Loss of Serum Glucocorticoid-Inducible Kinase 1 SGK1 Worsens Malabsorption and Diarrhea in Microvillus Inclusion Disease (MVID)

Md Kaimul Ahsan; Diego Carlos Dos Reis; Andrea Barbieri; Kaelyn D Sumigray; Timothy Nottoli; Pedro J Salas; Nadia A Ameen

doi:10.3390/jcm11144179

Loss of Serum Glucocorticoid-Inducible Kinase 1 SGK1 Worsens Malabsorption and Diarrhea in Microvillus Inclusion Disease (MVID)

J Clin Med. 2022 Jul 19;11(14):4179. doi: 10.3390/jcm11144179.

Authors

Md Kaimul Ahsan¹, Diego Carlos Dos Reis¹, Andrea Barbieri², Kaelyn D Sumigray³, Timothy Nottoli⁴, Pedro J Salas⁵, Nadia A Ameen^{1

6}

Affiliations

¹ Department of Pediatrics, Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06510, USA.
² Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
³ Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
⁴ Genome Editing Center, Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
⁵ Department of Cell Biology, Miller School of Medicine, University of Miami, Miami, FL 33146, USA.
⁶ Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Abstract

Microvillus inclusion disease (MVID), a lethal congenital diarrheal disease, results from loss of function mutations in the apical actin motor myosin VB (MYO5B). How loss of MYO5B leads to both malabsorption and fluid secretion is not well understood. Serum glucocorticoid-inducible kinase 1 (SGK1) regulates intestinal carbohydrate and ion transporters including cystic fibrosis transmembrane conductance regulator (CFTR). We hypothesized that loss of SGK1 could reduce CFTR fluid secretion and MVID diarrhea. Using CRISPR-Cas9 approaches, we generated R26^CreER;MYO5B^f/f conditional single knockout (cMYO5BKO) and R26^CreER;MYO5B^f/f;SGK1^f/f double knockout (cSGK1/MYO5B-DKO) mice. Tamoxifen-treated cMYO5BKO mice resulted in characteristic features of human MVID including severe diarrhea, microvillus inclusions (MIs) in enterocytes, defective apical traffic, and depolarization of transporters. However, apical CFTR distribution was preserved in crypts and depolarized in villus enterocytes, and CFTR high expresser (CHE) cells were observed. cMYO5BKO mice displayed increased phosphorylation of SGK1, PDK1, and the PDK1 target PKCι in the intestine. Surprisingly, tamoxifen-treated cSGK1/MYO5B-DKO mice displayed more severe diarrhea than cMYO5BKO, with preservation of apical CFTR and CHE cells, greater fecal glucose and reduced SGLT1 and GLUT2 in the intestine. We conclude that loss of SGK1 worsens carbohydrate malabsorption and diarrhea in MVID.

Keywords: CFTR; MVID; SGK1; diarrhea.

Abstract

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