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Loss-of-function SLC30A2 mutants are associated with gut dysbiosis and alterations in intestinal gene expression in preterm infants.
Kelleher, Shannon L; Alam, Samina; Rivera, Olivia C; Barber-Zucker, Shiran; Zarivach, Raz; Wagatsuma, Takumi; Kambe, Taiho; Soybel, David I; Wright, Justin; Lamendella, Regina.
Afiliación
  • Kelleher SL; Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Alam S; Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Rivera OC; Department of Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Barber-Zucker S; Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, USA.
  • Zarivach R; Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Wagatsuma T; Department of Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Kambe T; Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Soybel DI; Department of Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
  • Wright J; Department of Life Sciences, The National Institute for Biotechnology in the Negev and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva, Israel.
  • Lamendella R; Department of Life Sciences, The National Institute for Biotechnology in the Negev and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Gut Microbes ; 14(1): 2014739, 2022.
Article en En | MEDLINE | ID: mdl-34965180
Loss of Paneth cell (PC) function is implicated in intestinal dysbiosis, mucosal inflammation, and numerous intestinal disorders, including necrotizing enterocolitis (NEC). Studies in mouse models show that zinc transporter ZnT2 (SLC30A2) is critical for PC function, playing a role in granule formation, secretion, and antimicrobial activity; however, no studies have investigated whether loss of ZnT2 function is associated with dysbiosis, mucosal inflammation, or intestinal dysfunction in humans. SLC30A2 was sequenced in healthy preterm infants (26-37 wks; n = 75), and structural analysis and functional assays determined the impact of mutations. In human stool samples, 16S rRNA sequencing and RNAseq of bacterial and human transcripts were performed. Three ZnT2 variants were common (>5%) in this population: H346Q, f = 19%; L293R, f = 7%; and a previously identified compound substitution in Exon7, f = 16%). H346Q had no effect on ZnT2 function or beta-diversity. Exon7 impaired zinc transport and was associated with a fractured gut microbiome. Analysis of microbial pathways suggested diverse effects on nutrient metabolism, glycan biosynthesis and metabolism, and drug resistance, which were associated with increased expression of host genes involved in tissue remodeling. L293R caused profound ZnT2 dysfunction and was associated with overt gut dysbiosis. Microbial pathway analysis suggested effects on nucleotide, amino acid and vitamin metabolism, which were associated with the increased expression of host genes involved in inflammation and immune response. In addition, L293R was associated with reduced weight gain in the early postnatal period. This implicates ZnT2 as a novel modulator of mucosal homeostasis in humans and suggests that genetic variants in ZnT2 may affect the risk of mucosal inflammation and intestinal disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Recien Nacido Prematuro / Proteínas de Transporte de Catión / Disbiosis / Mutación con Pérdida de Función / Enfermedades del Recién Nacido / Intestinos Tipo de estudio: Risk_factors_studies Límite: Animals / Female / Humans / Male / Newborn Idioma: En Revista: Gut Microbes Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Recien Nacido Prematuro / Proteínas de Transporte de Catión / Disbiosis / Mutación con Pérdida de Función / Enfermedades del Recién Nacido / Intestinos Tipo de estudio: Risk_factors_studies Límite: Animals / Female / Humans / Male / Newborn Idioma: En Revista: Gut Microbes Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos