Host-microbiome determinants of ready-to-use supplemental food efficacy in acute childhood malnutrition

BACKGROUND. Ready-to-use supplemental foods (RUSF) are energy-dense meals used to treat moderate and severe acute childhood malnutrition. Weight recovery with RUSF is heterogeneous, therefore we investigated whether environmental enteric dysfunction (EED), systemic inflammation, and gut microbiota predict RUSF response. METHODS. We followed nutritional status and RUSF outcomes in a rural birth cohort of 416 Pakistani infants. Acha Mum, a chickpea-based RUSF, was administered daily for 8 weeks to children who developed wasting (weight-for-length Z-score <–2). RESULTS. Of 187 treated with RUSF, 112 showed no immediate improvement in weight-for-age. Machine learning identified nine biomarkers that collectively predicted RUSF response with 73% accuracy. Gut microbiome composition before and after supplementation predicted response with 93% and 98% accuracy, respectively. Responders showed microbiome restructuring, with increased growth-associated taxa and reduced Gammaproteobacteria relative to nonresponders. A subset of extreme nonresponders—whose microbiome profiles resembled those of responders—displayed markedly abnormal biomarkers of inflammation, suggesting adverse host factors constrain gut microbiota benefits for RUSF efficacy. CONCLUSION. EED, systemic inflammation, and gut microbiota predict acute nutritional responses to Acha Mum, setting the stage for precision use of RUSF and adjunctive therapies in addressing the global burden of childhood malnutrition in low- and middle-income countries.