Using multiple research platforms, including a machine learning approach, researchers have identified environmental factors that promote gastrointestinal inflammation.
Inflammatory bowel disease (IBD), an increasingly common condition in industrialized countries, is characterized by chronic gastrointestinal inflammation. Although researchers have identified approximately 200 disease-associated genetic markers, understanding of the specific environmental factors that influence IBD risk and severity is limited.
A new study leverages multiple research platforms to systematically identify environmental chemicals that influence gastrointestinal inflammation. The results identify a common herbicide, propyzamide, which may promote inflammation in the small and large intestines. Led by scientists from Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, the study will be published today (October 19) in the journal Nature.
Inflammatory bowel disease (IBD) is a broad term that describes conditions characterized by chronic inflammation of the gastrointestinal (GI) tract. Crohn’s disease and ulcerative colitis are the two most common inflammatory bowel diseases.
“Environmental factors are known to be just as important as genetic factors in influencing autoimmune and inflammatory diseases, but we lack a method or a platform to systematically identify the effect of chemical candidates on the ‘inflammation,” said Francisco Quintana, PhD, corresponding author of the study. . He is a researcher at Brigham’s Ann Romney Center for Neurologic Diseases, whose lab has previously studied the environmental determinants of neurodegeneration. “Our methodology allowed us to identify a chemical that disrupts one of the body’s natural ‘brakes’ against inflammation. This method can identify new chemical candidates for epidemiological studies, as well as new mechanisms that regulate autoimmune responses. Furthermore, this platform can also be used to screen and design therapeutic anti-inflammatory drugs.
The investigators conducted their work by integrating IBD genetic databases with a large Environmental Protection Agency database, ToxCast, which includes biochemical data on consumer, industrial and agricultural products. They identified chemicals believed to modulate inflammatory pathways, then used a new zebrafish IBD model to test these compounds and determine whether they improved, worsened, or did not affect gut inflammation. Next, the researchers used a machine learning algorithm trained on the compounds studied to identify additional chemicals in the ToxCast database that may promote inflammation. Of the top 20 candidates, 11 of which are used in agriculture, the researchers chose to further examine propyzamide, which is commonly applied to sports fields and fruit and vegetable crops for weed control.
In subsequent studies in cell cultures, zebrafish, and mice, researchers demonstrated that propyzamide interferes with 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 RHA maintained intestinal homeostasis by suppressing a second pro-inflammatory pathway (the NF-κB-C/EBPβ-mediated response). C/EBPβ has previously been shown to be genetically linked to IBD, but this study describes the specific mechanism by which the genetic biomarker leads to increased intestinal inflammation.
The researchers are currently working to design nanoparticles and probiotics capable of targeting the inflammatory pathway they have identified. Notably, the United States Food and Drug Administration recently approved a topical cream for psoriasis, called tapinarof, which works by activating the AHR anti-inflammatory pathway, raising the possibility that a similar drug for IBD could be developed by taking advantage of this mechanism. Activation of the AHR pathway may 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) directed by the pro -inflammatory NF-κB-C/EBPβ response.
“The anti-inflammatory AHR pathway that we have identified could be enhanced to ameliorate the disease, and later we could also look for other ways to turn off the pro-inflammatory NF-κB-C/EBPβ response,” Quintana said. . “As we learn more about the environmental factors that could contribute to disease, we can develop state-level and national-level strategies to limit exposures. Some chemicals do not appear to be toxic when tested under basic conditions, but we don’t yet know the effect of chronic low-level exposures over decades or early in development.
Reference: “Identification of environmental factors that promote intestinal inflammation” by Sanmarco, LM et al., October 19, 2022, Nature.
Funding: This work was supported by the National Institutes of Health (NS087867, ES025530, ES032323, AI126880, and AI093903).