| First Author | Terry NA | Year | 2018 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 315 |
| Issue | 4 | Pages | G580-G591 |
| PubMed ID | 29953253 | Mgi Jnum | J:273403 |
| Mgi Id | MGI:6281519 | Doi | 10.1152/ajpgi.00135.2018 |
| Citation | Terry NA, et al. (2018) Lipid malabsorption from altered hormonal signaling changes early gut microbial responses. Am J Physiol Gastrointest Liver Physiol 315(4):G580-G591 |
| abstractText | Infants with congenital diarrheal disorders caused by enteroendocrine cell dysgenesis, or the loss of intestinal endocrine cells, causes severe malabsorptive diarrhea, though the mechanism is not fully understood. The transcription factor "aristaless-related homeobox" (Arx) is specifically expressed in intestinal endocrine cells. This study seeks to characterize the early malabsorptive phenotype of mice deficient for Arx using cell-type specific gene ablation in Villin-Cre; Arx(loxP/Y) ( Arx(int)) mice. In neonatal mice, the loss of intestinal Arx caused the loss of intestinal hormones, such as cholecystokinin, secretin, neurotensin, glucose-dependent insulinotropic peptide, glucagon-like peptide (GLP)-1 and GLP-2 but also upregulation of somatostatin. Arx(int) mice exhibited steatorrhea with the loss of lipid transport in duodenal enterocytes, upregulation of lysozyme-positive Paneth cells, and a secondary increase in antimicrobial peptides, specifically Reg3beta. When the epithelium from Arx(int) mice was cultured ex vivo into enteroids, however, the Reg3beta upregulation was lost under the sterile conditions. Thus, Arx is required for the appropriate lineage allocation of multiple enteroendocrine subtypes. We concluded that altered hormonal signaling caused by Arx deficiency results in lipid malabsorption, premature Paneth cell differentiation, and an inflammatory response, including neutrophilic infiltrates and a microbiota-triggered upregulation of Reg3beta. NEW & NOTEWORTHY The enteroendocrine transcription factor aristaless-related homeobox (Arx) plays a key role in lineage specification. Changes in hormonal expression mediated by Arx lead to lipid malabsorption and premature Paneth cell development. Furthermore, global profiling of whole intestine from Arx-deficient mice revealed significant upregulation of antimicrobial peptides. This antimicrobial response in Arx-deficient animals is lost under sterile culture conditions of enteroids. |
