Nr1i2, also known as the gene encoding the Pregnane X Receptor (PXR), is a nuclear receptor classified as a xenoreceptor. Upon activation by xenobiotics like drugs, it regulates the transcription of major drug-metabolizing enzymes and transporters, facilitating xenobiotic elimination from the body [1]. It is also involved in modulating intestinal inflammation and fibrosis, and maintaining gastrointestinal barrier function [2,3].

In the context of disease, Nr1i2 -/- mice showed exacerbated fibrosis after DSS-induced colitis, with greater neutrophil infiltration and innate cytokine production compared to wild-type mice. This indicates Nr1i2's role in regulating intestinal inflammation and fibrosis [2]. In addition, Nr1i2 -/- mice had a "leaky" gut physiology with upregulated Toll-like receptor (TLR) signaling pathway, suggesting its importance in maintaining gastrointestinal barrier function [3].

In conclusion, Nr1i2 is essential for drug metabolism, regulating intestinal inflammation, fibrosis, and gastrointestinal barrier function. Findings from Nr1i2 knockout mouse models have provided insights into its role in inflammatory bowel diseases and maintaining gut integrity, which could potentially contribute to the understanding and treatment of related diseases.

References:

1. Mbatchi, Litaty Céphanoée, Brouillet, Jean-Paul, Evrard, Alexandre. 2017. Genetic variations of the xenoreceptors NR1I2 and NR1I3 and their effect on drug disposition and response variability. In Pharmacogenomics, 19, 61-77. doi:10.2217/pgs-2017-0121. https://pubmed.ncbi.nlm.nih.gov/29199543/

2. Flannigan, Kyle L, Nieves, Kristoff M, Szczepanski, Holly E, Mani, Sridhar, Hirota, Simon A. 2022. The Pregnane X Receptor and Indole-3-Propionic Acid Shape the Intestinal Mesenchyme to Restrain Inflammation and Fibrosis. In Cellular and molecular gastroenterology and hepatology, 15, 765-795. doi:10.1016/j.jcmgh.2022.10.014. https://pubmed.ncbi.nlm.nih.gov/36309199/

3. Venkatesh, Madhukumar, Mukherjee, Subhajit, Wang, Hongwei, Khanna, Kamal M, Mani, Sridhar. 2014. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. In Immunity, 41, 296-310. doi:10.1016/j.immuni.2014.06.014. https://pubmed.ncbi.nlm.nih.gov/25065623/