Overexpression of the Cd14 gene offers protection against IBD in mice, suggesting a new therapeutic approach

Inflammatory bowel disease (IBD), characterized by chronic recurrent inflammation of the intestine, is a common problem in the industrialized world. However, how IBD develops remains unknown. There is currently no cure, and treatment options are expensive and limited to symptom relief. A new study in The American Journal of Pathology reveals that the Cd14 gene is a protective factor in experimental inflammatory bowel disease by improving gut barrier function.

It is well known that patient genetics as well as microbial factors contribute to IBD. The researchers identified Cd14 in a genetic screen in a mouse model system for IBD. They showed that the Cd14 molecule played a protective role in their model system of intestinal functioning in mice. Cd14-deficient mice developed more severe gut inflammation with gut barrier destabilization compared to controls, while stimulation of Cd14 expression enhanced barrier integrity.

“Our understanding of the microbiome and its interaction with host genetic factors is increasing dramatically, particularly in the pathogenesis of IBD. Cd14 is implicated 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,” explained lead researcher André Bleich, PhD, Professor and Director, Institute of Laboratory Animal Sciences, Hannover Medical School, Hannover (Germany).

As part of the innate immune system, Cd14 helps the body respond to bacterial infections by producing a protein that binds to lipopolysaccharides in the outer membranes of certain bacteria. The protein can be found attached to cell surfaces or secreted in a soluble form. The Cd14 protein is found among different cell types, including epithelial, blood, and dendritic cells. In mice, Cd14 levels may depend on mouse strain and tissue location, with the highest concentration found in the furthest parts of the gut, which contain the greatest number of bacteria.

Researchers examined the effects of Cd14 deficiency on bowel function and studied an acute and chronic model of colitis. In the acute model, Cd14-deficient mice showed greater weight reduction and gut barrier disruption than controls, including more severe intestinal lesions and ulcerations. They also secreted higher amounts of inflammatory cytokines. “Cd14 appears to play a central role in maintaining barrier integrity. Further analyzes suggest that the presence of Cd14 becomes even more important when the epithelial layer is disrupted rather than under steady-state conditions,” said commented Dr. Bleich.

On the other hand, the stimulation of the expression of Cd14 played a protective role on the intestine. After administration of zinc, which increases Cd14 levels in a transgenic mouse model, researchers found less inflammation in the colon and reduced levels of pro-inflammatory cytokines.

According to Dr. Bleich and his co-investigators, “Epithelial barrier function is primarily dependent on tight junction proteins, which regulate transport within and between cells. The loss of gut barrier integrity, initiated by bacteria or by treatment with a chemical, can lead to bacterial invasion and inflammation.Pro-inflammatory cytokines also cause dysregulation of barrier permeability during inflammation.Our work provides evidence that Cd14 is essential for regulating proteins of tight junctions by reducing the expression of the pro-inflammatory cytokine. Our results suggest that soluble Cd14 could be an interesting new therapeutic target for future clinical research.”

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