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