Microbiota-directed Complementary Food (MDCF) Trial

Background:

Moderate acute malnutrition (MAM), a major global health problem, is defined as wasting (i.e. weight-for-height between < -2 and -3 Z-scores of the WHO Child Growth Standards) and/or mid-upper-arm circumference (MUAC) greater or equal to 115 mm and less than 125 mm. According to the Global Nutrition Report 2017, 8% or 52 million under-five children were acutely malnourished globally in 2016. Stunting affected 23% or 155 million children. Approximately one in 6 children under 5 years in South Asia suffered from MAM in 2013 (i.e. 17%). These children are at increased risk of severe acute malnutrition (SAM), and have a three times higher risk of mortality from common communicable diseases than the well-nourished peers. Bangladesh has one of the highest childhood malnutrition burdens in the world. According to Bangladesh Demographic Health Survey (BDHS) 2014, the prevalence of stunting among under-five children is 36%, among them 12% suffer from severe stunting (Length-for-Age-Z score, LAZ <-3). Around 15% of children are wasted (Weight-for-Length Z score, WLZ <-2); more than 2 million children suffer from MAM, while 3% or 450,000 children suffer from the deadly form of SAM. Malnutrition costs Bangladesh an estimated US $1 billion a year. According to WHO recommendations, infants and children aged 6-59 months with MAM need to consume nutrient-dense foods to meet their extra needs for weight and height gain and functional recovery. Currently there are no evidence-informed recommendations on the composition of supplementary foods used to treat children with MAM. In situations of food shortage, supplementary foods have been used to treat children with moderate acute malnutrition. Interventions to address under nutrition should therefore include a strong component of MAM management. MAM prevention should be taken into consideration in food security and other development strategies as the situation becomes critical in populations where food insecurity is rampant. Food insecurity has become a worldwide concern due to the increasing number of people who remain undernourished amounting to 842 million, approximately 12% of the total world's population. From the National Micro nutrient Status Survey in Bangladesh which we conducted in 2011-12, severe insecurity of food was found most commonly in slum settlements (17.2 %), compared to 12.3% at the national level, 12% in rural areas and 12.4% in urban areas of the country. Since food insecurity cannot be overcome quite readily, it is important therefore to develop interventions that depend upon locally available food ingredients and are able to harness the beneficial power of the gut microbiota on infant and child growth.

One of the major factors limiting the impact of nutrition intervention is the inability of the malnourished children to increase their intake to meet increased metabolic demands. In collaborative studies between icddr,b and the Gordon Lab at Washington University in St. Louis during the Jump start Phase of the Breast Milk, Microbiota and Immunity (BMMI) Project, we applied Random Forests, a machine-learning-based approach, to bacterial 16S rRNA (ribosomal ribonucleic acid) datasets generated from monthly fecal samples obtained from a birth-cohort of children living in an urban slum of Dhaka, Bangladesh. These children exhibited consistently healthy growth (WLZ -0.32+0.98). Bacterial strains were identified whose proportional representation defines a healthy gut microbiota as it assembles during the first 2-3 postnatal years. In a randomized clinical trial at icddr,b of two therapeutic foods (imported ready-to-use therapeutic food [RUTF (Ready to Use Therapeutic Food), Plumpy'Nut] versus locally prepared rice/lentil-based Khichuri and Halwa) in Bangladeshi children with severe acute malnutrition (SAM), it was observed that the microbiota immaturity is incompletely and only transiently improved, with children remaining markedly stunted and underweight throughout the follow-up period. Bangladeshi children with MAM also exhibited significant microbiota immaturity, although less severe than children with SAM. Microbiota immaturity thus serves as a potential biomarker to identify infants at risk for undernutrition and to monitor treatment and prevention strategies.

Investigators recently developed ready-to-use therapeutic foods using locally available food ingredients-rice, lentil, and chickpeas that are culturally relevant and acceptable. They found through a double-blind RCT (Randomized Controlled Trial) that chickpea-based and rice-lentil-based RUTF were as effective as the commercial peanut based-RUTF and well accepted by children with SAM. Through a combination of the above mentioned RCT and clinical translational studies, they have identified growth promoting age-discriminatory beneficial microbiota and locally available food ingredients that support proliferation of these beneficial microbiota. Besides, results of earlier studies done on gnotobiotic animals in Washington University Centre for Genome Science has led us to suggest that a combination of food ingredients (chickpea, soy flour, peanut and green banana) will be worth studying with respect to the diet's impact on stimulating proliferation of growth-discriminatory microbiota as well as cost and sustainability. To assess the degree to which the results obtained from the gnotobiotic mouse and piglet models translate to humans, investigators recently performed a RRC (Research Review Committee) and ERC (Ethecial Review Committee)approved study, icddr,b protocol (PR-16099) 'Pre-Proof of Concept clinical trials to optimize lead microbiota-directed complementary food (MDCF) prototypes for their ability to repair microbiota immaturity and establish their organoleptic acceptability 'and successfully completed the study. This study was designed to test the effects of three locally produced MDCF prototypes (MDCF-1, MDCF-2 and MDCF-3) and a locally produced rice-lentil-based RUSF. The objective of this pilot study was to demonstrate a Pre-proof of Concept that certain complementary foods would have a beneficial effect on young children suffering from moderate acute malnutrition by stimulating the proliferation of particular members of the gut microbiota that are known for their growth promoting effect. In that pilot study they investigated microbiota-for-age Z score as well as the impact of the proliferation of good members of the gut microbiota on certain body systems. The results of the Pre-POC pilot trial conclusively showed that one of the three microbiota directed complementary foods namely (MDCF-2; composed of a combination of chickpea, soy flour, peanut, green banana, oil, sugar and micronutrients) was associated with increased levels of certain amino acids, that have a key role in development of the long bones, development of the brain and increased production of IGF-1. This was done using the state-of-the-art DNA aptamer based SomaLogic scan. And the results suggest that this candidate MDCF-2 is effective in stimulating the growth of growth promoting members of the gut microbiota, for example Faecalibacterium prausnitzii. Thus, MDCF-2 promotes gut microbiota that induces the hormone insulin-like growth factor 1 (IGF-1), which promotes bone growth and remodelling.

Based on this evidence investigators would now like to do a much larger clinical trial using the most promising MDCF which is MDCF-2 with the primary end point being linear growth. This trial would be on children with primary MAM.