Researchers at the University of Toronto have discovered natural compounds in the gut that can be used to reduce inflammation and other symptoms of digestive problems. This can be achieved by binding the compounds to an important, but poorly understood, nuclear receptor.
The gut microbiome is home to bacteria that produce compounds as by-products of eating our digestive waste. The compounds can bind to nuclear receptors, which aid in the transcription of DNA to produce proteins and non-coding RNA segments.
By identifying which microbial byproducts can be used to modulate the receptors, researchers hope to harness their potential to treat disease.
We performed an unbiased small molecule screening of the entire human gut microbiome. We found that these molecules act similarly to the artificial compounds currently used to modulate the constitutive androstane receptor, otherwise known as CAR. This makes them viable candidates for drug development.”
Jiabao Liu, first author on the study and research associate at U of T’s Donnelly Center for Cellular and Biomolecular Research
The study was recently published in journal Nature Communications.
CAR plays a critical role in regulating the breakdown, uptake, and removal of foreign substances in the liver, including drugs. It is also involved in intestinal inflammation.
“One of the challenges with studying CAR is that there isn’t a useful compound that binds to the human and mouse versions of the receptor – the latter is essential for research and disease modeling before testing in humans,” Henry said. Krause. principal investigator on the study and professor of molecular genetics at the Donnelly Center and Temerty School of Medicine. “Previous efforts have focused on developing molecules with strong binding and activation capacity. This has resulted in synthetic modulators that overactivate the receptor, which can lead to unwanted effects. The natural compounds we discovered do not cause this problem.”
Two of the compounds found in the metabolite screening were diindolylmethane (DIM) and diindolylethane (DIE). While DIM has previously been identified from human gut sampling, DIE has not. This study is the first time DIE has been detected in the human microbiome.
The two compounds upregulated CAR in both human and mouse livers. They were also found to match the effectiveness of an artificial human CAR modulator called CITCO.
A promising finding for future research on CAR regulation was that neither substance caused side effects, such as swelling of the liver, in mice. This means that DIM and DIE can be used to study CAR function and regulation in mice, where the findings can be applied to humans.
“This receptor plays a role in diabetes, fatty liver disease and ulcerative colitis of the small intestine,” Liu said. “We could potentially address all of these issues with the two natural compounds that we found are already present in the human gut.”
This research was supported by the Agence Nationale de la Recherche, the American Cancer Society, the Canadian Institutes of Health Research, the National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, and the New Frontiers in Research Fund.
Source:
Journal Reference:
Liu, J., et al. (2024). Diindoles produced by metabolites of common microflora function as endogenous CAR/Nr1i3 ligands. Nature communications. doi.org/10.1038/s41467-024-46559-3.
