Microbiota Directed Complementary Food (MDCF) Post-SAM MAM 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 and stunting or chronic malnutrition 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 2014, the prevalence of stunting in the country among under-five children is 36%, among them 12% suffer from severe stunting (LAZ <-3).1 Around 15% of children are wasted (weight-for-length, 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. Interventions to address undernutrition 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. It is important therefore to develop interventions that depend upon locally available food ingredients which in small quantities 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 interventions 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 Jumpstart Phase of the Breast Milk, Microbiota and Immunity (BMMI) Project, we applied Random Forests, 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, 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. In our previous study approved by the ERC (PR-09023), we compared the gut microbiota of healthy children living in slum of Mirpur with children hospitalized for the treatment of severe acute malnutrition. The microbiota was assessed by 16S Ribosomal RNA sequencing. We found that the gut microbiota of children with SAM lags chronologically behind microbiota of healthy children. For example, a two year old child with SAM may have the gut microbiota similar to that of a one year old healthy child. This is known as immaturity of the gut microbiota. We have developed two metrices to represent this gut immaturity - the relative microbiota maturity index and the microbiota-for-age Z score; SAM is associated with significant relative microbiota immaturity that is only partially ameliorated following nutritional interventions. .

We recently developed ready-to-use therapeutic foods using locally available food ingredients-rice, lentil, and chickpeas that are culturally relevant and acceptable. We found through a double-blind RCT (Randomized Controlled Trial ) that the Bangladeshi chickpea-based and rice-lentil-based RUTF (Ready To Use Therapeutic Food) we developed 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 conducted over the last 7-8 years, we have identified growth promoting age-discriminatory beneficial microbiota and locally available food ingredients that support proliferation of these beneficial microbiota. Besides, 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) being informed by studies done in Dhaka will be worth studying with respect to the diet's impact on stimulating proliferation of growth-discriminatory microbiota as well as cost and sustainability.