Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis

• DOI: 10.1016/j.molmet.2021.101183
• Publication Date: 2021-02-05T18:56:02Z
• Authors: Séverine Olivier; Camille Pochard; Hanna Diounou; Vanessa Castillo; Jordane Divoux; Joshua Alcantara; Jocelyne Leclerc; Sandra Guilmeau; Camille Huet; Wafa Charifi; Thibault V. Varin; Noëmie Daniel; Marc Foretz; Michel Neunlist; Benoit L. Salomon; Pradipta Ghosh; André Marette; Malvyne Rolli-Der...; Benoit Viollet
• Keywords: Intestinal Permeability; AMP-Activated Protein Kinase; Paracellular transport; Barrier function; Ex vivo; Homeostasis

The intestinal epithelial barrier (IEB) restricts the passage of microbes and potentially harmful substances from lumen through paracellular space, rupture its integrity is associated with a variety gastrointestinal disorders extra-digestive diseases. Increased IEB permeability has been linked to disruption metabolic homeostasis leading obesity type 2 diabetes. Interestingly, recent studies have uncovered compelling evidence that AMP-activated protein kinase (AMPK) signaling pathway plays an important role in maintaining cell function. However, our understanding function AMPK regulating glucose remains sparse. We generated mice lacking two α1 α2 catalytic subunits specifically cells (IEC KO) determined physiological consequences intestinal-specific deletion response high-fat diet (HFD)-induced obesity. combined histological, functional, integrative analyses ascertain effects gut loss on vivo ex development dysfunction. also impact inducible mouse model (i-IEC by measuring function, homeostasis, composition microbiota via fecal 16S rRNA sequencing. While there were no differences WT IEC KO mice, transcellular measured Ussing chambers was significantly increased distal colon mice. This reduction pSer425 GIV phosphorylation, marker leaky barrier. expression tight junction proteins pro-inflammatory cytokines lamina propria not different between genotypes. Although HFD-fed displayed suppression stress polarity concomitant increase permeability, did exacerbate body weight gain or adiposity. Deletion sufficient alter acute glucose-lowering action metformin control (CD)- CD-fed i-IEC presented higher under homeostatic conditions but, surprisingly, this detected upon HFD feeding. Alteration shift levels Clostridiales Desulfovibrionales. Altogether, results revealed significant but homeostasis. Our data highlight complex interaction host AMPK.