The intestinal epithelial barrier (IEB) has a dual function in the gastrointestinal system. On the one hand, it allows the absorption of nutrients and, on the other hand, it guarantees the protection of the organism against attacks from the external environment (pathogens and toxins present in the luminal compartment) ensured by the integrity of the intestinal mucosa. The epithelial cells, organized in a monolayer, are tightly bound together by a network of intercellular proteins, in particular those of the tight junctions which mainly regulate the paracellular permeability. Dysfunctions of the intestinal barrier function, characterized by an increase in intestinal permeability or " leaky gut", have been associated with the severity of IBD, such as Crohn disease and ulcerative colitis. Strengthening the EIB could thus be a therapeutic approach to limit the pathological consequences of intestinal hyper-permeability. However, this strategy requires a better understanding of the mechanisms of EIB regulation and the identification of new therapeutic targets.
AMPK (AMP-activated protein kinase), a protein kinase mainly known for its role as a sensor of cellular energy status, is also an important player in the stabilization and assembly of tight junctions, as shown by the authors in recently published work (Olivier et al. Int J Mol Sci. 2019 Oct 18;20(20):5171 ; Olivier et al. Mol. Metab. 2021 May;47:101183).
To characterize the role of AMPK in maintaining intestinal barrier integrity, mice deficient in AMPK activity specifically in intestinal epithelial cells (IEC AMPK KO) were subjected to treatment with DSS (Dextran Sulfate), a colitis model commonly used to mimic IBD development. Markers of colitis severity (weight loss, colon length, and intestinal permeability) were similar between control and IEC AMPK KO mice after 4 days of treatment corresponding to the acute inflammatory phase of colitis. However, inflammation in the colon remained greater in the IEC AMPK KO animals. In contrast, during the regenerative phase (repair of the intestinal epithelium), IEC AMPK KO mice showed increased intestinal permeability, reduced expression of junctional proteins, and more extensive colonic ulceration associated with severe inflammation compared to control mice. The absence of AMPK activity causes a delay in the re-epithelization of the intestinal mucosa which is associated with an impairment of goblet cell restitution, a key player in the intestinal wound healing process.
To test the therapeutic relevance of AMPK activation in the intestine, administration of an indirect AMPK activator, metformin, a molecule used for the treatment of type 2 diabetes, was performed during the regeneration phase after colitis induction. Treatment with metformin significantly improves the repair capacity of the colonic epithelium but this beneficial effect is independent of the presence of AMPK in the intestinal epithelium.
This work demonstrates the importance of AMPK in the regeneration of the intestinal epithelium and also highlights the therapeutic potential of metformin in the treatment of IBD.
This work was funded by Agence Nationale de la Recherche (ANR) and Société Francophone du Diabète (SFD).
Olivier S, Diounou H, Pochard C, Frechin L, Durieu E, Foretz M, Neunlist M, Rolli-Derkinderen M, Viollet B. Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis. Cells. 2022 Feb 9;11(4):590. doi: 10.3390/cells11040590. PMID: 35203241
Olivier S, Diounou H, Foretz M, Guilmeau S, Daniel N, Marette A, Rolli-Derkinderen M, Viollet B. AMPK activity is a gatekeeper of the intestinal epithelial barrier. Med Sci (Paris). 2022 Feb;38(2):136-138. doi: 10.1051/medsci/2021251. Epub 2022 Feb 18. PMID: 35179465
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, Viollet B. Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis. Mol Metab. 2021 May;47:101183. doi: 10.1016/j.molmet.2021.101183. PMID: 33548500
Olivier S, Leclerc J, Grenier A, Foretz M, Tamburini J, Viollet B. AMPK Activation Promotes Tight Junction Assembly in Intestinal Epithelial Caco-2 Cells. Int J Mol Sci. 2019 Oct 18;20(20):5171. doi: 10.3390/ijms20205171. PMID: 31635305