Use of an Orally Delivered Oxysterol, a Lipid Membrane-Order (Lo) Disruptor, to Relieve IBD Symptoms in IL-10 Deficient Mouse Model

Abstract

Abstract Inflammatory bowel disease (IBD) is a life-long condition that currently has no cure. Existing treatments fail in a significant proportion of IBD patients who are either nonresponsive to treatment or lose their initial responsiveness to these therapies over time. Genetic susceptibility of an individual in combination with environmental triggers can contribute to inflammation in the gastrointestinal (GI) tract and disease onset. Increasingly, microbiome composition is considered critical for chronic disease expression; IBD patients show altered microbiome composition as compared to healthy individuals. While IBD is of unknown explicit cause, disease etiology is perpetrated by the heightened response of immune cells (T, Innate Lymphoid, Natural Killer, B) and their secreted mediators interacting with the GI tract’s epithelial cells. Given the complexity of IBD and involvement of multiple cell types in triggering and fueling inflammation, we have tested the effectiveness of 7-Ketocholesterol (7-KC), an oxysterol, to treat IBD symptoms in IL-10 gene-deficient mice. 7-KC is known to disrupt membrane order in cells and inhibit cellular responses. IL-10 knockout mice gavaged with 7-KC show significant reduction in inflammatory gut pathology. Examination of the microbiome composition using metagenomic shotgun sequencing showed restoration of microbiome constitution in treated mice that was comparable to the normal non-disease wildtype mouse. These preliminary findings shed light on the potential for 7-KC in treating IBD symptoms. Mechanism of 7-KC action, either its effects on the microbiota and/or gut immune/non-immune cell membrane for its immune suppressing effect is currently under investigation.