Prevotella copri-related effects of a therapeutic food for malnutrition
Authors: Chang Hao-Wei , Lee Evan M. , Wang Yi , Zhou Cyrus , Pruss Kali M. , Henrissat Suzanne , Chen Robert Y. , Kao Clara , Hibberd Matthew C. , Lynn Hannah M. , Webber Daniel M. , Crane Marie , Cheng Jiye , Rodionov Dmitry A. , Arzamasov Aleksandr A. , Castillo Juan J. , Couture Garret , Chen Ye , Balcazo Nikita P. , Lebrilla Carlito B. , Terrapon Nicolas , Henrissat Bernard , Ilkayeva Olga , Muehlbauer Michael J. , Newgard Christopher B. , Mostafa Ishita , Das Subhasish , Mahfuz Mustafa , Osterman Andrei L. , Barratt Michael J. , Ahmed Tahmeed , Gordon Jeffrey I. 
Published: August 2023

Preclinical and clinical studies are providing evidence that the healthy growth of infants and children reflects, in part, healthy development of their gut microbiomes1–5. 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 period5. Bangladeshi children with moderate acute malnutrition (MAM) participating in a previously reported 3-month-long randomized controlled clinical study of one such formulation, MDCF-2, exhibited significantly improved weight gain compared to a commonly used nutritional intervention despite the lower caloric density of the MDCF6. 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 twoPrevotella copriMAGs of metabolic pathways involved in processing of MDCF-2 glycans1. To provide a direct test of these relationships, we have now performed ‘reverse translation’ experiments using a gnotobiotic mouse model of mother-to-offspring microbiome transmission. Mice were colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains cultured from Bangladeshi infants/children in the study population, with or withoutP. copriisolates 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 principal role forP. copriin mediating metabolism of MDCF-2 glycans, characterize its interactions with other consortium members includingBifidobacterium longumsubsp.infantis, and demonstrate the effects ofP. copri-containing consortia in mediating weight gain and modulating 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 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.