Inflammatory bowel disease (IBD) is a condition characterized by chronic inflammation in the gut.
IBD is becoming more common in industrialized countries and also among people who move into areas with a higher prevalence of IBD, leading scientists to suspect that environmental factors may play a role in IBD risk and severity. Researchers have identified about 200 genetic biomarkers associated with IBD, but their understanding of environmental factors associated with IBD is, as yet, imprecise.
That could soon be changing. A team led by researchers from Harvard Medical School and Brigham and Women’s Hospital in Boston has developed a screening platform to systematically identify environmental chemicals that could promote or suppress gastrointestinal inflammation.
“Environmental factors are known to be just as important as genetic factors in influencing autoimmune or inflammatory diseases, yet we lack a method to systematically test the effect of chemical candidates on inflammation,” Francisco Quintana, corresponding author on the study, told TheDoctor.
Propyzamide is a herbicide often applied to sports playing fields and fruit and vegetable crops to control weeds. It has been found to interfere with immune regulation.
To begin to do this, the researchers integrated an IBD genetics database with ToxCast, an Environmental Protection Agency database that includes biochemical data on consumer, industrial, and agricultural products.
Chemicals thought to influence inflammatory pathways were tested on a model of IBD in zebrafish to see how they affected gut inflammation — whether they caused it to worsen, improve or had no effect on inflammation in the gut. The researchers then used a machine learning algorithm to identify more compounds in the ToxCast database that may promote inflammation.
Of the 20 compounds most likely to promote gut inflammation, the researchers decided to study propyzamide more closely. Propyzamide is a herbicide often applied to sports playing fields and fruit and vegetable crops to control weeds.
In subsequent studies done in mice and zebrafish, and in cell culture, propyzamide was found to interfere with the aryl hydrocarbon receptor (AHR), a transcription factor involved in immune regulation. The AHR pathway maintains homeostasis, or stable conditions, in the gut by suppressing the proinflammatory NF-KB-C/EBPβ-driven response. C/EBPβ is a genetic biomarker previously shown to be associated with IBD, but this study specifies the pathway by which it causes intestinal inflammation.
The screening platform could also be used to identify potential anti-inflammatory drugs. “What is exciting is that the molecular mechanism by which these chemicals act is actually a pathway we can regulate with smaller molecules,” said Quintana, a professor of neurology at Harvard Medical School.
The U.S. Food and Drug Administration recently approved tapinarof, a topical cream for the treatment of psoriasis, which works by activating the AHR pathway. A treatment for IBD could also take advantage of this mechanism, the researchers said.
Treatment for other autoimmune diseases such as type 1 diabetes and multiple sclerosis could be based on AHR pathway activation as well. These diseases are mediated by similar T-cells in the immune system driven by the NF-KB-C/EBPβ pathway. Nanoparticles and probiotics that target the anti-inflammatory AHR pathway are currently in development.
The study is published in Nature.