Safety and Viability of an E. Coli Nissle Colibactin Knockout in Healthy Volunteers

Phase 1

Completed

• Conditions: Diabetes
• Interventions: Dietary Supplement: EcN Colibactin knockout; Dietary Supplement: E Coli Nissle

• Registration Number: NCT05816577
• Lead Sponsor: Max Nieuwdorp

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.

Study Timeline

• Study First Submitted: 2023-03-09
• Study First Submitted QC: 2023-04-04
• Study First Posted: 2023-04-18
• Study Start: 2023-09-18
• Primary Completion: 2024-03-19
• Study Completion: 2024-03-19
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-22
• Last Update Posted: 2024-05-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

Not provided

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EcN colibactin-knockout	EcN Colibactin knockout	EcN colibactin-knockout 10\^11 once daily for 7 days
EcN	E Coli Nissle	E Coli Nissle wildtype 10\^11 once daily for 7 days

Primary Outcome Measures

Name	Time	Method
Renal function	Weekly, during 3 weeks	Changes in renal function, expressed as kreatinin levels (micromol/L) throughout the study
Hemoglobin	Weekly, during 3 weeks	Changes in hemoglobin in mmol/L throughout the study
basophils	Weekly, during 3 weeks	Changes in basophils in 10\^9/L throughout the study
monocytes	Weekly, during 3 weeks	Changes in monocytes in 10\^9/L throughout the study
Leucocytes	Weekly, during 3 weeks	Changes in leucocytes (10\^9/L)
Bilirubin	Weekly, during 3 weeks	Changes in bilirubin in micromol/L throughout the study
gamma-GT in U/L	Weekly, during 3 weeks	Changes in gamma-GT in U/L throughout the study
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.
ALT	Weekly, during 3 weeks	Changes in ALT in U/L throughout the study
eosinophils	Weekly, during 3 weeks	Changes in eosinophils in 10\^9/L throughout the study
Homeostatic model of insulin resistance (HOMA-IR)	Weekly, during 3 weeks	Changes in HOMA-IR throughout the study
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.
CRP	Weekly, during 3 weeks	Changes in CRP (mg/L)
AST	Weekly, during 3 weeks	Changes in AST in U/L throughout the study
neutrophils	Weekly, during 3 weeks	Changes in neutrophils in 10\^9/L throughout the study
Lipid profile	Weekly, during 3 weeks	Changes in lipid profile 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.
alkaline phosphatase	Weekly, during 3 weeks	Changes in alkaline phosphatase in U/L throughout the study
trombocytes	Weekly, during 3 weeks	Changes in trombocytes in 10\^9/L throughout the study

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Amsterdam UMC location AMC; 🇳🇱 Amsterdam, Netherlands