Protective Role of Gene Overexpression in Inflammatory Bowel Disease

The Cd14 gene may play a protective role in the development of inflammatory bowel disease (IBD) by enhancing intestinal barrier function, a study published in the American Journal of Pathology suggests.

Although it remains unclear exactly how IBD develops, it is well known that genetics and microbial factors contribute to IBD.

For the study, investigators examined the effects of Cd14 deficiency on intestinal function in acute and chronic mouse models of colitis.

They investigated Intestinal permeability by fluorescein isothiocyanate-dextran uptake assay, quantitative RT-PCR analysis of tight junction proteins, myosin light chain kinase, and proinflammatory cytokine expression.

In the acute model, the Cd14-deficient mice showed a greater reduction in weight and intestinal barrier disruption compared with a control group. This included ulcerations and more severe intestinal lesions. Additionally, the investigators observed the secretion of higher amounts of inflammatory cytokines.

“Cd14 seems to play a pivotal role in the maintenance of barrier integrity,” said lead investigator André Bleich, PhD. “Further analyses suggested that the presence of Cd14 becomes even more important when the epithelial layer is distributed rather than during steady-state conditions.”

Contrastingly, stimulation of cd14 expression played a protective role on the intestine, according to the study. After the mouse models were administered zinc to increase Cd14 levels, the investigators found reduced levels of proinflammatory cytokines and less inflammation in the colon.

“Epithelial barrier function is predominantly dependent on tight junction proteins, which regulate transport into and between cells,” Dr Bleich said. “Loss of gut barrier integrity, initiated by bacteria or by treatment with a chemical, can result in bacterial invasion and inflammation. Proinflammatory cytokines also cause dysregulation of barrier permeability during inflammation. Our work provides evidence that Cd14 is pivotal for regulating tight junction proteins by reducing the expression of proinflammatory cytokine. Our findings suggest that soluble Cd14 could be an interesting new therapeutic target for future clinical research.”

Cd14 produces a protein that binds to lipopolysaccharides within the outer membranes of some bacteria to help the body respond to bacterial infections. In mice, Cd14 levels can depend on the strain of mice and the location of the tissue. The highest concentrations of Cd14 can be found in the furthest areas of the intestine, which contains the highest number of bacteria.

“Our understanding of the microbiome and its interaction with host genetic factors is increasing dramatically, especially in the pathogenesis of IBD,” Dr Bleich said. “Cd14 is involved in the detection of bacterial factors and has been identified as a candidate gene in genetic screens. Our study helps to understand the link between genetic susceptibility and microbial alterations in the gut in IBD.”