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Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine
Published on: February 26, 2019
Lipid malabsorption from altered hormonal signaling changes early gut microbial responses
Natalie A Terry1,2, Lucie V Ngaba1, Benjamin J Wilkins2,3
1Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
Insights
The transcription factor aristaless-related homeobox (Arx) is crucial for intestinal endocrine cell development. Its deficiency causes lipid malabsorption and premature Paneth cell differentiation, impacting gut health.
Area of Science:
- Gastroenterology
- Developmental Biology
- Molecular Endocrinology
Background:
- Congenital diarrheal disorders stem from enteroendocrine cell dysgenesis, leading to severe malabsorptive diarrhea.
- The precise mechanisms underlying these disorders, particularly the role of specific transcription factors, remain incompletely understood.
- Intestinal endocrine cells are vital for nutrient absorption and gut homeostasis, and their dysfunction has significant health implications.
Purpose of the Study:
- To investigate the role of the transcription factor aristaless-related homeobox (Arx) in intestinal endocrine cell development and function.
- To characterize the early malabsorptive phenotype in mice with cell-type specific ablation of Arx in intestinal cells.
- To elucidate the impact of Arx deficiency on hormone production, lipid transport, and innate immune responses in the intestine.
Main Methods:
- Utilized Villin-Cre;ArxloxP/Y (Arxint) mice for cell-type specific gene ablation of Arx in intestinal cells.
- Analyzed neonatal Arxint mice for changes in intestinal hormone expression, lipid transport, and Paneth cell markers.
- Employed ex vivo enteroid cultures derived from Arxint mice to assess the role of the microbiota in observed phenotypes.
Main Results:
- Loss of Arx in intestinal endocrine cells led to a significant decrease in key intestinal hormones (e.g., GLP-1, GLP-2) and an increase in somatostatin.
- Arxint mice exhibited steatorrhea, indicating impaired lipid transport in duodenal enterocytes.
- Premature differentiation of lysozyme-positive Paneth cells and increased expression of antimicrobial peptide Reg3β were observed, which was lost under sterile culture conditions.
Conclusions:
- Arx is essential for the proper lineage allocation and differentiation of multiple enteroendocrine cell subtypes.
- Arx deficiency results in hormonal signaling alterations that cause lipid malabsorption and premature Paneth cell development.
- The observed upregulation of antimicrobial peptides like Reg3β is microbiota-dependent and linked to an inflammatory response in Arx-deficient intestines.
Abstract:
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; ArxloxP/Y ( Arxint) 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. Arxint 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 Reg3β. When the epithelium from Arxint mice was cultured ex vivo into enteroids, however, the Reg3β 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 Reg3β. 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.
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