Biomedical research institute
     
    You are here: Home / Institute / News / AMP-activated protein kinase (AMPK) controls intestinal permeability

    AMP-activated protein kinase (AMPK) controls intestinal permeability

    Team Benoit Viollet

    Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability

     

    Disruption of intestinal epithelial barrier (IEB) integrity is associated with a variety of gastrointestinal disorders. In particular, intestinal epithelial permeability is increased in inflammatory bowel disease or upon obesity and strengthening of the IEB has been associated with better clinical outcomes. Thus, interventions ameliorating the IEB function could be a promising therapeutic option. In a recent article published in Molecular Metabolism, the team of Benoit Viollet reports that the energy sensor AMPK (AMP-activated protein kinase) plays a key role in the IEB function and contributes to the interaction between the gut microbiota and the host.

     

    This work has been performed in collaboration with Malvyne Rolli-Derkinderen (UMR1235, TENS, directed by M. Neunlist, Nantes) as part of the project “TACI” founded by Agence Nationale de la Recherche, and with the contribution of the teams from André Marette (IUCPQ/INAF, Canada), Pradipta Ghosh (UCSD, USA), Benoit Salomon (CIMI, Paris), and Sandra Guilmeau (Institut Cochin, team insulin signaling, glucose sensing and glucotoxicity).

     

    The intestinal epithelial barrier (IEB) is a single-cell layer that constitutes the largest and the most important barrier to maintain an effective defense against intraluminal toxins, antigens, and enteric microbiota. Over the past decade, there has been increasing recognition of an association between disrupted IEB function and increased intestinal permeability or "leaky gut" in the pathogenesis and exacerbation of many chronic diseases. Altered intestinal permeability contributes to pathological conditions primarily occurring within the gastrointestinal system, such as inflammatory bowel disease (Crohn's disease and ulcerative colitis). Interestingly, the degree of intestinal permeability was also found to be associated with various risk factors for metabolic diseases, suggesting that disrupted intestinal barrier could be an early event contributing to extra-digestive disease pathogenesis. The “leaky gut” concept has been associated to the development of obesity and its metabolic complications such as systemic low-grade inflammation. Indeed, it has been proposed in rodent models that increased blood endotoxins upon diet‐induced obesity is a direct consequence of gut barrier function alterations and disruption of the gut microbiota composition, thereby allowing the translocation of bacterial components such as lipopolysaccharides (LPS) into the systemic circulation and peripheral tissues. Similarly, increased circulating levels of LPS, changes of the gut microbiome signature and impairment of BEI function have been described in various cohorts of obese patients. Considering the contribution of increased intestinal permeability to the pathogenesis of digestive and systemic diseases, alleviating gut leakiness appears to be an attractive therapeutic strategy.

    AMPK is an evolutionarily conserved fuel-sensitive protein kinase and a cellular nutrient sensor implicated in the regulation of energy homeostasis. Once activated by energy balance deficit, AMPK initiates metabolic changes to reprogram metabolism by inhibiting non-essential anabolic ATP-consuming processes while stimulating ATP-delivering catabolic pathways. Recent studies have highlighted the role of AMPK, independently of its function as a metabolic sensor, in the maintenance of IEB. Previously published work from the authors has shown that pharmacological activation of AMPK protected structure and barrier function of tight junctions in vitro in intestinal epithelial cells (Olivier et al. IJMS, 2019 ; 20(20):5171).

     

    In the present study, the authors have questioned the role of AMPK in the maintenance of IEB homeostasis. Using mouse models lacking the two catalytic subunits of AMPK (AMPKa1 and AMPKa2) in intestinal epithelial cells, they evaluated the consequences of AMPK deficiency on IEB permeability, junctional protein expression, gut inflammation susceptibility and gut microbiota composition in response to diet-induced obesity. They show that gut AMPK contributes to the maintenance of IEB in the distal colon.

     

     

     

    Legend: Schematic summarizing the impact of intestinal AMPK activation/deletion on Girdin/GIV phosphorylation, intestinal barrier integrity and microbiota composition.

    © Pradipta Ghosh (UCSD)

     

     

     

    Loss of gut AMPK was associated with reduced phosphorylation of the multimodular polarity scaffold protein Girdin, a substrate of AMPK and a marker of leaky gut barrier. Alteration in epithelial barrier function in intestinal AMPK-deficient mice was also associated with a disruption of the gut microbiota composition, highlighting the complex interaction between intestinal flora and host AMPK.

    Thus, future studies will help deciphering whether targeting AMPK signaling via pharmacological and nutritional approaches may lead to new therapeutic avenues for leaky gut syndrome.

     

    Reference

    Olivier S, Pochard C, Diounou H, Castillo V, Divoux J, Alcantara J, Leclerc J, Guilmeau S, Huet C, Charifi W, Varin TV, Daniel N, Foretz M, Neunlist M, Salomon BL, Ghosh P, Marette A, Rolli-Derkinderen M, and Viollet B. Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis. Mol Metab. 2021 Feb 4;47:101183.

     

    Researcher contacts

    (Institut Cochin, Paris)

    malvyne.derkinderen@univ-nantes.fr (UMR1235, TENS, Nantes)