Prevotella copri -linked effects of a therapeutic food for malnutrition.

Preclinical and clinical studies are providing evidence that the healthy growth of infants and children reflects, in part, healthy development of their gut microbiomes 1-5 . This process of microbial community assembly and functional maturation is perturbed in children with acute malnutrition. Gnotobiotic animals, colonized with microbial communities from children with severe and moderate acute malnutrition, have been used to develop microbiome-directed complementary food (MDCF) formulations for repairing the microbiomes of these children during the weaning period 5 . In the accompanying paper 1 , we analyze bacterial genomes assembled from sequencing the fecal microbiomes of Bangladeshi children with moderate acute malnutrition (MAM) who had participated in a previously reported 3-month randomized controlled clinical study of an MDCF 6 . This formulation, MDCF-2, produced significantly improved weight gain compared to a commonly used nutritional intervention despite the lower caloric density of the MDCF. Characterizing the metagenome assembled genomes (MAGs) of bacterial strains present in the microbiomes of study participants revealed a significant correlation between accelerated ponderal growth and the expression by two Prevotella copri MAGs of metabolic pathways involved in processing of MDCF-2 glycans 1 . To provide a direct test of these relationships, in this report we perform 'reverse translation' experiments. These experiments center on a gnotobiotic mouse model of mother-to-offspring microbiome transmission involving sequential introduction of defined consortia of age- and ponderal growth-associated gut bacterial strains cultured from Bangladeshi infants/children in the study population, with or without P. copri isolates resembling the MAGs. By combining analyses of microbial community assembly, gene expression and processing of glycan constituents of MDCF-2 with single nucleus RNA-Seq and mass spectrometric analyses of the intestine, we establish a key role for the P. copri strains in mediating metabolism of MDCF-2 glycans, as well as the activities of metabolic pathways involved in lipid, amino acid, carbohydrate plus other facets of energy metabolism within epithelial cells positioned at different locations in intestinal crypts and villi. Together, the results described in these two papers provide insights into structure/function relationships between MDCF-2 and members of the gut communities of malnourished children; they also have implications for developing future prebiotic, probiotic and/or synbiotic therapeutics for microbiome restoration in children with already manifest malnutrition, or who are at risk for this pervasive health challenge.