Using a variety of methods, including machine learning, scientists have found a chemical that causes inflammation in the gut and is more common in industrialized countries.

In industrialized countries, the number of people with inflammatory bowel disease (IBD), which causes chronic inflammation in the intestines, is growing.

Researchers have found about 200 genetic markers that are linked to the disease, but they don’t know much about the environmental factors that affect the risk and severity of IBD.

Researchers from Brigham and Women’s Hospital, a founding institution of the Mass General Brigham healthcare system, have conducted a novel study that makes systematic use of several research platforms to uncover environmental chemical compounds that affect gastrointestinal inflammation.

Their results, which were published in the journal Nature, show that a common herbicide called propyzamide may make inflammation worse in the small and large intestines.

“Environmental factors are known to be just as important as genetic factors in influencing autoimmune and inflammatory disease, yet we lack a method or platform to systematically identify the effect of chemical candidates on inflammation,” says corresponding author Francisco Quintana. 

With the help of their methodology, they were able to pinpoint a chemical that interferes with one of the body’s built-in “brakes” against inflammation. 

This method can be used to find new chemicals to study in epidemiological studies and new ways to control autoimmune responses. This platform can also be used to screen and create therapeutic anti-inflammatory medications, according to the authors.

The researchers combined the IBD genetics databases with ToxCast, a sizable database from the Environmental Protection Agency that contains biochemical information on consumer, industrial, and agricultural products.

Using a novel zebrafish IBD model, they identified chemicals anticipated to impact inflammatory pathways and tested them to see if they reduced, increased, or had no effect on intestinal inflammation.

Next, the researchers trained a machine learning algorithm on the compounds they had studied to find other chemicals in the ToxCast database that were likely to cause inflammation.

From the top 20 candidates, 11 of which are utilized in agriculture, the researchers selected to investigate propyzamide, which is often used to control weeds on sports grounds and fruit and vegetable crops.

The researchers showed that propyzamide interferes with the aryl hydrocarbon receptor (AHR), a transcription factor Quintana initially discovered to be involved in immune regulation in 2008. This interference was seen in later cell-culture, zebrafish, and mouse investigations.

In this study, researchers discovered that the AHR preserves gut homeostasis by inhibiting a second pro-inflammatory pathway (the NF-κB-C/EBPβ-driven response).

Although the genetic relationship between C/EBP and IBD has already been established, this work describes the precise mechanism by which the genetic biomarker causes elevated intestinal inflammation.

The researchers are now trying to make nanoparticles and probiotics that can target the inflammatory pathway they have found.

Recent FDA approval of tapinarof, a topical cream for psoriasis that works by stimulating the anti-inflammatory AHR pathway, suggests that this mechanism may also be exploited in the development of a medication for inflammatory bowel disease.

Activating the AHR pathway may potentially help treat autoimmune disorders like multiple sclerosis and type 1 diabetes, which is mediated by T-cells driven by the pro-inflammatory NF-κB-C/EBPβ response.

Treatment for autoimmune diseases like type 1 diabetes and multiple sclerosis, which are mediated by T-cells activated by the pro-inflammatory NF-B-C/EBPβ response, may benefit from activating the AHR pathway.

In the future, Quintana said, “The anti-inflammatory AHR pathway we identified could be strengthened to ameliorate disease, and, further down the road, we could also investigate additional ways to deactivate the pro-inflammatory NF-κB-C/EBPβ response.” 

“As we learn more about the environmental factors that might contribute to disease, we can develop state- and national-level strategies to limit exposures. Some chemicals don’t seem to be toxic when tested under basic conditions, but we do not yet know about the effect of chronic, low-level exposures over decades, or early-on in development.”

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