Host-Microbiome Determinants of Ready-To-Use Supplemental Food Efficacy in Acute Childhood Malnutrition

Ready-to-use-supplemental foods (RUSF) are an essential intervention against severe and moderate childhood acute malnutrition (SAM and MAM) in community-based settings. However, ponderal growth recovery with RUSF is inconsistent. To test the hypothesis that environmental enteric dysfunction (EED)–and EED-associated perturbations of gut microbiota–undermine RUSF efficacy, we measured EED biomarkers, 16S fecal microbiome composition, and RUSF response in a birth cohort of 416 nutritionally at-risk rural Pakistani children. 9-month-old infants with wasting (weight-for-length Z [WLZ] score 0, n=75) or RUSF nonresponders (RUSF-NR, ΔWAZ≤0, n=112). Machine learning identified fecal, serum, and urine biomarkers of inflammation, EED, and nutritional status (fecal myeloperoxidase and neopterin; serum prealbumin, glucagon like peptide-2, and C-reactive protein; and urine claudin-15 and creatinine) that predicted RUSF response with 73% accuracy. Remarkably, gut microbiome composition before or after RUSF supplementation predicted response with 93% and 98% accuracy, respectively. RUSF-R harbored an increased relative abundance of Negativicutes (including chickpea-fermenting Veillonella) and Clostridia prior to RUSF and decreased Gammaproteobacteria thereafter. Seven RUSF-NR outliers whose microbiome predicted RUSF-R experienced high burdens of inflammation and infection. EED, systemic inflammation, and gut microbial signatures herald RUSF nonresponse in childhood wasting. Effective biomarkers and adjunct therapies targeted to host-microbiome factors underlying wasting are urgently needed to unlock the full potential of ready-to-use supplemental foods in high-risk settings.