Mechanism of action of a microbiota-directed complementary food that promotes ponderal growth in Bangladeshi children with moderate acute malnutrition

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PROJECT ABSTRACT 144 million children suffer from undernutrition, a condition with numerous long co-morbidities. A delay in growth, including stunting of height and wasting of weight, is one of the most prominent morbidities of undernutrition. While current therapeutics against undernutrition have reduced mortality, they have had very limited efficacy in repairing the associated morbidities. Recent studies have indicated that undernutrition is also associated with failed gut microbiota development, resulting in undernourished children having an immature gut microbiota. Research efforts in mice have shown that transplanting immature gut microbial communities transmits the growth faltering phenotypes seen in undernourished children. Repair of microbiota immaturity could represent a new therapeutic strategy for treating childhood growth delays caused by undernutrition. To investigate whether more mature gut microbiota could rescue this delayed growth, the Gordon Lab designed a series of microbiota-directed complementary foods (MDCF) that were able to repair microbiota immaturity. Recently, we performed a proof-of-concept controlled feeding trial where undernourished Bangladeshi children consumed either our most promising MDCF (MDCF-2) or a ‘standard’ ready-to-use supplementary food (RUSF) not designed to repair microbiota immaturity. MDCF-2 produced a significantly greater rate of weight gain than RUSF even though MDCF-2 has a lower caloric density than RUSF. This study also revealed 23 bacterial strains whose abundance in the gut was associated with host weight changes. Recently, it was also shown that MDCF-2 has a different set of carbohydrates compared to RUSF. These very encouraging results provide the motivation for this proposal which seeks to better understand the genomic features of these weight-associated taxa and uncover the mechanisms by which they respond to MDCF-2. Given that the gut microbiota plays a key role in processing of dietary polysaccharides and that differences in carbohydrate-associated enzymes (CAZymes) gene repertoires are known to affect bacterial fitness, I hypothesize MDCF-2 promotes host weight gain through the presence of specific bioactive carbohydrates that are metabolized by CAZymes in growth-promoting members of the developing microbiota. The goal of this proposal is to identify these putative weight-promoting CAZymes first in silico and then validating those CAZymes in vitro and in vivo. In Aim 1, I seek to computationally identify CAZymes associated with weight gain, characterize the genomes of their ‘host’ bacterial strains, and characterize their expression in the gut. In Aim 2, I will directly test whether bacterial strains containing these CAZymes promote weight gain in gnotobiotic mice fed a diet supplemented with MDCF-2. This effort to identify specific microbes containing growth-promoting CAZymes will allow us to develop effective therapeutic foods in different populations of undernourished children and expand our understanding of the mechanisms by which the microbiome influences postnatal development.