A microbiota-directed complementary food, developed and characterized in gnotobiotic mice and piglets colonized with microbial therapeutic targets, has wide-ranging beneficial effects on biomarkers and mediators of postnatal development in Bangladeshi children with moderate acute malnutrition

We illustrate an approach for integrating preclinical gnotobiotic animal models with human studies to understand the contributions of impaired gut microbial community development to childhood undernutrition. Combining metabolomic and proteomic analyses of serially collected plasma samples with metagenomic analyses of fecal samples, we characterized the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, following standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Gnotobiotic mice were subsequently colonized with a defined consortium of bacterial strains representing different stages of microbiota development in healthy children. Administering different combinations of Bangladeshi complementary food ingredients to colonized and germ-free mice revealed diet-dependent changes in the relative abundance and metabolism of weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota, plus diet- and colonization-dependent effects on host metabolism and growth-associated signaling pathways. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes were subsequently examined in gnotobiotic mice colonized with post-SAM MAM microbiota and in gnotobiotic piglets colonized with a defined consortium of targeted age- and growth-discriminatory bacteria. Finally, a randomized, double-blind study identified a lead MDCF that changes the abundances of targeted bacterial taxa and increases plasma levels of biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function.