Primary objective: to assess and compare the effect of lean-donor phage transplantation with placebo treatment (PBS) on glucose tolerance in obese, insulin resistant subjects at risk to develop diabetes. Secondary objective: to assess and compare…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess and compare the effect of lean-donor phage transplantation with
placebo on glucose tolerance in obese, insulin resistant subjects at risk to
develop diabetes. HbA1c, fasted glucose and insulin levels will be determined
at baseline and 28days after the intervention (prior to the OGTTs). Area under
the curve for glucose excursion during OGTTs will be the primary determinant of
changes in glucose metabolism following the transplantations. Furthermore,
insulin sensitivity will be estimated from the OGTT by oral glucose insulin
sensitivity (OGIS) methodology. In addition, HOMA-IR and Matsuda index will be
calculated as secondary readouts for insulin sensitivity.
Secondary outcome
To assess and compare changes in gut microbiota and phage composition following
phage transplantation and placebo. In addition, microbiota and virome
composition at baseline will be determined and compared between lean donors and
obese recipients.
Bacterial and phage composition will be assessed by 16S rRNA analysis and
NanoPore technology, resp., in fecal samples of donors and recipients.
Background summary
Alterations in gut microbiota composition and bacterial metabolites have been
increasingly recognized to affect host metabolism and are at the basis of
metabolic diseases such as obesity and type 2 diabetes (T2DM). As shown by our
group, modulation of the gut microbial composition by fecal microbiota
transplantation (FMT) improves insulin sensitivity in insulin resistant
subjects at risk to develop T2DM. Importantly, however, the effect of FMT is
transient and effect size differs strongly between subjects. We have shown that
subjects with lower diversity at baseline are more likely to benefit from donor
FMT than subjects with higher bacterial diversity. In addition, the level of
engraftment of the transplant (i.e., presence of donor bacterial composition in
gut of recipient) might determine in part the efficacy of this procedure.
Factors that determine gut microbiota diversity and engraftment after FMT and
subsequent effects on glucose metabolism are largely unexplored.
Bacteriophages (phages) are viruses that exclusively infect and
eliminate bacteria. There is substantial evidence for a role of phages in
shaping microbial communities in many ecosystems. However, insight in and
attention for the role of phages in the human gut microbial community is
limited. The effect of interventions that have significant consequences for
both bacteria and phage communities, such as FMT, have never been assessed.
Since one gram of feces contains ~109 phage-containing particles and
~109 bacterial cells, a vast number of phages are co-transplanted during FMT.
The contribution of phages to FMT success (improved glucose metabolism) might
therefore be quite substantial but has thus far never been studied. We
therefore here propose a study in which we will transfer fecal bacteriophages
from lean, healthy subjects to the gut of obese, insulin resistant subjects and
assess the effect on engraftment and glucose metabolism.
Hypothesis: We speculate that the virome composition of the lean donor and the
subsequent interaction between phages and bacteria in the recipients are
crucial determinants of stability and diversity of gut bacterial composition
and glucose metabolism in humans after FMT. We hypothesize that lean donor
phage transplantation will increase gut microbial diversity and improves
glucose handling in insulin resistant recipients at risk to develop T2DM.
Study objective
Primary objective: to assess and compare the effect of lean-donor phage
transplantation with placebo treatment (PBS) on glucose tolerance in obese,
insulin resistant subjects at risk to develop diabetes.
Secondary objective: to assess and compare changes in gut microbiota and phage
composition following phage transplantation and placebo.
Study design
Prospective, double-blinded, randomised, single-center intervention study.
N=24 metabolic syndrome subjects will be randomised in the placebo arm (N=12)
or the phage arm (N=12) of the study.
Healthy lean males will be phage donors
Intervention
Twelve MetSyn subjects will receive PBS (placebo) whereas another group of
twelve MetSyn subjects will receive a fecal filtrate transplant (FFT), which
lacks bacteria and mainly consists of phages.
1. morning stool sample is collected by recipient and donor
2. randomisation of participant in placebo or phage arm of the study
3. gastroduodenoscopy will be performed to place the duodenal tube. A abdominal
Xray will be performed to check for correct placement of the tube.
4. Bowel lavage (2-3liters of KleanPrep) will be performed to Ensure bowel
lavage (2-3hrs)
5. Phage or placebo transplant will be prepared and administered through the
duodenal tube (500ml).
Study burden and risks
Duration of the study is 7weks during which participants will visit the AMC
three times. Participants will spend 12hours in total during this time and
around 180ml of blood will be drawn.
Oral glucose tolerance test: no risk
Intravenous cannula: there is a low risk of flebitis at the intravenous
injection sites, this is unpleasant, but not harmful, of temporary nature and
self-limiting
Abdominal Xray: participants will undergo radiation exposure of 0.7mSv. This
has negligible risk.
Phage transplantation: phages are present in the fecal microbiota transplant as
we perform them regularly. The risk associated with phage transplantation is
therefore considered similar and minimal due to extensive donor screening. In
the past decade, around 600 fecal transplant have been performed and no short-
or long-term complications were obeserved.
Gastroscopy: the risk of bleeding of perforation during gastroscopy is
considered small. The placing of the duodenal tube can unpleasant but there are
no risks involved.
Discomfort: placing of cannula, blood draw and placing of nasoduodenal tube can
be experienced as uncomfortable.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
Participants:
• Caucasian male/female
• Age: >=18 years old
• BMI: >=25 kg/m2
• At least 3 of the following criteria:
o Fasting plasma glucose >=5.6 mmol/L OR HOMA-IR index >=2.5
o Waist-circumference >=102 cm
o HDL cholesterol <=1.02 mmol/L
o Blood pressure >=130/85 mmHg
o Triglycerides >=1.7 mmol/L
• Subjects should be able to give informed consent
Donors:
• Caucasian male/female
• Age: >18 years old
• BMI: 18-25 kg/m2
• Subjects should be able to give informed consent
Exclusion criteria
Participants:
• A history of cardiovascular event (cerebrovascular accident (CVA), myocardial
infarction (MI)) or pacemaker implantation
• Use of any medication including proton pump inhibitors, antibiotics and
pro-/prebiotics in the past three months or during the study period
• (Expected) prolonged compromised immunity (due to recent cytotoxic
chemotherapy or human immunodeficiency viruses (HIV) infection with a CD4 count
< 240/mm3)
• Presence of overt type 1 diabetes mellitus (T1DM) or T2D
• History of chronic diarrhoea (>=3 stools/day for >4 weeks), chronic
obstipation (<2 defecations/week for >3 months), Irritable Bowel Syndrome (IBS)
(according to Rome IV criteria) or Inflammatory Bowel Disease (IBD).
• Smoking or illicit drug use (MDMA/amphetamine/cocaine/heroin/GHB) in the past
three months or use during the study period
• Use of >5 units of alcohol daily on average in the past three months or use
of >2 units of alcohol during the study period
• History of cholecystectomy
Donors:
• Use of any medication including proton pump inhibitors, antibiotics and
pro-/prebiotics in the past three months or during the study period
• History of, or known exposure to HIV, hepatitis B (HBV) or C virus (HCV),
syphilis, human T-lymphotropic virus (HTLV) I and II, malaria, trypanosomiasis,
tuberculosis
• Known systemic infection not controlled at the time of donation
• Smoking or illicit drug use (MDMA/amphetamine/cocaine/heroin/GHB) in the past
three months or use during the study period
• Use of >5 units of alcohol daily on average in the past three months or use
of >2 units of alcohol during the study period
• Risky sexual behaviour (anonymous sexual contacts; sexual contacts with
prostitutes, drug addicts, individuals with HIV, viral hepatitis, syphilis;
work as prostitute; history of sexually transmittable disease)
• Previous reception of tissue/organ transplant
• Previous (<12 months) reception of blood products
• Recent (<6 months) needle stick accident
• Recent (<6 months) body tattoo, piercing, earring, acupuncture
• Recent medical treatment in poorly hygienic conditions
• Risk of transmission of diseases caused by prions
• Recent parasitosis or infection from rotavirus, Giardia lamblia and other
microbes with GI involvement
• Recent (<6 months) travel in tropical countries, countries at high risk of
communicable diseases or traveller's diarrhoea
• Recent (<6 months) history of vaccination with a live attenuated virus, if
there is a possible risk of transmission
• Healthcare providers having frequent patient contact (to exclude the risk of
transmission of multidrug-resistant organisms)
• Individual working with animals (to exclude the risk of transmission of
zoonotic infections)
• History of IBS (according to Rome IV criteria), IBD, functional chronic
constipation, coeliac disease, other chronic GI disorders
• History of chronic, systemic autoimmune disorders with GI involvement
• History of, or high risk for, GI cancer or polyposis
• Recent appearance of diarrhoea (>=3 stools/day), hematochezia
• History of neurological/neurodegenerative disorders
• History of psychiatric conditions
• Presence of chronic low grade inflammation or metabolic syndrome (NCEP
criteria)
• Presence of T1DM, T2DM or hypertension
• History of cholecystectomy
• Positive serologic test for HIV 1/2, hepatitis A virus (HAV), HBV, HCV,
hepatitis E virus (HEV), cytomegalovirus (CMV) or Epstein-Barr virus (EBV),
strongyloides or lues
• Presence of faecal bacterial pathogens Salmonella spp., Shigella spp.,
Campylobacter spp., Yersinia spp., C. difficile, H. pylori, shigatoxigenic
Escherichia coli (STEC), Aeromonas spp. or Pleisiomonas Shigelloides in faeces.
• Positive Dual Faeces Test (DFT) for Giardia Lamblia, Dientamoeb fragilis,
Entamoeba histolytica, Microsporidium spp., Cryptosporidium spp., Cyclospora,
Isospora or Blastocystis Hominis. Positive microscopic exam for eggs, cysts and
larves (e.g. helminth eggs)
• Presence of extended spectrum beta-lactamase (ESBL) producers,
carbapenemase-producing Enterobacteriaceae (CPE), vancomycin-resistant
enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) in
faeces
• Presence of Rotavirus, Norovirus I/II, Enterovirus, Parechovirus, Astrovirus,
Sapovirus or Adenovirus in faeces
• Abnormal liver or renal function (creatinine >110 µmol/l, ureum >8,2 mmol/l,
ASAT >40 U/L, ALAT >45 U/L, AF >120 U/L, GGT >60 U/L, bilirubin >17µmol/L) or
impaired immunity (CRP >5 mg/L, haemoglobin <8,5 mmol/L, MCV 80-100 fL,
leukocytes 4,0-10,5 x109/L, thrombocytes 150-400 x109/L).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL67136.018.18 |