Microbiota-directed complementary food (MDCF) formulations have been designed to repair the gut communities of malnourished children. A randomized controlled trial demonstrated that one formulation, MDCF-2, improved weight gain in malnourished Bangladeshi children compared to a more calorically dense standard nutritional intervention. Metagenome-assembled genomes from study participants revealed a correlation between ponderal growth and expression of MDCF-2 glycan utilization pathways by *Prevotella copri* strains. To test this correlation, here we use gnotobiotic mice colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains, with or without *P. copri* isolates closely matching the metagenome-assembled genomes. Combining gut metagenomics and metatranscriptomics with host single-nucleus RNA sequencing and gut metabolomic analyses, we identify a key role of *P. copri* in metabolizing MDCF-2 glycans and uncover its interactions with other microbes including *Bifidobacterium infantis*. *P. copri*-containing consortia mediated weight gain and modulated energy metabolism within intestinal epithelial cells. Our results reveal structure-function relationships between MDCF-2 and members of the gut microbiota of malnourished children with potential implications for future therapies.

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