Probiotic For the Improvement of Environmental Enteropathy in Pregnant Women in Senegal (PROFE-Sen)

Ability of the Probiotic Vivomixx to Improve Environmental Enteropathy in Pregnant Women: a Proof of Concept Trial in Senegal

Stunting in young children refers to attenuated linear growth. In the year 2020, 149.2 million children under the age of 5 were stunted, accounting for 22% of stunting globally. Stunting has short- and long-term consequences of increased morbidity and mortality, impairment of neurocognitive development , impaired responses to oral vaccines, and increased risk of non-communicable diseases. Stunting is partly driven by Environmental Enteric Dysfunction (EED), an enteropathic condition characterised by altered gut permeability, infiltration of immune cells and changes in villous architecture and cell differentiation. EED may help explain why nutritional supplementation either during pregnancy or early childhood has minimal value in correcting childhood stunting.

Probiotics may serve to overcome the problem of EED through all mechanisms of pathogenicity, by providing additional bacteria that may help in intestinal decolonization of pathogenic microorganisms (changing the microbiological niche), promoting epithelial healing, improving nutrient absorption, and restoration of an appropriate immune balance between tolerance and responsiveness.

This trial will explore the conceptual framework, that a well known probiotic, that can improve the composition of the gut microbiota, can reduce biomarkers of intestinal inflammation and gut health. This will restore healthy microbial signalling to the host epithelium, ameliorate barrier function through secretion of mucus and antimicrobial factors, and improve nutrient availability.

Study Overview

• Status: Recruiting
• Conditions: Environmental Enteric Dysfunction
• Intervention / Treatment: Drug: Placebo; Device: CapScan®; Drug: Probiotic

Detailed Description

Stunting in young children refers to attenuated linear growth. In the year 2020, 149.2 million children under the age of 5 years of age were stunted, accounting for 22% of stunting globally. Stunting has short- and long-term consequences of increased morbidity and mortality, impairment of neurocognitive development5 , impaired responses to oral vaccines, and increased risk of non-communicable diseases. Stunting is partly driven by Environmental Enteric Dysfunction (EED), an enteropathic condition characterised by altered gut permeability, infiltration of immune cells and changes in villous architecture and cell differentiation. EED may help explain why nutritional supplementation either during pregnancy or early childhood has minimal value in correcting childhood stunting. Indeed, EED is believed to be responsible for 40% of childhood stunting. Disruption in intestinal barrier function affects gut immune homeostasis, nutrient flows, and consequently dysbiosis in the gut microbiome. The gut microbiota consists of 100 trillion bacteria which interact with epithelial cells, the mucus layer and the mucosal immune system that balances tolerance and effector functions. Thus the gut microbiome has an important role in shaping the responsiveness of the gut immune system. The mucus barrier and the normal gut microbiota limit enteropathogen colonisation. Influx of bacteria from the lumen to the systemic circulation represents microbial translocation and initiation of systemic of inflammatory process through recognition of pathogen-associated molecular patterns (PAMPs) by Pattern Recognition Receptors (PRRs) present on Antigen Presenting Cells (APCs). Three fundamental processes drive the epithelial damage which is so important in EED: infection, undernutrition, and immune dysfunction. Multiple clinical trials show that efforts to correct malnutrition through conventional therapies and improving hygiene and sanitation do not overcome growth deficits by more than about 10%. There is increasing interest in the use of probiotics which may allow pathogen decolonization, improve barrier function and restore overall gut homeostasis. Such therapies are at early stage of trials but may have potential in addressing the global burden of EED, by improving barrier function and gut pathophysiology.

Colonization of gut by enteropathogens is common in children with EED. These include ETEC, Campylobacter, Shigella and Salmonella species. Consistent data from Bangladesh and Zambia show that children with refractory stunting carry over four pathogens on average, whilst controls carry less than two. There is also clear evidence of altered composition of the microbiota in children with EED.

Probiotics may serve to overcome the problem of EED through all mechanisms of pathogenicity, by providing additional bacteria that may help in intestinal decolonization of pathogenic microorganisms (changing the microbiological niche), promoting epithelial healing, improving nutrient absorption, and restoration of an appropriate immune balance between tolerance and responsiveness.

To date the focus of research on childhood stunting has been on the young child. It is increasingly appreciated, however, that stunting often begins in utero and the focus has shifted to women's health and pregnancy. For example, the Lancet 2021 Series on maternal and child undernutrition states that "Investments to reduce undernutrition in women are important not only for women's own health but also for the health and nutrition of their children". Results from rural Bangladesh reveal poor gestational weight gain that ultimately leads to intrauterine growth restriction, low birth weight and ultimately stunting and wasting. Furthermore, another study recently completed in slum settlements of Dhaka, Bangladesh demonstrated a high prevalence of EED among undernourished women. Intestinal histopathology was abnormal in more than 80% of women. We postulate that growth retardation in utero is a consequence of EED in the mother during pregnancy and lactation. This leads to systemic inflammation, which leads to disadvantageous partitioning of nutrients, and reduced nutrient availability.

This trial will explore the conceptual framework that a well known probiotic, that can improve the composition of the gut microbiota, can reduce biomarkers of intestinal inflammation and gut health. This will restore healthy microbial signalling to the host epithelium, ameliorate barrier function through secretion of mucus and antimicrobial factors, and improve nutrient availability.

The primary objective of this trial is to determine if a probiotic, Vivomixx, can reduce inflammation and epithelial damage in pregnant women with environmental enteropathy in the target countries.

The secondary objectives of this trial are:

To determine if Vivomixx can reduce enteropathogen colonisation To determine if Vivomixx can impact the structure and function of the microbiome To determine if Vivomixx can reduce permeability. To determine if Vivomixx can impact the host metabolome in pregnant woman To evaluate variability in endpoints across geographies and participating laboratories.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yakhya Dieye, PhD; Email: yakhya.dieye@pasteur.sn
• Study Contact Backup: Name: Billo TALL, MD; Phone Number: +221 77 535 81 35; Email: billo.tall@pasteur.sn

Study Locations

• Senegal
  • Dakar
    • Guédiawaye, Dakar, Senegal
      • Recruiting
      • Centre de santé de Wakhinane
      • Contact: Omar G Diop, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women over the age of 18, living in Guediawaye district, Senegal

Exclusion Criteria:

• • have had diarrhea, defined as the passage of three or more loose stools per 24 hours, in the preceding 14 days

  • have taken antibiotics or probiotics in the preceding 14 days
  • have taken non-steroidal anti-inflammatory drugs in the preceding 14 days
  • have any illness which in the opinion of the investigator will complicate assessment of safety or efficacy
  • have any gastrointestinal contraindication to ingestion of a capsule (known or suspected gastrointestinal obstruction, stricture, fistula, gastroparesis, or any swallowing disorder.)
  • have a plan to leave the study area within the follow-up period

but may be enrolled if/when these disqualifiers have expired.

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
Experimental: Probiotic; Participant in the treatment arm will receive a daily dose of the probiotic for 8 weeks.	Drug: Placebo; Placebo; Drug: Probiotic; Probiotic
Placebo Comparator: Placebo; Participant in the control arm will receive a daily dose of a placebo for 8 weeks.	Drug: Placebo; Placebo; Device: CapScan®; The only non-standard sample collection instrument is the CapScan® device. The CapScan Collection Capsule ("Capsule") is a non-invasive device that collects gastrointestinal samples along the GI tract that are then analyzed outside the body. Samples collected by the Capsule will be expressed, then undergo DNA sequencing and mass spectrometric analysis to determine the identity and function of the bacterial and host cells in the different regions of the GI tract and compared to similar analyses conducted on concomitantly collected stool samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in inflammation and epithelial damage in pregnant women with environmental enteropathy	Percentage change (mean, unweighted) in a multiple panel of biomarkers between baseline and last sample collected after 56 days of treatment, compared to control group.	Day 0 (screening) - Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in enteropathogen colonisation	Change in colonisation with specific enteropathogens (Salmonella, Shigella, Campylobacter, ETEC, EPEC, EAEC, rotavirus, norovirus, Giardia and Cryptosporidium), by qPCR, between baseline and last sample collected after 56 days of treatment, in Vivomixx compared to placebo groups	Day 1 - Day 56
Impact on the structure and function of the microbiome	Change in microbiome at community and composition level (as measured by whole-genome shotgun metagenomic sequencing, post versus pre-intervention), in the intervention and placebo groups	Day 1 - Day 56
Change in permeability	Change in LR ratio in Vivomixx compared to placebo groups	Day 1 - Day 56
Impact of the host metabolome in pregnant woman	Change in metabolome, measured by Nuclear Magnetic Resonance (NMR) spectroscopy in faecal and CAPSCAN samples before and after intervention	Day 1 - Day 56
Rate of weight gain in the 2nd trimester of pregnancy	Weight gain velocity in the 2nd trimester of pregnancy	Day 0 (screening) - Day 56
Variability in endpoints across geographies and participating laboratories	Measurements of variability, including standard deviations and kappa values; Preliminary work across all sites using identical kits and harmonised SOPs	Beginning of recruitment in the first study site - end of recruitment in the last study site (approximately 12 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CapScan success rate in delivering an assessment of the microbiome	Recovery of useful data from CapScan; completion of whole gut microbiome profiles	Day 1 and Day 56

Collaborators and Investigators

• Sponsor: Institut Pasteur de Dakar
• Collaborators: Bill and Melinda Gates Foundation; Aga Khan University; International Centre for Diarrhoeal Disease Research, Bangladesh; University of Zambia
• Investigators: Principal Investigator: Yakhya Dieye, PhD, Institut Pasteur de Dakar

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2024
• Primary Completion (Actual): July 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: August 4, 2022
• First Submitted That Met QC Criteria: August 11, 2022
• First Posted (Actual): August 15, 2022

Study Record Updates

• Last Update Posted (Actual): May 13, 2025
• Last Update Submitted That Met QC Criteria: May 8, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: probiotics; gut microbiota; Senegal; Gut health; VSL3; Vivomixx
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases
• Other Study ID Numbers: 2022-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual data for all primary and secondary outcome measures will be made available.
• IPD Sharing Time Frame: Data will be available within 24 months of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed by the Trial Management Group. Requestors will be required to sign a Data Access Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No