Gene expression profiling of the duodenum and ileum of mice lacking enteroendocrine cells and fed a high fat diet

ABSTRACT: Background and aims: Enteroendocrine cells (EECs) and their hormones are essential regulators of whole-body energy homeostasis. EECs sense luminal nutrients and microbial metabolites and subsequently secrete a variety of hormones acting locally or at distance. Impaired development of EECs during embryogenesis is life-threatening in newborn mice and humans due to compromised nutrient absorption. However, the physiological importance of the EEC system in adult mice has not been directedly studied. Herein, we aimed to determine the long-term consequences of a total loss of EECs in healthy adults on energy metabolism, intestinal transcriptome and microbiota. Methods: We depleted intestinal EECs by tamoxifen treatment of adult Neurog3fl/fl; Villin-CreERT2 male mice. We studied intestinal cell differentiation, food efficiency, lipid absorption, microbiota composition, fecal metabolites and transcriptomic responses in the proximal and distal small intestine of mice lacking EECs. We also determined the high-fat diet induced transcriptomic changes in sorted Neurog3eYFP/+EECs. Results: Induction of EECs deficiency in adults is not life-threatening unless fed with a high-fat diet. Under a standard chow diet, mice lose 10% of weight due to impaired food efficiency. Blood concentrations of cholesterol, triglycerides, and free fatty acids are reduced and lipid absorption is impaired and delayed to the distal small intestine. Genes controlling lipogenesis, carbohydrate metabolism and neoglucogenesis are upregulated. Microbiota composition is rapidly altered after ECCs depletion and characterized by decreased alpha-diversity. Bacteroides and Lactobacillus were progressively enriched while Lachnospiraceae declined without impacting fecal short chain fatty acid concentrations. Conclusions: EECs are dispensable for survival in adult male mice under a standard chow diet. The absence of EECs impairs intestinal lipid absorption leading to transcriptomic and metabolic adaptations and remodeling of the gut microbiota.

ORGANISM(S): Mus musculus

PROVIDER: GSE224026 | GEO | 2023/03/01

REPOSITORIES: GEO