Chronic infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high risk of developing gastric and duodenal ulcers, gastric cancer and gastric lymphoma, but has also recently been shown to protect against certain allergic and chronic inflammatory disorders. The immunomodulatory properties that allow the bacteria to persist for decades in infected individuals in the face of a vigorous innate and adaptive immune response may at the same time confer protection against allergies, asthma and inflammatory bowel diseases. Experimental evidence from mouse models suggests that H. pylori has evolved to skew the adaptive immune response towards immune tolerance rather than immunity, which promotes persistent infection on the one hand, and inhibits auto-aggressive and allergic T-cell responses on the other.
Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal (GI) tract. Two main types of IBDs – Crohn’s disease and ulcerative colitis – are distinguished clinically based on the affected GI region and transmural involvement. IBDs are believed to result from a complex interaction between genetic predisposition and environmental factors such as smoking and the composition of the endogenous microflora, which together lead to the multifactorial hyperactivation of the intestinal immune system. A recent meta-analysis of 30 articles examining a possible inverse epidemiological link between H. pylori infection and IBDs confirmed that the bacteria may indeed confer protection against IBDs. The purpose of the present proposal was to examine the underlying protective mechanism in experimental models and to harness the immunomodulatory properties of H. pylori for the prevention and treatment of IBDs.
The etiology of IBDs is incompletely understood and curative treatment strategies therefore do not exist, but are very much needed. Symptoms are currently treated with various classes of immunomodulatory compounds, but patients progressively get worse and may ultimately require surgery for the alleviation of disease symptoms. Parasitic worms such as the pig worm are in clinical trials for treatment of the worst forms of the disease; no such strategies exist to date to explore and exploit the preventive and/or curative potential of live H. pylori. We have shown in our GRF-funded project that it is possible to exploit the immunomodulatory properties of live H. pylori for the prevention and treatment of IBDs in mouse models.
In the course of the project, we were able to deliver proof-of-concept that H. pylori protects against IBDs in experimental models (Engler et al, Inflammatory Bowel Diseases, 21:854-61, 2015) and that the protective mechanism involves the NLRP3/caspase-1/IL-18 signaling axis.
Both the detrimental and beneficial effects of chronic H. pylori infection can be modeled in laboratory mice. Particularly susceptible mice (and a subset of human carriers) develop severe gastritis, which can progress to preneoplastic gastric lesions such as atrophy, intestinal metaplasia, epithelial hyperplasia and even gastric cancer. On the other hand, mice that have been experimentally infected with Helicobacter in early life are protected from gastric preneoplastic lesions preceding gastric cancer, and also fail to develop allergen-induced asthma. The mechanism conferring asthma protection requires H. pylori-specific, regulatory T-cells (Tregs); in fact, asthma protection can be adoptively transferred to naive recipients via Tregs. Protective Tregs are induced in H. pylori-infected mice through the activity of dendritic cells that have been reprogrammed by the bacteria towards a tolerance-promoting phenotype, facilitating persistent infection. Investigating in detail the mechanism of H. pylori-specific immunomodulation remains a major goal of this project.
Arnold, I., Lee, J.Y., Amieva, M.R., Flavell, R.A., Sparwasser, T. and Müller, A. Tolerance rather than immunity protects from Helicobacter-induced gastric preneoplasia. Gastroenterology 140, 199–209 (2011);
Hitzler, I., Oertli, M., Becher, B., Agger, E.M. and Müller, A. Dendritic cells prevent rather than promote immunity conferred by a novel mycobacterially adjuvanted Helicobacter vaccine. Gastroenterology 141, 186-196 (2011);
Arnold, I.C., Dehzad, N., Reuter, S., Martin, H., Becher, B., Taube, C. and Müller, A. Neonatal infection with Helicobacter pylori prevents asthma through impaired dendritic cell maturation and induction of regulatory T-cells. Journal of Clinical Investigation 121, 3088–3093 (2011) http://www.jci.org/articles/view/45041
Oertli, M., Sundquist, M., Hitzler, I., Engler, D.B., Arnold, I.C., Reuter, S., Maxeiner, J., Hansson, M., Taube, C., Quiding-Järbrink, M. and Müller, A. Dendritic cell-derived interleukin-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. Journal of Clinical Investigation 12, 1082-96 (2012);
Oertli, O., Noben, M., Engler, D.B., Semper, R.P., Reuter, S., Maxeiner, J., Gerhard, M., Taube, C. and Müller, A. Helicobacter pylori -glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci U S A 110, 3047-52 (2013);
Engler, D.B., Reuter, S., van Wijck, Y., Urban, S., Kyburz, A., Maxeiner, J., Martin, H., Yogev, N., Waisman, A., Gerhard, M., Cover, T.L., Taube, C., and Müller, A. Effective treatment of allergic airway inflammation by tolerization with Helicobacter pylori-derived immunomodulators requires BATF3-dependent dendritic cell lineages and IL-10. Proc Natl Acad Sci U S A 111, 11810-5 (2014);
Engler, D.B., Leonardi, I., Hartung, M.L., Kyburz, A., Spath, S., Becher, B., Rogler, G. and Müller, A. Helicobacter pylori-specific protection against inflammatory bowel disease requires the NLRP3 inflammasome and IL-18. Inflammatory Bowel Diseases 21, 854-61 (2015).