Helicobacter pylori-specific protection against inflammatory bowel disease requires the NLRP3 inflammasome and IL-18.
BACKGROUND
The Gram-negative bacterium Helicobacter pylori is a constituent of the human gastric microbiota. Chronic infection with H. pylori causes gastritis and predisposes to gastric carcinoma but has also been inversely linked to various allergic and chronic inflammatory conditions. In particular, large meta-analyses have documented an inverse association between H. pylori infection and the risk of developing ulcerative colitis and Crohn's disease.


METHODS
We investigated possible protective effects of experimental H. pylori infection and of regular treatment with H. pylori extract in 2 mouse models of colitis and in mouse models of type I diabetes and multiple sclerosis. The mechanism of protection was examined in mouse strains lacking specific innate immune recognition pathways and cytokines.


RESULTS
We show here that experimental infection with H. pylori and administration of regular doses of H. pylori extract both alleviate the clinical and histopathological features of dextran sodium sulfate-induced chronic colitis and of T-cell transfer-induced colitis. High resolution endoscopy of the protected animals revealed the accumulation of large amounts of colonic mucus upon H. pylori exposure, which could be attributed to transcriptional activation of the mucin 2 gene. The protection against dextran sodium sulfate-induced colitis was dependent on the NLRP3 inflammasome and interleukin-18 signaling. Other autoimmune diseases, i.e., experimental autoimmune encephalomyelitis and type I diabetes, were not controlled by H. pylori.


CONCLUSIONS
In summary, we propose here that the immunomodulatory activity of an ancient constituent of the gut microbiota, H. pylori, may be exploited for the prevention and/or treatment of inflammatory bowel diseases.
*Institutes of Molecular Cancer Research, University of Zürich, Zürich, Switzerland; ‡Experimental Immunology, University of Zürich, Zürich, Switzerland; and †Division of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland.
Daniela B
DB
Engler
Irina
I
Leonardi
Mara L
ML
Hartung
Andreas
A
Kyburz
Sabine
S
Spath
Burkhard
B
Becher
Gerhard
G
Rogler
Anne
A
Müller
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000382:microbiology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000382:microbiology / Q000517:prevention & control; D016481:Helicobacter Infections / Q000139:chemically induced / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D015533:Transcriptional Activation; D015854:Up-Regulation
D002352:Carrier Proteins; D020382:Interleukin-18; C524626:Muc2 protein, mouse; D055262:Mucin-2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016264:Dextran Sulfate