Currently, peptic ulcers are widely studied as an infectious disease caused by Helicobacter pylori primarily due to 3 supporting evidences, and this etiology may explain the other 3 observations, but cannot confront the challenges of the 15 major characteristics and the other 75 observations/phenomena of peptic ulcers. To address the challenges, a recently published Complex Causal Relationship with its accompanying methodologies was applied to analyze existing data. Peptic ulcers are identified as a psychosomatic disease triggered by psychological stress, where Helicobacter pylori plays a secondary role in only the late phase of ulceration. This new etiology elucidated all the 15 major characteristics and 81 observations/phenomena of peptic ulcers in a series of 6 articles. This sixth article focuses exclusively on the controversies surrounding the role of Helicobacter pylori in peptic ulcers. In-depth analyses find that all the 3 evidences supporting “peptic ulcers are an infectious disease caused by Helicobacter pylori” are deceiving, and 2 of the 3 explainable observations may have been misinterpreted. Meanwhile, the definitions of ‘etiological factor’ and ‘causality’ do not support ‘H. pylori infection is an etiological factor of peptic ulcers’, and existing literatures have presented a controversial view on the role of Helicobacter pylori in peptic ulcers. Interestingly, if “peptic ulcers are an infectious disease caused by Helicobacter pylori” is considered an illusion, all the characteristics of the disease, along with all the clinical, epidemiological, and laboratory observations/phenomena, can be fully understood. This illusion has misguided peptic ulcer research over the past 36 years with little progress in the field, and that may represent a widespread situation in modern medical research, resulting in a direct interference with the true understanding of disease. Evidently, keeping the concept “illusion” in mind may help remove a huge obstacle that impedes medical advance, thereby facilitating the in-depth study of disease.

Background: The seasonal variation of peptic ulcers is a rhythmic phenomenon reported worldwide, exhibiting diverse patterns and controversies. Unfortunately, it has remained an unresolved mystery for more than 90 years. Numerous studies have found that this phenomenon was closely associated with multiple environmental factors, but the underlying mechanism has never been elucidated. Objectives: This study aims to elucidate the seasonal variation of peptic ulcers and identify the role of environmental factors in the disease. Methods: Based on a recently identified etiology of peptic ulcers, two inverse operations in calculus, differentiation and integration, are iterated to analyze the existing data. First, the fluctuation curve in the seasonal variation is differentiated twice into the monthly incidences caused by multiple individual environmental factors, and the fluctuation curve due to each individual environmental factor is generated separately. Second, the monthly incidences caused by the individual environmental factors are integrated twice to reproduce the fluctuation curves in the seasonal variation of peptic ulcers. Results: The differentiations of the fluctuation curves in the season variation reveal a parallel relationship between the psychological impacts of each individual environmental factor and the monthly incidences of peptic ulcers. The integrations of the monthly incidences caused by 3 environmental factors reproduce the fluctuation curves in 3 representative seasonal patterns of peptic ulcers but make the parallel relationships invisible. Discussion: The parallel relationships revealed a causal role of environmental factors in peptic ulcers, whereas the reproduction of the fluctuation curves elucidated that multiple environmental factors cause the seasonal variation of peptic ulcers by Superposition Mechanism. The regional differences in environmental factors result in the diverse patterns, as well as the controversy questioning the seasonality of peptic ulcers. Significantly, the data analyses exemplify the application of a new concept, Superposition Mechanism, which might be an indispensable methodological complement to life science and medicine.

Background: In 1962, Susser and Stein observed that the mortality rates of peptic ulcers in England and Wales increased markedly in the 1910s, maintained at a high level during the 1910s-1940s, and began to decline steadily since the early 1950s. They termed this epidemic pattern a birth-cohort phenomenon, but its mechanism has never been elucidated. Susser and Stein speculated that the occurrences of extraordinary social environmental factors roughly fit the fluctuations, but the role of environmental factors in peptic ulcers has never been identified. Objectives: This study aims to elucidate the mechanism of the birth-cohort phenomenon of peptic ulcers and identify the role of environmental factors in the disease. Methods: Starting from an etiology identified recently, this study uses the two inverse operations in calculus, differentiation, and integration, to analyze the existing data. First, a fluctuation curve in the birth-cohort phenomenon is differentiated into multiple annual mortality rates caused by individual environmental factors. Second, these annual mortality rates are integrated to reproduce the fluctuation curve in the birth-cohort phenomenon. Results: The differentiation reveals a parallel relationship between the psychological impacts of environmental factors and the mortality rates of peptic ulcers, whereas the integration reproduces a representative fluctuation curve in the birth-cohort phenomenon. The successive occurrences of multiple social environmental factors from the 1910s to 1940s maintained the increase in mortality rates, while the sustained improvements in living environments explained the steady decline of the mortality rates from the early 1950s. Conclusion: The parallel relationship suggests a causal role of environmental factors in peptic ulcers, whereas the reproduction of a representative fluctuation curve indicates that multiple environmental factors caused the birth-cohort phenomenon by Superposition Mechanism. Significantly, this study challenges the current reductionist approach used to study disease in modern medicine by demonstrating the effectiveness of an opposite methodological concept focused on integration.

Background: The pathogenesis of duodenal ulcer has never been explained although the first description of this disease in medical literature appeared in 1817. Marshall et al. concluded that Helicobacter pylori was the most important etiological factor for duodenal ulcer in 1988, but the etiology based on this bacterium is controversial and how the bacterial infection leads to ulceration is presently unknown. Objectives: This study aims to identify the cause of duodenal ulcer, address the controversial issues surrounding Helicobacter pylori, elucidate the roles of gastric acid, and describe the pathological process of duodenal ulceration. Methods: First, a comprehensive systematic review on peptic ulcers (including gastric ulcer and duodenal ulcer) was conducted and the results were summarized. Second, a recently published causal relationship was employed to identify the etiology of peptic ulcers. Third, novel concepts and methods were applied to analyze the existing data on duodenal ulcer. Results: The etiology of duodenal ulcer and the roles of Helicobacter pylori and gastric acid in this disease were identified. The controversies surrounding Helicobacter pylori were addressed, and many characteristics and phenomena/observations of duodenal ulcer were elucidated. The pathological process of duodenal ulceration was described. Conclusion: Existing data accumulated over the past 300 years was sufficient, when analyzed using novel concepts, to understand the pathogenesis of duodenal ulcer. Duodenal ulcer is not an infectious disease caused by the infection of Helicobacter pylori, but a psychosomatic disease triggered by psychological stress. Helicobacter pylori plays a secondary role in only the late phase of duodenal ulceration.