Effectiveness of a microbiome-directed food (MDF) to promote programmatic and sustained nutritional recovery among children with uncomplicated severe acute malnutrition
Study design
Randomized clinical trial
Context
Acute malnutrition affects at least 45 million children worldwide each year (1). It is associated with an increased risk of infection and short-term mortality, as well as long-term impairments of the immune system and cognitive development. In 2007, a major shift in its management was adopted: children with uncomplicated severe acute malnutrition (SAM) could now be treated on an outpatient basis, through weekly clinical follow-up and the home use of ready-to-use therapeutic foods (RUTFs). Composed primarily of peanut paste, oil, skim milk powder, sugar, and essential micronutrients, RTFs require no preparation or refrigeration and have achieved nutritional recovery rates exceeding 90% in many settings. However, recent data highlight high rates of relapse and mortality after discharge from the nutritional program, suggesting that current RUTF formulations do not allow for complete restoration of physiological and immune functions. These findings have led the international scientific community to advocate for the evaluation of improved RUTF formulations capable of promoting a more complete and sustainable recovery.
Recent research has identified the gut microbiota - that is, the collection of microorganisms living in the digestive tract - as a promising target for the prevention and treatment of acute malnutrition. By playing a central role in nutrient absorption, metabolism, and the regulation of immune responses, the microbiota is increasingly recognized as a key factor in the development of malnutrition. Studies conducted in Bangladesh have shown that children suffering from acute malnutrition have a less mature gut microbiota than that of healthy children. In Malawi, a study demonstrated that transferring the microbiota from malnourished children to laboratory mice resulted in weight loss, abnormalities in bone development, and metabolic disturbances in the mice, suggesting for the first time a causal link between the immaturity of the gut microbiota and malnutrition.
Interest in the gut microbiota extends far beyond the context of childhood malnutrition. Its role is now being studied in numerous diseases, including metabolic and inflammatory conditions, as well as certain neurological and psychiatric disorders, underscoring its fundamental role in maintaining human health.
These recent findings suggest that interventions targeting the microbiota could be promising therapeutic approaches for preventing and treating a wide range of conditions, including malnutrition.
In response to research suggesting a link between gut microbiota immaturity and childhood malnutrition, a microbiome -targeted food (MDF) was developed by the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), in partnership with Washington University in St. Louis. An initial pilot study conducted in Bangladesh among children aged 12 to 18 months, who were followed for one month, showed that MDF improved several biomarkers associated with neurological development, immune function, and bone growth. Subsequently, a three-month randomized trial involving 123 malnourished children demonstrated that MDF promoted the maturation of the gut microbiota, improved growth, and led to a sustained increase in blood biomarkers associated with healthy development, effects that remained observable up to two years after treatment. These encouraging results support the hypothesis that restoring the microbiota could contribute to a lasting improvement in the recovery of children suffering from acute malnutrition. They also highlight the need to evaluate this approach in other geographic, nutritional, and epidemiological contexts.
- https://www.who.int/news-room/fact-sheets/detail/malnutrition/
Our role
- Coordination
Partners
- Ministry of Public Health and Social Affairs, Niger
- National Directorate of Nutrition, Niger
- Regional Directorate of Public Health, Maradi, Niger
- icddr,b, Bangladesh
- Washington University, St. Louis, United States
Funding
- MSF through a TIC
Project sponsor
- MSF
Study Objectives
Primary Objective
To assess the effectiveness of MDF in terms of program recovery by 12 weeks from admission among children with uncomplicated acute malnutrition in Niger compared to standard ready-to-use therapeutic foods (RUTF) for SAM.
To assess the effectiveness of MDF in terms of sustained recovery through 24 weeks from admission among children with uncomplicated acute malnutrition in Niger compared to standard ready-to-use therapeutic foods (RUTF) for SAM.
Secondary Objectives
To assess the effectiveness of MDF compared to standard RUTF for SAM in terms of programmatic non-response and default.
To estimate the safety of MDF compared to standard RUTF for SAM in terms of the incidence of serious adverse events and the combined endpoint of anthropometric relapse or death.
To determine the effect of MDF compared to standard RUTF for SAM on child anthropometry and neurocognitive development up to 24 weeks from admission.
To describe the influence of MDF compared to standard RUTF for SAM on the gut microbiota configuration, plasma proteome, environmental enteric dysfunction and body composition up to 24 weeks from admission.
To explore acceptability and household utilization of MDF compared to standard RUTF for SAM.
To evaluate the cost effectiveness of MDF compared to standard RUTF for SAM in terms of the incremental cost per case of program recovery by 12 weeks from admission and the incremental cost per case of sustained recovery at 24 weeks from admission.
Methodology
The main study will be conducted as an individually randomized controlled trial comparing microbiome-directed foods to standard nutritional therapy among children aged 6 to < 24 months with uncomplicated severe acute malnutrition in terms of programmatic recovery by 12 weeks from admission and sustained recovery at 24 weeks from admission. Children presenting with uncomplicated SAM to study health centers will be followed on a weekly basis until programmatic recovery by 12 weeks and monthly from programmatic recovery to 24 weeks from admission.
Sub-samples of children enrolled in the main trial will be invited to participate in one or more sub-studies, including mechanistic sub-studies and a cost-effectiveness sub-study
Mechanistic sub-studies
Two sub-samples of children with SAM enrolled in the main trial will be invited to participate in a mechanistic sub-study as follows:
- A proof-of-principle cohort (n=280) is proposed to evaluate the effect of the MDF intervention compared to standard RUTF with a fixed duration of 12 weeks. This design allows for a longer exposure period to evaluate the potential intervention effect beyond the variable and potentially shorter period limited to program treatment (variable between 3 to 12 weeks).
- An operational cohort (n=280) is proposed to evaluate the effect of the MDF intervention compared to standard RUTF until program discharge (variable between 3 to 12 weeks). This design reflects current global and national practice to administer nutritional therapy only until anthropometric discharge/nutritional recovery and children in this cohort will receive the trial intervention (MDF or RUTF) until program discharge.
In addition, a cohort of 120 children (known as the “healthy community cohort”) will be enrolled in the community from the same geographic area when the child is 3 months of age and followed until 24 months of age.
Biological samples will be collected from these sub-samples of children to consider 3 pathways: microbiome and plasma proteome repair, body composition and environmental enteric dysfunction analysis (see Section 8.11). Assays will be run at the Epicentre laboratory in Maradi, Niger and by partner laboratories in St Louis, Missouri, USA and Lusaka, Zambia.
Cost effectiveness sub-study
A sub-sample of children enrolled in the main trial will be invited to participate in a cost-effectiveness study. This sub-study aim to assess the economic implications of the intervention.
Expected Impacts
For children and their families
- Reduction in childhood morbidity and mortality.
- Improved long-term health, growth, and development.
- Reduced health care costs and income losses for households.
- Contribution to breaking the vicious cycle of poverty, malnutrition, and infections.
For MSF programs
- Fewer relapses and shorter treatment durations.
- Reduced workload for medical teams.
- Optimization of resources thanks to the potentially lower cost of MDF compared to standard therapeutic foods.
- Sustainable strengthening of research and innovation capacities in nutrition.
For global health policies
- Generation of high-quality data to inform future WHO recommendations.
- Collaboration with key international stakeholders (WHO, UNICEF, WFP) involved in developing global policy changes
- Facilitation of large-scale programmatic adoption if effectiveness is demonstrated.
Toward a more sustainable model
- A non-patented formulation that promotes local production.
- Reduced production costs due to the absence of milk.
- Use of regional ingredients, adapted to local contexts.
- Reduced transportation needs and dependence on imports.
- Reduced environmental and carbon footprints.
- Support for local economic development and regional capacity building.
