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other·gastroenterology, endocrinology, preclinical research, biomedical research, nutrition·PMC10149283

Gut Microbiota Remodeling and Intestinal Adaptation to Lipid Malabsorption After Enteroendocrine Cell Loss in Adult Mice

Cellular and Molecular Gastroenterology and Hepatology · 12 authors, 10 centres

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TL;DR

Tamoxifen-induced enteroendocrine cell depletion in adult male Neurog3fl/fl;Villin-CreERT2 mice causes impaired lipid absorption, weight loss, and rapid gut microbiota remodeling on a standard chow diet.

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Adult male Neurog3fl/fl;Villin-CreERT2 mice were treated with tamoxifen to deplete intestinal enteroendocrine cells, and energy metabolism, intestinal transcriptome, and microbiota were assessed. Under a standard chow diet, EEC-deficient mice lost 10% of body weight due to impaired food efficiency, with reduced blood cholesterol, triglycerides, and free fatty acids. Lipid absorption was impaired and spatially delayed in the distal small intestine. Transcriptomic profiling revealed upregulation of lipogenesis, carbohydrate metabolism, and neoglucogenesis genes in the ileum. Microbiota composition was rapidly altered, with decreased alpha-diversity, progressive enrichment of Bacteroides and Lactobacillus, and decline of Lachnospiraceae, without changes in fecal short-chain fatty acid concentrations. All experiments were performed in males, precluding conclusions about female mice. The study identifies compensatory metabolic and transcriptomic adaptations to sustained lipid malabsorption in adults, a phenomenon not previously studied due to neonatal lethality of constitutive EEC deficiency.

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other

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gastroenterology

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ORIGINAL PAPER

PMC10149283

Gut Microbiota Remodeling and Intestinal Adaptation to Lipid Malabsorption After Enteroendocrine Cell Loss in Adult Mice

Cellular and Molecular Gastroenterology and Hepatology

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ABSTRACT

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 Neurog3 fl/fl ; Villin-CreER T2 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 Neurog3 eYFP/+ 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.

CITATION EXPORT

Florence Blot, Justine Marchix, Miriam Ejarque 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). https://doi.org/10.1016/j.jcmgh.2023.02.013

AUTHORS

12 · 10 CENTRES

Florence Blot, Justine Marchix, Miriam Ejarque, Sara Jimenez, Aline Meunier, Céline Keime, Camille Trottier, Mikaël Croyal, Céline Lapp, Maxime M. Mahe, Adèle De Arcangelis, Gérard Gradwohl

1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Institut National de la Santé et de la Recherche Médicale (INSERM) U1258, Illkirch, France
3Centre National de Recherche Scientifique (CNRS) UMR7104, Illkirch, France
4Université de Strasbourg, Illkirch, France
5Nantes Université, CHU Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Nantes, France
6L’Institut du Thorax, INSERM UMR_S1087, CNRS UMR_6291, Université de Nantes, Nantes, France
7CRNH-Ouest Mass Spectrometry Core Facility, Nantes, France
8Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France
9Department of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
10Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio