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

Area of Science:

• Gastroenterology and Immunology
• Cellular Biology
• Dietary Metabolism

Background:

• Macroautophagy/autophagy is crucial for intestinal epithelial cell (IEC) health.
• A loss-of-function variant in ATG16L1 is linked to Crohn disease (CD) risk.
• Western diets, high in fatty acids, are associated with CD pathogenesis.

Purpose of the Study:

• To investigate the role of ATG16L1-mediated autophagy in diet-induced metabolic enteritis.
• To explore the unexpected inflammatory function of ATG16L1 in the context of Western diets.

Main Methods:

• Induction of Crohn-like metabolic enteritis in mice using excess polyunsaturated fatty acids (PUFAs) in a Western diet.
• Transcriptomic and lipidomic profiling of IECs.
• Analysis of ATG16L1-mediated autophagy and its downstream signaling pathways.

Main Results:

• Dietary PUFAs induce ATG16L1-mediated autophagy in IECs.
• This autophagy is essential for PUFA-induced chemokine production and metabolic enteritis.
• ATG16L1 mediates PUFA-induced inflammatory signaling via TLR2 and arachidonic acid metabolites.

Conclusions:

• ATG16L1-mediated autophagy acts as an inflammatory driver in metabolic enteritis induced by PUFA excess.
• This finding challenges the established view of autophagy as solely protective, particularly in the context of Western diets.
• Highlights a potential therapeutic target for diet-related intestinal inflammation.