Comparing the effects of microbiota-directed therapeutic foods in gnotobiotic mice, gnotobiotic piglets and undernourished children. Comparing the effects of microbiota-directed therapeutic foods in gnotobiotic mice, gnotobiotic piglets and undernourished children

We illustrate an approach for integrating preclinical gnotobiotic animal models with human studies to understand the contributions of perturbed gut microbiota development to childhood undernutrition, and to identify new microbiota-directed therapeutic concepts/leads. Combining metabolomic and proteomic analyses of serially collected plasma samples with metagenomic analyses of serially collected fecal samples, we characterized the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned to moderate acute malnutrition (MAM) after standard treatment. Gnotobiotic mice were subsequently colonized with a defined consortium of bacterial strains representing different stages of microbiota development in healthy children from Bangladesh. Administering different combinations of Bangladeshi complementary food ingredients to colonized mice and germ-free controls revealed diet-dependent changes in representation and metabolism of targeted weaning-phase strains, including accompanying increases in branched-chain amino acids, plus diet- and colonization-dependent augmentation of IGF-1/mTOR signaling. 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, ar andomized, double-blind study revealed a lead MDCF that affected the representation of targeted bacterial taxa and increased levels of biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function. Overall design: 191 plasma samples total were measured from non-fasted venous blood, collected in EDTA-coated tubes, and rapidly cryoperserved before transfer to Washington University School of Medicine in St. Louis. The different groups include healthy (n = 21), ready-to-use supplementary food (RUSF) pre- (n = 14) and post-treatment (n = 14), microbiota-directed complementary food formulation 1 (MDCF1) pre- (n = 16) and post-treatment (n = 16), MDCF2 pre- (n = 16) and post-treatment (n = 16), MDCF3 pre- (n = 16) and post-treatment (n = 16), severe acute malnutrition (SAM, n = 30), post-SAM moderate acute malnutrition (post-SAM MAM) immediately after discharge from acute stabilizaiton (n = 8), and post-SAM MAM 6 months after discharge from acute stabilization (n = 8).