The gut microbiome hosts bacteria that produce compounds as by-products of feeding on our digestive remnants. Some of them can bind to nuclear receptors; and by identifying which microbial by-products can be leveraged to regulate receptors, researchers hope to tap into their potential to treat disease. Researchers at the University of Toronto have found naturally occurring compounds in the gut that can be harnessed to reduce inflammation and other symptoms of digestive issues. This can be achieved by binding the compounds to an important, but poorly understood, nuclear receptor. Researchers conducted an unbiased screen of small molecules across the human gut microbiome; they found that these molecules act similarly to artificial compounds that are currently being used to regulate the constitutive androstane receptor, otherwise known as CAR.
This receptor 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. Previous studies have shown that CAR expression and activity in the large intestine is dependent on the presence of gut flora. Conversely, the absence of CAR leads to a decrease in the richness and composition of microbiota. A recent study also found that immune cells that infiltrate the small intestinal mucosa rely on CAR to increase expression of the drug transporter MDR1, along with other drug metabolizing enzymes, thereby protecting against bile acid toxicity and intestinal inflammation. One of the challenges with studying CAR is that there isn’t a useful compound that binds to both the human and mouse versions of the receptor – the latter being necessary for research investigations.
Prior efforts focused on developing molecules with strong binding and activation capability. This has resulted in synthetic regulators that over-activate the receptor, which can lead to unintended outcomes. The natural compounds discovered don’t cause this issue. Two of the compounds found in the metabolite screen were diindolyl-methane (DIM) and diindolyl-ethane (DIE). While DIM has been previously identified from sampling the human gut, DIE has not. This study is the first time DIE has been detected in the human microbiome. The two compounds regulated CAR in both the human and mouse liver. They were also found to match the effectiveness of an artificial human CAR regulator called CITCO. Indole derivatives, including the diindole DIM, have previously been reported to also act as PXR and aryl hydrocarbon receptor (AhR) ligands.
To test whether the diindoles identified here also bind to PXR or AhR, scientists tested for their potential effects on PXR and AhR reporters in cultured cells. While some of the diindoles were able to activate PXR, the required concentrations (5–15 µM) far exceed the lower physiological range that activates CAR. No AhR responses were observed at the relatively high tested concentration of 10 µM. A promising finding for future research on CAR regulation was that neither compound produced side effects, like liver enlargement, in mice. Mouse treatments with the mouse CAR synthetic agonist TCPOBOP tend to highly activate resulting in robust liver cell proliferation, toxicity and occasional carcinogenesis. This did not happened with DIM and DIE. This means that they can be used to study CAR function and regulation in mice, where the findings can be applied to humans.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Scientific references
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Oh KK, Gupta H et al. Sci Rep. 2023; 13(1):724.