastro-intestinal (GI) infections, dietary intake, and stress may all play a
role in disease development. No golden standard exists for treatment of IBS.
Treatment decisions are often based on severity of symptoms and the
relationship of IBS with possible influential factors such as diet, or
psychosocial comorbidities. The current consensus is that milder symptoms are
primarily related to visceral hypersensitivity and treatment therefore
constitutes pharmacology targeting the GI tract itself14. More severe symptoms
are generally correlated to psychosocial difficulties and treatment often
requires the use of antidepressant medications or psychological treatment14.

The aim of this study is to investigate efficacy of a manuka honey lavage in
the treatment of three distinct disorders; persistent clostridium difficile
infection (CD), budesonide dependent microscopic colitis (MC), and therapy
refractory irritable bowel syndrome patients with the diarrhea subtype
(IBS-D).

We propose a single center RCT in which 3 groups of patients who have been
deemed therapy refractory will undergo treatment with a colonic lavage using
Manuka honey. These groups will be compared to a placebo group within each
diagnostic criteria. These three patient groups consist of:
1. Patients with a persistent clostridium difficile infection who either do not
respond to antibiotic therapy or do not tolerate antibiotics
2. Patients with diagnosed microscopic colitis who have received maximum
budesonide treatment, and experience relapse of symptoms during step-down
dosages, defined as budesonide dependent patient*s
3. Patients diagnose with irritable bowel syndrome patients of diarrhea subtype
according to the Rome IV criteria, whose symptoms persist despite 6 months of
treatment via the outpatient clinic

All patients who fulfill the inclusion and exclusion criteria will be asked for
inclusion via the gastroenterology outpatient clinic. Upon inclusion, patients
will be entered into an anonymous database, only accessible to the primary
researcher at each intervention site.

Following inclusion and informed consent a planned colonoscopy will take place.
This will occur according to standard procedure at each intervention site. At
the time of colonoscopy a colonic lavage will be performed. A dilution of 20%
manuka honey (MGO 550+) in a quantity of 250 ml will be sprayed through a
specialized nozzle attached to the endoscope, and will be distributed
throughout the entire colon starting at the cecum.

Following colonoscopy a patient will be discharged and will receive follow up
check-ups at 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks and 1 year. At each of
these follow-up momentsthe following outcome measures will be gathered: the
GSRS, Birmingham IBS questionnaire, Quality of Life (QOL) Index and specifics
regarding frequency and consistency of stool according to the Bristol Stool
Scale.

Successful treatment will be defined as a stool frequency less than 3 times
daily and a consistency of 4 or less according to the Bristol stool scale.

In the case of microscopic colitis patients receiving treatment with
budesonide, following successful treatment at week 2 follow-up, all patients
will be asked to slowly decrease dosages of budesonide and resume the follow-up
period, with instructions to contact the primary researcher should symptoms
reoccur. If symptoms reoccur this will be defined as failure of therapy, and
the original therapy with budesonide will resume.

Following inclusion and informed consent a planned colonoscopy will take place.
This will occur according to standard procedure at each intervention site. At
the time of colonoscopy a colonic lavage will be performed. A dilution of 20%
manuka honey (MGO 550+) in a quantity of 250 ml will be sprayed through a
specialized nozzle attached to the endoscope, and will be distributed
throughout the entire colon starting at the cecum.

The burden and risks associated with participation are conform the risks of a
colonoscopy. These risks include bleeding, perforation of the bowel, and
adverse reactions to the sedation. These risks are limited by not performing
any biopsies during colonoscopy within the parameters of this trial.

The patients to be included in the trial are therapy refractory. This means
that they suffer from severe gastrointestinal symptoms, with the chief
complaint being diarrhea, often having a severe impact on their quality of
life. No treatments in the standard care are sufficient to aid in symptom
relief. The possibility of this experimental treatment doing so, and the
possible improvement in quality of life justifies the risks and burdens
associated with participation in this trial.