Lipid malabsorption from altered hormonal signaling changes early gut microbial responses

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.