NAD+ precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction.
Sci Transl Med
; 16(728): eabq4145, 2024 01 03.
Article
em En
| MEDLINE
| ID: mdl-38170788
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos e Sais Biliares
/
NAD
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Child
/
Humans
Idioma:
En
Revista:
Sci Transl Med
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos