Timeline of peptic ulcer disease and Helicobacter pylori

Before the 1950s, there were many microbiological descriptions of bacteria in the stomach and in gastric acid secretions, lending credence to both the infective theory and the hyperacidity theory as being causes of peptic ulcer disease. A single study, conducted in 1954, did not find evidence of bacteria on biopsies of the stomach stained traditionally; this effectively established the acid theory as dogma. This paradigm was altered when Warren and Marshall effectively proved Koch's postulates for causation of PUD by H. pylori through a series of experiments in the 1980s; however, an extensive effort was required to convince the medical community of the relevance of their work. Now, all major gastrointestinal societies agree that H. pylori is the primary nondrug cause of PUD worldwide, and advocate its eradication as essential to treatment of gastric and duodenal ulcers. Additionally, H. pylori has been associated with lymphomas and adenocarcinomas of the stomach, and has been classified by the World Health Organization as a carcinogen. Advances in molecular biology in the late 20th century led to the sequencing of the H. pylori genome, resulting in a better understanding of virulence factors responsible for its colonization and infection, on the DNA level. ==Pre-20th century==

;Pre 16th century :Hippocrates first describes gastric symptoms. :Avicenna notes the relationship between gastric pain and mealtimes. ;1688 :Johannes von Murault observes duodenal ulcers. ;1799 :Matthew Baillie publishes a description of ulcers. ;1889 :Walery Jaworski describes spiral organisms in sediment washings of humans. He suggests these organisms might be involved with gastric disease. ==1900–1950==

;1905 :F. Reigel suggests that ulcers are caused by excess acid. ;1907 :Berkley Moynihan suggests that acid is a cause of ulcers. ;1915 :Antacids are first recommended for the treatment of PUD. ;1919 :Katsuya Kasai and Rokuzo Kobayashi isolate spirochetes in cats and transmit them to rabbits, producing ulcers. ;1921 :Luger discovers spirochetes in the gastric juice, and associates their presence with gastric cancer. ;1925 :Hoffman injects a small sample from a human with PUD into a guinea pig, producing ulcers, and isolates a bacterium which he believes caused the ulcers. ;1936 :First edition of the Russian Large Medical Encyclopedia suggests infection is one of the causes of PUD. ;1939 :A. Stone Freedberg begins a study to look for bacteria in the human stomach at Beth Israel Hospital. He finds H. pylori. It is rumored that others cannot reproduce the results, although no negative results are published. :James Doenges describes spirochetes in autopsies. ;1940 :Freedberg and Baron observe spirochetes in autopsies. Freedberg abandons his research, however, after his boss advises him to move to another subject. In 2005, Marshall speculates that Freedberg would have won the Nobel Prize in 1951 had he continued his work. ;1948 :Fitzgerald and Murphy hypothesize that PUD is caused by acid eating away mucosa, and demonstrate the effectiveness of urea as a treatment for PUD. ==1950–1970==

;1951 :J. Allende publishes a book describing the treatment of gastric ulcers with penicillin. ;1954 :Palmer publishes a study which finds no bacteria in the human stomach. He concludes earlier discoveries were a result of contamination. He chooses not to use a silver staining method, which will be later used to reveal H. pylori by Warren and Marshall. ;1955 :Tarnopolskaya observes that penicillin seems to cure some peptic ulcers. ;1957 :Charles Lieber and Andre Lefèvre discover that antibiotics reduce gastric urea to ammonia conversion. ;1958 :Gordon observes that penicillin cures some peptic ulcers. :Lieber and Lefèvre present their results at the World Congress of Gastroenterology in Washington. It is not well received because of the widespread belief that bacteria cannot survive in the human stomach, due to Palmer. ;1959 :Lieber and Lefèvre publish a follow-up study demonstrating that antibiotics prevent the conversion of urea to ammonia in the human stomach. :Conway et al. call into question the extent of urease produced by bacteria in mice, as an argument against the bacterial theory of PUD. ;1960 :Vital and Orrego observe Campylobacter-like organisms in the stomachs of cats and dogs. :Lykoudis is awarded a Greek patent (#22,453) for his antibiotic treatment of PUD. ;1964 :Lykoudis presents his antibiotic treatment for PUD at a meeting of the Medico-Surgical Society in Greece. He is largely shunned by the medical establishment. ;1968 :Lykoudis is fined 4,000 drachmas for treating PUD patients with his treatment, which includes antibiotics. ==1970–21st century==

;1971 :Howard Steer observes H. pylori from biopsies of a patient with ulcers. ;1972 :The first report of successfully using furazolidone (an antibacterial agent) to treat PUD in China. ;1974 :Morozov observes H. pylori; he does not connect this discovery to PUD. ;1975 :Steer and Colin-Jones publish their results regarding H. pylori and its relation to PUD. They decide that it was Pseudomonas, a contaminant, and not related to PUD. ;1978 :At a meeting of the American Gastroenterology Association in Las Vegas, several papers are presented which suggest that acid control via H2 blockers is ineffective at curing PUD. ;1979 :Ramsey publishes a study demonstrating that bismuth can help eradicate PUD. Bismuth is an antibacterial agent, although this is not recognized by Ramsey. :J. Robin Warren first observes H. pylori in a gastric biopsy. :Fung, Papadimitriou, and Matz observe H. pylori. ;1981 :Yao Shi observes bacteria in the stomach, but he believes they are passing through the stomach and not colonizing it. :October: Marshall and Warren successfully treat their first PUD patient with antibiotics. :Marshall and Warren begin their first study to determine the relationship between H. pylori and PUD. :September: H. pylori is observed in patients outside of Australia. :June 12: Marshall intentionally consumes H. pylori and becomes ill. He takes antibiotics and is relieved of his symptoms. He states in 2002, "I’ve never seen the medical community more defensive or more critical of a story" since he joined the newspaper in 1969. :Thomas Borody developed the bismuth-based "Triple Therapy" consisting of bismuth and two antibiotics. This became the first truly successful treatment for H. pylori with an eradication rate greater than 90%. ;1985 :Marshall publishes the results of self-induced infection. on Helicobacter pylori. :Morris intentionally consumes H. pylori. Like Marshall, he becomes ill, but unlike Marshall, he is not completely cured by antibiotics. The infection will remain with him for three years. :An extensive study in Dublin demonstrates that eradicating H. pylori substantially reduces recurrence of ulcers. ;1990 :Borody's triple therapy became commercialized in the United States under the product name Helidac. :Rauws and Tytgat describe cure of duodenal ulcer by eradication of H. pylori using Borody's triple therapy combination. Triple-therapy, modernized to a proton pump inhibitor and two antibiotics, soon becomes first line therapy for eradication. :World Congress of Gastroenterology recommends eradicating H. pylori to cure duodenal ulcers. Resistance of H. pylori to treatment will lead to the development of many different antibiotic and proton pump inhibitor regimens for eradication. ;1992 :Fukuda et al. prove ingestion of H. pylori causes gastritis in rhesus monkeys. ;1994 :Fujioka et al. prove similar results as those from Fukuda et al. :Parsonnet et al. describe an association between H. pylori and lymphomas of the gastrointestinal tract. These malignant ulcers can also be treated by eradicating Helicobacter. ;1997 :Tomb et al. complete sequencing of the entire 1,667,867 base pairs of the H. pylori genome. This assists in identifying new virulence factors for the infectivity of H. pylori on the molecular level. ;2001 :Chan et al. show in a randomized control trial that eradication of H. pylori even prevents bleeding from ulcers that is caused by aspirin and non-steroidal anti-inflammatory drugs. ;2002 :The European Helicobacter Pylori Study Group published the Maastricht 2-2000 Consensus Report, suggesting a "test-and-treat" strategy for H. pylori in young patients without atypical symptoms. This strategy advocates the use of noninvasive testing to evaluate for H. pylori and simply treating if found, even in the absence of ulcer disease documented on endoscopy. == References ==