Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy

Macroautophagy/autophagy exerts multilayered protective functions in intestinal epithelial cells (IECs) while a loss-of-function genetic variant in ATG16L1 (autophagy related 16 like 1) is associated with risk for developing Crohn disease (CD). Westernization of diet, partly characterized by excess of long-chain fatty acids, contributes to CD, and a metabolic control of intestinal inflammation is emerging. Here, we report an unexpected inflammatory function for ATG16L1-mediated autophagy in Crohn-like metabolic enteritis of mice induced by polyunsaturated fatty acid (PUFA) excess in a western diet. Dietary PUFAs induce ATG16L1-mediated conventional autophagy in IECs, which is required for PUFA-induced chemokine production and metabolic enteritis. By transcriptomic and lipidomic profiling of IECs, we demonstrate that ATG16L1 is required for PUFA-induced inflammatory stress signaling specifically mediated by TLR2 (toll-like receptor 2) and the production of arachidonic acid metabolites. Our study identifies ATG16L1-mediated autophagy in IECs as an inflammatory hub driving metabolic enteritis, which challenges the perception of protective autophagy in the context of diet westernization.<b>Abbreviations</b>: AA: arachidonic acid; ATG16L1: autophagy related 16 like 1; CD: Crohn disease; CXCL1: C-X-C motif chemokine ligand 1; ER: endoplasmic reticulum; GFP: green fluorescent protein; GPX4: glutathione peroxidase 4; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; PUFA: polyunsaturated fatty acid; SDA: stearidonic acid; TLR2: toll-like receptor 2; WT: wild-type.

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Publication Details

Journal
Autophagy
Published
2025-12-12
DOI
https://doi.org/10.1080/15548627.2025.2600906
Citations
1
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
1.35
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article

Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy

Günter Weiß, Qitao Ran, Alessandro Simonini, Stefanie Auer et al.
1 citations
Autophagy
Autophagy in Disease and Therapy
1.35
article

Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy

Günter Weiß, Qitao Ran, Alessandro Simonini, Stefanie Auer, Felix Grabherr, Zhigang Rao, M Philipp, Andreas Koeberle, Timon Erik Adolph, Julian Schwärzler, Johannes Leierer, Almina Jukic, Herbert Tilg, Arthur Kaser, Philip Rosenstiel, Richard S. Blumberg, Verena Wieser, Jakob Scheler, Dietmar Rieder, Andreas Zollner, Lisa F. Amann, Richard Hilbe, Zlatko Trajanoski, Laura Scheffauer, Lisa Mayr, Moritz Meyer, Patrizia Moser, Luis Zundel
article en
1 citations

Abstract

Macroautophagy/autophagy exerts multilayered protective functions in intestinal epithelial cells (IECs) while a loss-of-function genetic variant in ATG16L1 (autophagy related 16 like 1) is associated with risk for developing Crohn disease (CD). Westernization of diet, partly characterized by excess of long-chain fatty acids, contributes to CD, and a metabolic control of intestinal inflammation is emerging. Here, we report an unexpected inflammatory function for ATG16L1-mediated autophagy in Crohn-like metabolic enteritis of mice induced by polyunsaturated fatty acid (PUFA) excess in a western diet. Dietary PUFAs induce ATG16L1-mediated conventional autophagy in IECs, which is required for PUFA-induced chemokine production and metabolic enteritis. By transcriptomic and lipidomic profiling of IECs, we demonstrate that ATG16L1 is required for PUFA-induced inflammatory stress signaling specifically mediated by TLR2 (toll-like receptor 2) and the production of arachidonic acid metabolites. Our study identifies ATG16L1-mediated autophagy in IECs as an inflammatory hub driving metabolic enteritis, which challenges the perception of protective autophagy in the context of diet westernization.<b>Abbreviations</b>: AA: arachidonic acid; ATG16L1: autophagy related 16 like 1; CD: Crohn disease; CXCL1: C-X-C motif chemokine ligand 1; ER: endoplasmic reticulum; GFP: green fluorescent protein; GPX4: glutathione peroxidase 4; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; PUFA: polyunsaturated fatty acid; SDA: stearidonic acid; TLR2: toll-like receptor 2; WT: wild-type.

AutophagyVol. 22(2)
Brigham and Women's Hospital (US), Harvard University (US), Innsbruck Medical University (AT), University of Graz (AT), The University of Texas at San Antonio Health Science Center (US), Universität Innsbruck (AT), University of Cambridge (GB), Christian-Albrechts-Universität zu Kiel (DE), University Hospital Schleswig-Holstein (DE), Addenbrooke's Hospital (GB), University Hospital Innsbruck (AT), The University of Texas Health Science Center at Houston (US), University of Lübeck (DE)
Openalex Percentile: Top 13%
Autophagy in Disease and Therapy
1.35
DOIOpen Access PDFOpenAlex
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