Box 3: H. pylori-mediated protection against allergic and chronic inflammatory disorders
Helicobacter pylori is an ancient member of the human microbiota145 that began to disappear from individuals in developed countries in the twentieth century127. This has led to diminishing rates of peptic ulcer disease and gastric cancer146. Coincident with the decline in H. pylori colonization rates, especially during the second half of the last century, the incidence of allergic asthma and other allergic disease manifestations has reached epidemic proportions in large parts of the developed world. Cross-sectional studies have documented that the two phenomena are inversely correlated, with H. pylori carriers having a decreased risk of developing childhood- or early-onset allergic asthma, rhinitis and atopic dermatitis than the non-infected population129, 130, 131, 147. A large meta-analysis documented a similar inverse relationship between H. pylori infection and the risk of developing one of two inflammatory bowel diseases — Crohn's disease and ulcerative colitis84.
A limited amount of experimental evidence from animal studies is now available to support both of these observations (see the figure). In a model of acute Salmonella enterica subsp. enterica serovar Typhimurium-induced intestinal inflammation, experimental co-infection with H. pylori suppresses S. Typhimurium-specific T helper 17 (TH17) responses, as well as cecal S. Typhimurium-induced inflammation, probably by increased production of interleukin-10 (IL-10)148. Similarly, the administration of a single dose of H. pylori DNA reduced sodium dextran sulphate-induced colitis, in both acute and chronic experimental settings83. With respect to asthma, murine infection with H. pylori efficiently prevents allergic airway inflammation that is induced by ovalbumin or house dust mite allergen133. Infected mice are protected against airway hyperresponsiveness (measured after methacholine exposure), as well as tissue inflammation and goblet cell metaplasia, and show reduced pulmonary and bronchoalveolar infiltration of eosinophils, TH2 cells and TH17 cells133. Asthma protection could be attributed to H. pylori-induced, highly suppressive CD4+CD25+ regulatory T (TReg) cells, which accumulate in the lungs of infected mice and block allergen-specific effector T cell responses (see the figure). In line with this observation, the adoptive transfer of mesenteric lymph node (MLN)-derived TReg cells from infected donors is sufficient to protect naive recipients against asthma133. The induction of H. pylori-specific TReg cells with suppressive properties in turn involves tolerogenic dendritic cells (DCs)98, which presumably encounter H. pylori or its tolerizing persistence determinants in the gastric mucosa and subsequently migrate to the stomach-draining MLNs, where they prime effector T cells (particularly TReg cells). Alternatively, soluble antigens can be transported via the lymph to the MLNs for presentation by resident DC populations. MLN-derived, H. pylori-specific TReg cells enter the circulation and accumulate not only in the gastric mucosa, but also at other mucosal surfaces of the body, such as those in the airways and lower bowel. According to current models, pathogenic effector T cell populations (allergen-specific TH17 and TH2 cells and colitogenic TH1 and TH17 cells) are suppressed by H. pylori-specific TReg cells through soluble mediators, such as IL-10, as well as by contact-dependent mechanisms (see the figure).
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, Washington 981091024, USA.
- Nina R. Salama
Institute of Molecular Cancer Research, University of Zürich, Winterthurerstr. 190, 8057 Zürich, Switzerland.
- Mara L. Hartung &
- Anne Müller
Competing interests statement
The authors declare no competing interests.
Nina R. Salama
Nina R. Salama investigates Helicobacter pylori pathogenesis with a focus on bacterial determinants that promote persistent colonization. Current interests include generation and consequences of helical cell morphology, genetic variation during chronic colonization, mechanisms of transmission and H. pylori interactions with other bacteria and tissues in the upper gastrointestinal tract. She received her Ph.D. in 1995 at the University of California, Berkeley, USA, and then moved to the laboratory of Stanley Falkow at Stanford University, California, USA, to pursue postdoctoral researcher on H. pylori genetics. She has been an independent research and Faculty member at the Fred Hutchinson Cancer Research Center and Affiliate Professor of Microbiology at the University of Washington in Seattle Washington, USA, since 2001.
Mara L. Hartung
Mara L. Hartung studied biology at the University of Tübingen, Germany. She is currently pursuing her doctoral studies at the Institute of Molecular Cancer Research, University of Zürich, Switzerland. Her research focuses on investigating the mechanism of DNA damage inflicted on gastric epithelial cells by H. pylori and the implications of this process for gastric carcinogenesis.
Anne Müller studies the pathogenesis of Helicobacter pylori-induced gastric cancer and gastric lymphoma. Additional research interests include H. pylori virulence factors, persistence mechanisms and innate immune recognition. She received her Ph.D. in 2000 at the Max Planck Institute of Infection Biology, Berlin, Germany, and then moved to the laboratory of Stanley Falkow at Stanford University, California, USA, to pursue postdoctoral research on H. pylori–host interactions. She has been an independent researcher and faculty member at the Institute of Molecular Cancer Research, University of Zürich, Switzerland, since 2006.