Study Finds Lack of Angptl4 Gene Triggers Long-Term Protection Against Inflammatory Bowel Disease by Reprogramming the Immune System

A novel study using a mouse model has found that the absence of the angiopoietin-like 4 (ANGPTL4) protein during development triggers a long-lasting reprogramming of the immune system that protects against intestinal inflammation. The findings from the study in The American Journal of Pathology, published by Elsevier, may have important implications for identifying molecular or cellular signatures that predict disease susceptibility, and for developing therapeutic strategies that enhance protective immune programs in inflammatory bowel disease and inflammation-driven colorectal cancer.

ANGPTL4 is a secreted glycoprotein primarily recognized for its pivotal role in lipid metabolism. Beyond its metabolic functions, ANGPTL4 is important for tissue stability and health (homeostasis) and has been implicated in various disease processes including cancer, wound healing, pulmonary inflammation, atherosclerosis, and notably, intestinal homeostasis.

The intestine is an important organ for nutrient absorption and immune defense, which is continuously exposed to a multitude of antigens and microbes. Disruptions in intestinal homeostasis can result in pathologic outcomes, such as inflammatory bowel disease and colitis, with prolonged inflammation increasing the risk of colorectal cancer.

Previous research on Angptl4 knockout mice (with the gene “switched off”) uncovered striking outcomes; while some pups died within the first two weeks of life due to impaired intestinal lymphatic development and severe intestinal inflammation, survivors developed normally without obvious lymphatic defects.

While prior studies focused mainly on the mice that developed fatal early-life complications, this study examined the long-term health of surviving Angptl4 knockout mice.

“We hypothesized that the surviving Angptl4 knockout mice might undergo developmental adaptation that enables them to overcome those early intestinal challenges,” says co-lead investigator Hoon-Ki Sung, MD, PhD, The Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. “This made us wonder how these surviving knockout mice respond later in life when challenged with intestinal inflammation, and what the long-term consequences of Angptl4 deficiency in inflammatory settings are.”

Unexpectedly, these mice were strongly protected against both intestinal inflammation and inflammation-driven colon tumors compared with normal, wild-type controls. This protection was associated with a shift in macrophage (a type of immune cell) behavior toward an alternatively activated state, suggesting that altered immune responses contribute to reduced disease severity and tumor formation.

“A major novel insight from our study is that intestinal inflammation experienced during development can shape long-term immune programming, resulting in increased resistance to recurrent inflammatory challenges later in life,” notes co-lead investigator Joe Eun Son, PhD, Department of Advanced BioConvergence, Kyungpook National University Daegu, Republic of Korea. “Understanding how early-life inflammatory events ‘train’ or reprogram intestinal immune responses may reveal new mechanisms by which the body prepares for future inflammatory insults.”

To evaluate the clinical relevance in human colorectal cancer, The Cancer Genome Atlas Colorectal Adenocarcinoma data set was analyzed, showing that low ANGPTL4 expression levels correlated with lower inflammatory levels and improved survival rates in human colorectal adenocarcinoma.

These findings present a previously unrecognized impact of Angptl4 deficiency in intestinal pathogenesis and support the concept of trained immunity (epigenetic programming), in which early-life exposures can induce long-lasting reprogramming of the innate immune system.

“Our study highlights the significance of ANGPTL4 as a prognostic biomarker for bowel inflammation and colorectal cancer. Understanding the distinct roles of ANGPTL4 in different tissues will be crucial for developing targeted therapies that maximize benefits while minimizing adverse effects,” concludes Dr. Son.

Notes for editors

The article is “Loss of Angptl4 Protects Mice from Intestinal Colitis and Tumorigenesis with Alternative Activation of Macrophages,” by Jeong-ah Yoo, Yun Hye Kim, Min Seon Choe, Hamza Sghayare, Qiwei Zhang, Gaeun Kwon, Yeeun Kim, Seoyeon Lee, Chaewon Lee, Hoon-Ki Sung, and Joe Eun Son (https://doi.org/10.1016/j.ajpath.2025.11.003). It appears in The American Journal of Pathology, volume 196, issue 3 (March 2026), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(25)00434-1/fulltext.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] to request a PDF of the article or more information. To reach the study’s authors contact Hoon-Ki Sung, MD, PhD, at [email protected], or Joe Eun Son, PhD, at [email protected].

This study was supported by the Canadian Institute of Health Research grants PJT-162083 and 190016; Natural Sciences and Engineering Research Council grant RGPIN-2016-06610 of Canada; Diabetes Canada grant OG-3-23-5715-HS; Canada Foundation for Innovation grant 40249; Novo Nordisk Pilot and Feasibility grant from Banting & Best Diabetes Centre of University of Toronto; the Global-Learning & Academic research institution for Master’s PhD students; Postdocs (LAMP) Program of the National Research Foundation of Korea funded by the Ministry of Education number RS-2023-00301914; the Biological Materials Specialized Graduate Program of the Korea Environmental Industry and Technology Institute funded by the Ministry of Environment; and the Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education grant 2021R1A6C101A416.

About The American Journal of Pathology

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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