At the Digestive Health Research Institute that she has helped create around her laboratory, Nathalie Vergnolle tracks down proteases, intestinal enzymes whose deregulation is linked to a number of disabling bowel diseases. She has received support from the European Research Council (ERC) for her work.
Your lab is interested in intestinal proteases. How are these enzymes essential to digestive health?
Proteases are normally produced by the pancreas, and are involved in digestion within the gut lumen. But in some bowel diseases, such as irritable bowel syndrome (IBS), Crohn’s disease, ulcerative colitis, and even colorectal cancer, these enzymes seem to be present in much larger numbers. They are also no longer directly active only in the gut lumen, but also in the tissues, and thus contribute to the symptoms associated with these illnesses. Thanks to major funding support received from the European Research Council in 2012 (ERC Starting Grant), we have been able to show that the tissue lining the inside of the intestine (the epithelial tissue) is able to secrete its own proteases, as well as their inhibitors, which play a crucial role in controlling protease activity. We have since described the key role played by some of these at a physiological and pathological level.
You have focused in particular on trypsin-3 in irritable bowel syndrome...
We have in fact observed that trypsin-3 is overexpressed by the intestinal mucosa of individuals affected by IBS. For the first time, we have shown its role in increasing intestinal permeability and its ability to act as a neurotransmitter. As a result, trypsin-3 is involved in activating local inflammation and in the symptoms of pain and bloating associated with this disease. This was an important discovery, as for many years IBS has been presented as a psychosomatic illness. Trypsin-3 shows direct alteration of the colon tissue. However, there is no known natural inhibitor of trypsin-3. We are therefore working on developing a synthetic inhibitor.
Elafin, on the other hand, is a natural molecule that you have shown to be anti-inflammatory. What are the therapeutic horizons for this discovery?
Elafin could be a promising treatment for inflammatory bowel disease. Elafin inhibits the action of elastases, a family of intestinal proteases, but its concentration is particularly low among patients with these diseases. As a result, elastases reduce the protection normally provided by the intestinal mucosa. They increase intestinal permeability and impair the barrier function of the epithelium, which promotes activation of the immune system and inflammation. We are currently developing a new therapeutic approach: the most attractive option is introducing the human elafin gene into a food-grade bacterium so that the protein can be delivered directly to where the bowel lesions are located. The manufacturing process is currently being fine-tuned in partnership with a company: the lactic acid bacteria that we have selected, which is usually present in dairy products, is genetically modified in order to produce elafin. The bacteria are further modified so that their lifespan does not exceed transit time, and so they cannot survive outside the intestine.
How has European funding contributed to the progress of this work?
ERC funding has sped up our rate of discovery by enabling our laboratory to grow from 3 to 9 researchers and clinicians. In this way we have strengthened our skills and broadened our research, moving in particular into the field of cancer. The funding has also springboarded recognition of our work, which has snowballed: other teams have joined us, allowing us to gradually build the Digestive Health Research Institute, which now has over 100 members. We now form an organization with expertise in the intestines and liver, bringing together a multidisciplinary skill-set (in microbiology, physiology, pharmacology, genetics, and neuroimmunology) that is unique in France.