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Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age z score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids. Children with refractory EED harbor single-nucleotide polymorphisms in key enzymes involved in NAD+ synthesis. In mice, deletion of Nampt, the gene encoding the rate-limiting enzyme in the NAD+ salvage pathway, from intestinal epithelium also reduced Paneth cell function, a deficiency that was further aggravated by LPD. Separate supplementation with NAD+ precursors or bile acid sequestrant partially restored LPD-associated Paneth cell defects and, when combined, fully restored all histopathology defects in LPD-fed mice. Therapeutic regimens that increase protein and NAD+ contents while reducing excessive bile acids may benefit children with refractory EED. Editor's summary: Environmental enteric dysfunction (EED) is an acquired condition of the small intestine that is associated with inflammation, poor nutrient absorption, and stunted growth in children. Malique et al. examined a cohort of children with EED and found pathophysiological changes in the cellular composition of the small bowel as well as increased serum bile acids and decreased nicotinamide adenine dinucleotide (NAD+). Work in a mouse model of EED suggested that increased dietary protein and NAD+ as well as reduction of bile acids should be further investigated as potential therapeutic avenues for this disorder. —Catherine Charneski [ABSTRACT FROM AUTHOR]