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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes
• Intervention / Treatment: Dietary supplement: E Coli Nissle; Dietary supplement: EcN Colibactin knockout

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 Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC location AMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: EcN; E Coli Nissle wildtype 10^11 once daily for 7 days	Dietary supplement: E Coli Nissle; E Coli wildtype strain
Experimental: EcN colibactin-knockout; EcN colibactin-knockout 10^11 once daily for 7 days	Dietary supplement: EcN Colibactin knockout; E coli Nissle strain with ClbP-gene removed and therefore not producing colibactin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
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

Secondary Outcome Measures

Outcome Measure	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	Comparison of relative abundances of species throughout the study using shotgun metagenomics	Weekly during 3 weeks

Other Outcome Measures

Outcome Measure	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.	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

Collaborators and Investigators

• Sponsor: Max Nieuwdorp

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2023
• Primary Completion (Actual): March 19, 2024
• Study Completion (Actual): March 19, 2024

Study Registration Dates

• First Submitted: March 9, 2023
• First Submitted That Met QC Criteria: April 4, 2023
• First Posted (Actual): April 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 23, 2024
• Last Update Submitted That Met QC Criteria: May 22, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: diabetes; safety; advanced microbiome therapeutics
• Other Study ID Numbers: NL83158.018.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No