Acute exposure to high-fat diet impairs ILC3 functions and gut homeostasis

Xiong, L; Diwakarla, S; Chatzis, R; Artaiz, O; Macowan, M; Zhang, S; Garnham, A; Morgan, PK; Mellett, NA; Meikle, PJ; Lancaster, GI; Marsland, BJ; Nutt, SL; Seillet, C

Author(s): Xiong, L; Diwakarla, S; Chatzis, R; Artaiz, O; Macowan, M; Zhang, S; Garnham, A; Morgan, PK; Mellett, NA; Meikle, PJ; Lancaster, GI; Marsland, BJ; Nutt, SL; Seillet, C;
Details: Publication Year 2025-05-13,Volume 58,Issue #5,Page 1185-1200 e8
Journal Title: Immunity
Abstract: Prolonged exposure to a high-fat diet (HFD) exacerbates intestinal disease pathology, yet the early events preceding the development of gut inflammation remain poorly understood. Here, we show that within 48 h, HFD impairs intestinal group 3 innate lymphoid cells (ILC3s) and their capacity to produce interleukin-22 (IL-22), critical for maintaining gut homeostasis. This loss of function was associated with rapid dysbiosis, increased gut permeability, and reduced production of antimicrobial peptides, mucus, and tight-junction proteins. While saturated fatty acids metabolized through oxidation impaired ILC3 function, unsaturated fatty acids sustained IL-22 secretion by ILC3s through the formation of lipid droplets using diacylglycerol O-acyltransferase (DGAT) enzymes. Upon inflammation, saturated fatty acids impaired IL-22 production by ILC3s and increased the susceptibility of the gut to injury. Our findings reveal the differential acute impact of saturated and unsaturated fatty acids on gut homeostasis through distinct metabolic pathways in ILC3s.
Publisher: Cell Press
Keywords: Animals; *Diet, High-Fat/adverse effects; *Homeostasis/immunology; Mice; Immunity, Innate; *Lymphocytes/immunology/metabolism; Interleukin-22; Mice, Inbred C57BL; Interleukins/metabolism; Fatty Acids/metabolism; Male; *Intestinal Mucosa/immunology/metabolism; Inflammation/immunology; Gastrointestinal Microbiome/immunology; Dysbiosis/immunology; Diacylglycerol O-Acyltransferase/metabolism; Mice, Knockout; Dgat; Il-22; group 3 innate lymphoid cells; high-fat diet; inflammation; inflammatory bowel disease; intestinal homeostasis; lipid droplets; metabolism; saturated fatty acid
Research Division(s): Immunology; Bioinformatics and Computational Biology
PubMed ID: 40233759
Publisher's Version: https://doi.org/10.1016/j.immuni.2025.03.017
Open Access at Publisher's Site: https://doi.org/10.1016/j.immuni.2025.03.017
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-06 09:11:29

Last Modified: 2025-05-29 02:29:00