Chemicals in the environment increase the risk of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a disease characterized by chronic gastrointestinal inflammation that is increasingly prevalent
in industrialized countries.
While researchers have identified about 200 genetic tags associated with the disease, there is limited
understanding of the specific environmental factors that influence IBD risk and severity.
Researchers from Brigham and Women's Hospital, one of the founding members of Massachusetts General Hospital's Brigham Health System, conducted a new study using multiple research platforms to systematically identify environmental chemicals that affect gastrointestinal inflammation
.
Their findings, published in the journal Nature, identified a common herbicide propionamide, which may exacerbate inflammation
in the small and large intestines.

"It is well known that environmental factors are as important as genetic factors in influencing autoimmune and inflammatory diseases, but we lack a method or platform to systematically determine the effects of chemical candidates on inflammation," said corresponding author Francisco Quintana, PhD, a researcher at the Brigham Ann Romney Center for Neurological Disorders, whose lab previously studied the environmental determinants of
neurodegeneration.
"Our approach allows us to identify a chemical that disrupts the body's natural 'brakes'
on inflammation.
" This approach could identify new chemical candidates for epidemiological studies, as well as new mechanisms
for regulating autoimmune responses.
In addition, the platform can be used for the screening and design
of therapeutic anti-inflammatory drugs.

The researchers conducted the study by integrating the IBD gene database with the Environmental Protection Agency's large database ToxCast, which includes biochemical data
on consumer, industrial and agricultural products.
They identified chemicals that could modulate inflammatory pathways and then tested these compounds using a new model of IBD in zebrafish and determined whether they improved, worsened, or did not affect gut inflammation
.
Next, the researchers used machine learning algorithms trained on the compounds studied to identify other chemicals
in the ToxCast database that might promote inflammation.
Among the top 20 drug candidates, 11 of which are used in agriculture, the researchers chose to further investigate propionamide, a drug commonly used in sports fields and fruit and vegetable crops to control weeds
.

In subsequent cell culture, zebrafish, and mouse studies, the researchers demonstrated that propionamide interferes with the aryl hydrocarbon receptor (AHR), a transcription factor that Quintana first reported in 2008 as implicated in
immune regulation.
In this study, the researchers found that AHR maintains homeostasis
in the gut by inhibiting a second pro-inflammatory pathway (NF-κB-C/ebp β driver response).
C/EBPβ has previously been shown to be associated with the IBD gene, but this study outlines the specific mechanism by
which genetic biomarkers lead to increased gut inflammation.

Researchers are currently working on designing nanoparticles and probiotics to target inflammatory pathways
they have identified.
Notably, the U.
S.
Food and Drug Administration (FDA) recently approved tapinarof, a topical ointment for psoriasis, which works by activating the anti-inflammatory AHR pathway, which increases the possibility of
using this mechanism to develop IBD-like drugs.
Activation of the AHR pathway may also be associated with the treatment of other autoimmune diseases, such as multiple sclerosis and type 1 diabetes, which are mediated by similar immune cells (T cells) driven by the pro-inflammatory NF-κB-C/EBPβ response
.

"The anti-inflammatory AHR pathway we found can be strengthened to improve disease, and, on the road ahead, we can also investigate other ways to inhibit the pro-inflammatory NF-κB-C/EBPβ response
," Quintana said.
"As we learn more about the environmental factors that can contribute to disease, we can develop state- and national-level strategies to limit exposure
.
" Some chemicals appear to be non-toxic when tested under basic conditions, but we don't yet know the effects
of long-term low-dose exposure or early development for decades.
”