Gut microbiota remodeling and intestinal adaptation to lipid malabsorption after enteroendocrine cell loss in adult mice

Florence Blot (1) , Justine Marchix (2) , Miriam Ejarque (1) , Sara Jimenez (1) , Aline Meunier (1) , Céline Keime (1) , Camille Trottier (2) , Mikaël Croyal (3, 4) , Céline Lapp (1) , Maxime Mahe (2, 5) , Adèle de Arcangelis (1) , Gérard Gradwohl (1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 TENS - The Enteric Nervous System in gut and brain disorders [U1235]
3 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
4 Nantes Univ - SFR François Bonamy - Structure fédérative de recherche François Bonamy
5 UC - University of Cincinnati

Background & 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 various hormones acting locally or at a 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 yet to be 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 intestines of mice lacking EECs. We also determined the high-fat diet-induced transcriptomic changes in sorted Neurog3eYFP/+ EECs. Results: Induction of EEC 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 in the distal small intestine. Genes controlling lipogenesis, carbohydrate metabolism, and neoglucogenesis are upregulated. Microbiota composition is rapidly altered after EECs depletion and is characterized by decreased α-diversity. Bacteroides and Lactobacillus were progressively enriched, whereas 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.

Mots clés: Enteroendocrine Cells; Food Efficiency; Lipid Absorption; Microbiota

Domaines: Endocrinologie et métabolisme; Organisation et fonctions cellulaires [q-bio.SC]; Hépatologie et Gastroentérologie

Florence Blot, Justine Marchix, Miriam Ejarque, Sara Jimenez, Aline Meunier, et al.. Gut microbiota remodeling and intestinal adaptation to lipid malabsorption after enteroendocrine cell loss in adult mice. Cellular and Molecular Gastroenterology and Hepatology, 2023, ⟨10.1016/j.jcmgh.2023.02.013⟩. ⟨hal-04007457⟩