Diabetes
Conditions
Keywords
advanced microbiome therapeutics, diabetes, safety
Brief summary
E. coli Nissle (EcN) is a well-established human probiotic. However, it has been found that it produces colibactin, linked to colorectal cancer. In this safety trial, the safety and properties of a novel, colibactin-knockout EcN strain (EcNΔClbP) is investigated.
Detailed description
In this randomised controlled intervention study, the investigators will compare EcN vs. EcN colibactin-knockout (EcNΔClbP), given once daily for 7 days, in a population of healthy individuals. Safety will be established using adverse event reporting, study visits and laboratory parameters. Pharmacokinetics will be established at the beginning and the end of the study. EcN/EcNΔClbP gut engraftment properties and effects on gut microbiome composition will be assessed using fecal analyses (qPCR, shotgun metagonmics). In addition, effects on glucose homeostasis will be studied using continuous glucose monitoring.
Interventions
DIETARY_SUPPLEMENTEcN Colibactin knockout
E coli Nissle strain with ClbP-gene removed and therefore not producing colibactin
DIETARY_SUPPLEMENTE Coli Nissle
E Coli wildtype strain
Sponsors
Max Nieuwdorp
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Participants will be randomised through Castor (eCRF). Treatment allocation is blinded for investigators and participants. The pharmacist has access to the randomisation list.
Intervention model description
Double-blind, randomised, controlled, safety study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female of Caucasian descent * If female, postmenopausal * Age: 18-65 years old * BMI: 18-25 kg/m2 * Subjects should be able to give informed consent
Exclusion criteria
* Use of any systemic medication (except for paracetamol), including proton pump inhibitors, antibiotics and pro-/prebiotics in the past three months or during the study period. * Use of the EcN probiotic strain (Mutaflor®) in the past 12 months. * (Expected) prolonged comprised immunity (e.g. due to recent cytotoxic chemotherapy or human immunodeficiency viruses (HIV) infection with a CD4-T cell count \< 240/mm3). * History of moderate to severe disease of the digestive tract, such as celiac disease, 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). * Any gastro-intestinal disorder within the past 6 months * Smoking or illicit drug use (e.g. amphetamine/cocaine/heroin/GHB) in the past three months or use during the study period. * Use of \>21 units of alcohol per week on average in the past three months or use of \>2 units of alcohol during the study period. * Simultaneous participation in other studies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bristol Stool Chart | Weekly, during 3 weeks | Changes in Bristol Stool Chart score throughout the study. Stools can be scored from 1 (hard stool) to 7 (watery stool). A score of 4 is considered ideal. |
| basophils | Weekly, during 3 weeks | Changes in basophils in 10\^9/L throughout the study |
| neutrophils | Weekly, during 3 weeks | Changes in neutrophils in 10\^9/L throughout the study |
| monocytes | Weekly, during 3 weeks | Changes in monocytes in 10\^9/L throughout the study |
| Lipid profile | Weekly, during 3 weeks | Changes in lipid profile throughout the study |
| Homeostatic model of insulin resistance (HOMA-IR) | Weekly, during 3 weeks | Changes in HOMA-IR throughout the study |
| Gastro-intestinal quality of life - questionnaire | Weekly, during 3 weeks | Changes in Gastro-intestinal quality of life (GIQLI) score. The maximum score is 155, the minimum score is 31. A higher score represents a better outcome. |
| Adverse events | 3 weeks | The number, duration and severity of adverse reactions to assess the safety/tolerability of the EcNΔClbP strain compared to the wild type strain. |
| CRP | Weekly, during 3 weeks | Changes in CRP (mg/L) |
| Leucocytes | Weekly, during 3 weeks | Changes in leucocytes (10\^9/L) |
| Renal function | Weekly, during 3 weeks | Changes in renal function, expressed as kreatinin levels (micromol/L) throughout the study |
| Bilirubin | Weekly, during 3 weeks | Changes in bilirubin in micromol/L throughout the study |
| alkaline phosphatase | Weekly, during 3 weeks | Changes in alkaline phosphatase in U/L throughout the study |
| gamma-GT in U/L | Weekly, during 3 weeks | Changes in gamma-GT in U/L throughout the study |
| AST | Weekly, during 3 weeks | Changes in AST in U/L throughout the study |
| ALT | Weekly, during 3 weeks | Changes in ALT in U/L throughout the study |
| Hemoglobin | Weekly, during 3 weeks | Changes in hemoglobin in mmol/L throughout the study |
| trombocytes | Weekly, during 3 weeks | Changes in trombocytes in 10\^9/L throughout the study |
| eosinophils | Weekly, during 3 weeks | Changes in eosinophils in 10\^9/L throughout the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of copies of EcN (qPCR) | Daily during 2 weeks | Quantification of EcN in faeces samples collected throughout the two weeks via quantitative polymerase chain reaction (qPCR) |
| Microbiome composition | Weekly during 3 weeks | Comparison of relative abundances of species throughout the study using shotgun metagenomics |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fasting blood bile acids | Weekly during 3 weeks | Changes in fasting plasma bile acids will be measured at V2, V3 and V4. |
| Fecal 24h short chain fatty acids | Weekly during 3 weeks | Changes in 24h faecal and fasting and short-chain fatty acids will be measured at V2, V3 and V4. |
| Fasting blood short chain fatty acids | Weekly during 3 weeks | Changes in fasting short-chain fatty acids will be measured at V2, V3 and V4. |
| Fecal 24h bile acids | Weekly during 3 weeks | Changes in 24h faecal bile acids will be measured at V2, V3 and V4. |
Countries
Netherlands
Outcome results
None listed