H. pylori colonization is associated with strong Th1 and Treg responses. We speculate that historically the Treg response has been sufficient to downregulate the local gastric Th1 response thereby avoiding excessive gastric inflammation and gastroduodenal disease. Tregs are also induced by other microbes and through bystander effects may downregulate the H. pylori–associated Th1 response and disease. A low level of gastric Tregs is associated with an increased risk of peptic ulceration. We speculate that pre-19th–century humans had healthy levels of Tregs and thus that H. pylori–associated diseases (particularly peptic ulceration) were unusual. Either of two hypotheses could causally explain the rise in atopic and allergic disease with the disappearance of H. pylori. In the first hypothesis, loss of other infections common in childhood has led to reduced Tregs and thus to loss of Th2 suppression and increased Th2 diseases. Over the same time frame, the loss of Th1 suppression has led to the rise in H. pylori–associated diseases. In modern life, H. pylori is a marker for other childhood infections and a strong Treg response, explaining the negative association between H. pylori and diseases such as asthma. In the second hypothesis, loss of H. pylori itself has led to reduced Treg populations and a subsequent increase in Th2 responses; this could only be the case if H. pylori–associated Tregs had a systemic effect, which now has been observed. These hypotheses are not mutually exclusive.