A recent study using a mouse model has shown that lacking the angiopoietin-like 4 (ANGPTL4) protein during development leads to long-term changes in the immune system that protect against intestinal inflammation. The research, published in The American Journal of Pathology by Elsevier, suggests that these findings could help identify new molecular or cellular markers for disease risk and support new treatments for inflammatory bowel disease and colorectal cancer caused by inflammation.
ANGPTL4 is known as a secreted glycoprotein important for lipid metabolism. It also plays a role in tissue health and stability, and it has been linked to diseases such as cancer, wound healing issues, lung inflammation, atherosclerosis, and particularly intestinal health.
The intestine is key for absorbing nutrients and defending against microbes but is often exposed to many antigens. Problems with intestinal balance can lead to diseases like inflammatory bowel disease and colitis. If inflammation continues over time, it increases the chance of developing colorectal cancer.
Earlier studies on mice without the Angptl4 gene found some young mice died soon after birth because of problems with lymphatic development in the intestine and severe inflammation. However, those that survived developed normally without clear lymphatic issues.
While most past research focused on mice with fatal early-life complications, this study looked at how surviving Angptl4 knockout mice fared later in life.
"We hypothesized that the surviving Angptl4 knockout mice might undergo developmental adaptation that enables them to overcome those early intestinal challenges," said co-lead investigator Hoon-Ki Sung, MD, PhD from The Hospital for Sick Children and University of Toronto. "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."
The researchers found these mice were significantly protected from both intestinal inflammation and colon tumors driven by inflammation compared to normal controls. This protection was linked to changes in macrophages—immune cells—that shifted toward an alternatively activated state. These altered immune responses appeared to reduce disease severity and tumor growth.
To see if their findings applied to humans with colorectal cancer, the team analyzed data from The Cancer Genome Atlas Colorectal Adenocarcinoma dataset. They found lower ANGPTL4 expression was associated with less inflammation and better survival rates among patients with colorectal adenocarcinoma.
These results reveal an unexpected effect of Angptl4 deficiency on gut disease development and support the idea of trained immunity—where early-life events cause lasting changes in innate immune function through epigenetic programming.
"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," concluded Dr. Son.
