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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EcN | Active Comparator | E Coli Nissle wildtype 10^11 once daily for 7 days |
|
| EcN colibactin-knockout | Experimental | EcN colibactin-knockout 10^11 once daily for 7 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EcN Colibactin knockout | Dietary Supplement | E coli Nissle strain with ClbP-gene removed and therefore not producing colibactin |
|
| Measure | Description | Time Frame |
|---|---|---|
| Adverse events | The number, duration and severity of adverse reactions to assess the safety/tolerability of the EcNΔClbP strain compared to the wild type strain. | 3 weeks |
| CRP | Changes in CRP (mg/L) | Weekly, during 3 weeks |
| Leucocytes | Changes in leucocytes (10^9/L) | Weekly, during 3 weeks |
| Renal function | Changes in renal function, expressed as kreatinin levels (micromol/L) throughout the study | Weekly, during 3 weeks |
| Bilirubin | Changes in bilirubin in micromol/L throughout the study | Weekly, during 3 weeks |
| alkaline phosphatase | Changes in alkaline phosphatase in U/L throughout the study | Weekly, during 3 weeks |
| gamma-GT in U/L | Changes in gamma-GT in U/L throughout the study | Weekly, during 3 weeks |
| AST | Changes in AST in U/L throughout the study | Weekly, during 3 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of copies of EcN (qPCR) | Quantification of EcN in faeces samples collected throughout the two weeks via quantitative polymerase chain reaction (qPCR) | Daily during 2 weeks |
| Microbiome composition |
| Measure | Description | Time Frame |
|---|---|---|
| Fecal 24h bile acids | Changes in 24h faecal bile acids will be measured at V2, V3 and V4. | Weekly during 3 weeks |
| Fasting blood bile acids | Changes in fasting plasma bile acids will be measured at V2, V3 and V4. |
Inclusion criteria:
Healthy male or female of Caucasian descent
Age: 18-65 years old
BMI: 18-25 kg/m2
Subjects should be able to give informed consent
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amsterdam UMC location AMC | Amsterdam | Netherlands |
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| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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Double-blind, randomised, controlled, safety study
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Participants will be randomised through Castor (eCRF). Treatment allocation is blinded for investigators and participants. The pharmacist has access to the randomisation list.
| E Coli Nissle | Dietary Supplement | E Coli wildtype strain |
|
| ALT |
Changes in ALT in U/L throughout the study |
| Weekly, during 3 weeks |
| Hemoglobin | Changes in hemoglobin in mmol/L throughout the study | Weekly, during 3 weeks |
| trombocytes | Changes in trombocytes in 10^9/L throughout the study | Weekly, during 3 weeks |
| eosinophils | Changes in eosinophils in 10^9/L throughout the study | Weekly, during 3 weeks |
| basophils | Changes in basophils in 10^9/L throughout the study | Weekly, during 3 weeks |
| neutrophils | Changes in neutrophils in 10^9/L throughout the study | Weekly, during 3 weeks |
| monocytes | Changes in monocytes in 10^9/L throughout the study | Weekly, during 3 weeks |
| Lipid profile | Changes in lipid profile throughout the study | Weekly, during 3 weeks |
| Homeostatic model of insulin resistance (HOMA-IR) | Changes in HOMA-IR throughout the study | Weekly, during 3 weeks |
| Gastro-intestinal quality of life - questionnaire | 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. | Weekly, during 3 weeks |
| Bristol Stool Chart | 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. | Weekly, during 3 weeks |
Comparison of relative abundances of species throughout the study using shotgun metagenomics
| Weekly during 3 weeks |
| Weekly during 3 weeks |
| Fecal 24h short chain fatty acids | Changes in 24h faecal and fasting and short-chain fatty acids will be measured at V2, V3 and V4. | Weekly during 3 weeks |
| Fasting blood short chain fatty acids | Changes in fasting short-chain fatty acids will be measured at V2, V3 and V4. | Weekly during 3 weeks |