Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, affects millions of people globally, with around 1.6 million Americans currently living with some form of IBD. Despite widespread attention and huge advances into the underlying cause and possible treatments of IBD, there are still very few treatment options available to the average patient.
However, researchers from San Francisco believe they have found a potential solution in the most unlikely of places – within the compounds of cholera toxin. By utilizing the impressive ability of the toxin to attack intestinal cells, the researchers have been able to target an important anti-inflammatory molecule at the intestines without causing toxicity throughout the rest of the body in mouse models. Their findings were published in the Journal Of Immunology.
One avenue of research that has appeared promising is the use of an anti-inflammatory signal molecule (known as cytokines) that seems to be less present in people who have the inflammatory condition. Called Interleukin-10 (IL-10), this cytokine usually stops the body from damaging itself by suppressing the inflammatory response during infection, preventing the immune system from going out of control. However, in patients with Crohn’s disease and ulcerative colitis, there seems to be a lack of IL-10 in the majority of cases, and scientists can simulate the disease in mice by stopping the activity of IL-10, suggesting it plays an important role in the onset of these diseases.
Therefore, if a therapy could supplement IL-10 in IBD patients, the symptoms might be alleviated. This theory was tested and showed promise in animal and even human trials, albeit to a lesser extent, but was deemed not viable – the compound spread throughout the body, resulting in anemia and lower platelet counts. If it is to be a safe treatment option, the IL-10 must instead be guided to the intestinal cells where it is most needed.
This is where cholera toxin could help. Whilst it seems counter-intuitive, toxins are a rapidly growing field of medical research due to their impressive ability to enter human cells and bind to receptors within. The bacteria that causes cholera, Vibrio cholerae, secretes a toxin that invades the inside walls of the intestine and rapidly draws water out of the surrounding cells into the gut, which is why patients with the deadly disease suffer extreme diarrhea and dehydration. However, by taking a component of the toxin that helps invade the intestinal cells and using it to assist the uptake of IL-10, the toxin could aid in the treatment of IBD.
In this pursuit, the researchers used genetic engineering to fuse a component of cholix, the cholera toxin, with IL-10 to create a new therapy called AMT-101. Due to the drug being packaged with the toxin, the AMT-101 could be administered orally and still target the intestinal cells.
In cell lines, the new therapy gained entry into the intestinal cells and activated receptors associated with IL-10, but did not show the systemic problems of previous IL-10 therapies. The results suggest that the cholix domain aided in cell uptake of the associated IL-10.
When administered to mouse models, AMT-101 successfully prevented the adverse effects of the induced colitis, suggesting the treatment is promising at reducing inflammation and the resulting symptoms from IBD.
As with all preliminary studies, the results must be taken with caution. It is an experimental therapy that must now be tested in a wide array of situations before both safety and efficacy can be understood, and inflammatory bowel disease models in mice may not relate well to human conditions. The relationship of IL-10 to IBD also remains controversial, with some stating it is not a viable treatment option.
The researchers explain that IL-10 treatments could be tested for how successful they are at reducing symptoms without being limited by potential toxic effects, which is a significant step forward for the treatment of IBD.