Nr1i2, also known as the Pregnane X Receptor (PXR), is a nuclear receptor classified as a xenoreceptor. It regulates the transcription level of major drug-metabolizing enzymes and transporters upon activation by various xenobiotics, including marketed drugs, thus facilitating the elimination of xenobiotics from the body [1]. It is also involved in multiple biological processes, such as influencing the intestinal mesenchyme to restrain inflammation and fibrosis [2].

In a study on inflammatory bowel diseases, Nr1i2-/-mice showed exacerbated fibrosis after DSS-induced colitis, along with greater neutrophil infiltration and innate cytokine production. Deletion of PXR in fibroblasts recapitulated this phenotype, highlighting the role of Nr1i2 in regulating intestinal inflammation and fibrosis [2]. In another study, Nr1i2-/-mice had a "leaky" gut physiology and up-regulation of the Toll-like receptor (TLR) signaling pathway, indicating its role in maintaining gastrointestinal barrier function [3].

In conclusion, Nr1i2 is crucial for drug metabolism and elimination. Model-based research, especially using Nr1i2 knockout mouse models, has revealed its significant role in intestinal inflammation, fibrosis, and gastrointestinal barrier function. These findings contribute to understanding the pathogenesis of related diseases such as inflammatory bowel diseases and potentially offer new therapeutic targets.

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/