Several research platforms are identifying environmental chemical agents that promote intestinal inflammation

Several research platforms are identifying environmental chemical agents that promote intestinal inflammation

Inflammatory bowel disease (IBD), a condition characterized by chronic gastrointestinal inflammation, is becoming increasingly common in developed countries. While researchers have identified about 200 genetic markers associated with the disease, there is limited knowledge about the specific environmental factors that influence the risk and severity of IBD. A new study by researchers at Brigham and Women's Hospital, a founding member of the Mass General Brigham Health System, uses multiple research platforms to systematically identify environmental chemicals that influence gastrointestinal inflammation. Their findings, published in Nature, identify a widely used herbicide, propyzamide, that can increase inflammation in the small and large intestines.

"It is known that environmental factors are as important as genetic factors in influencing autoimmune and inflammatory diseases, yet we lack a method or platform to systematically identify the effect of chemical candidates on inflammation," said corresponding author Francisco Quintana, PhD, a researcher in the Brigham's Ann Romney Center for Neurologic Diseases, whose laboratory has previously studied environmental determinants of neurodegeneration. “Our methodology allowed us to identify a chemical that disrupts one of the body’s natural “brakes” on inflammation. This method can be used to identify new chemical candidates for epidemiological studies as well as novel mechanisms that regulate autoimmune responses. In addition, this platform can also be used to screen and design therapeutic anti-inflammatory drugs.”

The researchers conducted their work by integrating IBD genetics databases with a large Environmental Protection Agency database, ToxCast, which contains biochemical data on consumer, industrial and agricultural products. They identified chemicals that were expected to modulate inflammatory pathways and then used a novel zebrafish IBD model to test these compounds and determine whether they improve, worsen, or do not affect intestinal inflammation. Next, the researchers used a machine learning algorithm trained on the studied compounds to identify additional chemicals in the ToxCast database that likely promote inflammation. From the top 20 candidates, 11 of which are used in agriculture, the researchers decided to further study propyzamide, which is often used on sports fields and in fruit and vegetable cultivation to control weeds.

In subsequent cell culture, zebrafish and mouse studies, the researchers showed that propyzamide disrupts the aryl hydrocarbon receptor (AHR), a transcription factor that Quintana first reported in 2008 to be involved in immune regulation. In this study, researchers found that AHR maintains intestinal homeostasis by suppressing a second, pro-inflammatory signaling pathway (the NF-κB-C/EBPβ-driven response). C/EBPβ has previously been shown to be genetically linked to IBD. However, this study describes the specific mechanism by which the genetic biomarker leads to increased intestinal inflammation.

The researchers are currently working on developing nanoparticles and probiotics that can target the inflammatory pathway they have identified. Notably, the U.S. Food and Drug Administration recently approved a topical cream for psoriasis called Tapinarof that works by activating the anti-inflammatory AHR pathway, raising the possibility that a similar drug for IBD could be developed taking advantage of this mechanism. Activation of the AHR signaling pathway could also be relevant for the treatment of other autoimmune diseases such as multiple sclerosis and type 1 diabetes, which are mediated by similar immune cells (T cells) controlled by the pro-inflammatory NF-κB-C/EBPβ response.

The anti-inflammatory AHR pathway we identified could be strengthened to alleviate disease, and in the future we may also explore additional ways to deactivate the pro-inflammatory NF-κB-C/EBPβ response. As we learn more about the environmental factors that can contribute to disease, we can develop strategies at the state and national levels to limit exposure. Some chemicals appear to be non-toxic when tested under normal conditions, but we do not yet know the effects of chronic, low-level exposure over decades or early in development.”

Francisco Quintana, PhD, researcher, Brigham's Ann Romney Center for Neurologic Diseases.

Source:

Brigham and Women's Hospital

Reference:

Sanmarco, L.M., et al. (2022) Identification of environmental factors that promote intestinal inflammation. Nature. doi.org/10.1038/s41586-022-05308-6.

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