Title: Intestinal permeability – a new target for autoimmune diseases prevention and therapy
Funder: Versus Arthritis

Abstract: Autoimmunity occurs when the cells of our own immune-system attack our tissues/organs. Although these diseases tend to be studied as separate entities, it is not uncommon that people with one autoimmune-disorder develop a secondary autoimmune-disease. For instance, people with celiac disease are more susceptible to developing type 1 diabetes, and people with lupus are prone to developing rheumatoid arthritis (RA). This may be partly due to shared genes, however the findings showing that only one of two genetically identical twins may develop autoimmunity challenges this idea. Genetics do not explain the whole story of how autoimmunity is initiated and there must be other environmental-triggers for disease. One factor that might contribute to disease symptoms or progression in multiple autoimmune conditions is gut-health. A healthy-gut provides a strong barrier against the entry of harmful germs whilst allowing through nutrients. In autoimmunity, the gut-barrier is damaged allowing abnormal movement of bacteria and chemical components from the gut to the blood (“leakiness”), enhancing inflammation. The composition of the specialised cells that make up the lining of the gut appears to change too, with some becoming inflamed and dying. These gut changes may be caused by the overgrowth of some types of gut-bacteria. We know that the composition of gut-bacteria in RA, multiple sclerosis, and lupus is different form healthy-individuals. We believe that by treating the gut to keep it intact, or by replacing some of the anti-inflammatory molecules that an healthy-gut makes, we will be able to help control the rest of the autoimmune disease. Previously we’ve found that people with RA have markers of gut-“leakiness” and gut-damage in their blood, and that in a mouse model of RA we can reduce the symptoms of arthritis by treating the mice with a drug that prevents the gut from becoming leaky, AT-1001. We also found that in pre-clinical models there was a loss of the gut-cells that produced an anti-inflammatory molecule called serotonin, and that giving mice serotonin reduced arthritic symptoms. In this grant we’re focussing on proving that gut “leakiness” and a loss of serotonin are both features of two other autoimmune diseases, lupus and multiple sclerosis, and whether preventing the development of “leakiness”, or making up for the loss of the serotonin for the gut, might help treat disease symptoms. We will use blood-tests to determine whether people with RA, MS and lupus have more gut-permeability/damage, and less serotonin, than healthy people. We will test whether levels of these markers correlate with symptoms and treatments. Using established preclinical models for RA, lupus, and MS we will test whether adding AT-1001 or serotonin alone or in a combination to existing treatments for these diseases reduces symptoms across all three diseases. The benefit for patients from this work will be that it will show in principle that addressing gut health may be beneficial for improving symptoms, either by adopting AT-1001 and serotonin into treatment protocols or by providing the groundwork to consider a more holistic approach to gut health in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL