The Acid Pathogen

Drinking Bacteria to Prove the Cause of Ulcers

Gastric juice in the fasting human stomach maintains a hydrochloric acid concentration around 0.03 molar, yielding a pH between 1.5 and 2.0—a chemical environment roughly ten thousand times more acidic than human blood and corrosive enough to pit stainless steel and denature almost any bacterial cell wall within minutes. For the entire twentieth century, this single chemical boundary condition formed the foundation of clinical gastroenterology: because no living bacterium could colonize a vat of hydrochloric acid, peptic ulcers of the stomach and duodenum could not possibly be an infectious disease.

Medical textbooks and hospital wards worldwide operated instead under the 1910 dictum of German surgeon Karl Schwarz: No acid, no ulcer. Peptic ulcers were classified as a chronic psychosomatic and lifestyle disorder caused by executive stress, smoking, and spicy diets overstimulating the vagus nerve to secrete excess acid. By 1981, this consensus underpinned the most lucrative franchise in the pharmaceutical industry. SmithKline's cimetidine (Tagamet) and Glaxo's ranitidine (Zantac)—$\text{H}_2$-histamine receptor antagonists that temporarily suppressed stomach acid secretion—had become the first billion-dollar blockbuster drugs in history. Because they healed ulcer craters without touching the underlying cause, 80 percent of patients relapsed within a year of stopping the pills, locking millions into lifelong maintenance prescriptions or surgical vagotomies.

In June 1979, on his fifty-second birthday, staff pathologist J. Robin Warren at Royal Perth Hospital in Western Australia examined a gastric biopsy stained with Warthin-Starry silver stain and saw a dense black border of S-shaped spiral bacteria clinging to the gastric epithelial cells beneath the stomach's mucus layer, surrounded by swarms of white blood cells. Clinical colleagues dismissed the organisms as harmless oral bacteria swallowed in saliva. In July 1981, Warren was joined by internal medicine registrar Barry Marshall to study 100 consecutive endoscopy patients and culture the organism. For eight months, thirty-four consecutive cultures failed because lab technicians followed standard throat-swab protocols and threw out agar plates that showed no growth after forty-eight hours.

On Thursday, April 10, 1982, biopsy specimen number 35 was plated just before the four-day Easter weekend. Left undisturbed inside the microaerophilic incubator for five days, the chocolate agar plate emerged on Tuesday, April 14 covered with transparent, one-millimeter colonies of spiral bacteria possessing sheathed flagella. Across their 100-patient trial, Marshall and Warren found the organism—later named Helicobacter pylori—in 100 percent of patients with duodenal ulcers and 80 percent of patients with gastric ulcers.

Biochemical assays revealed how H. pylori survives pH 1.5 long enough to burrow into the neutral pH 7.0 mucin layer coating the stomach wall. The bacterium devotes up to ten percent of its total protein weight to synthesizing a nickel-containing enzyme called urease, which hydrolyzes trace urea in gastric juice into carbon dioxide and alkaline ammonia:

The ammonia molecules immediately capture surrounding hydrogen protons ($\text{H}^+$) to form ammonium ions ($\text{NH}_4^+$), surrounding the bacterium in a microscopic cloud of neutralized acid.

When Marshall submitted these findings to the Gastroenterological Society of Australia in 1983, reviewers rejected his abstract in the bottom ten percent of submissions. Critics argued reverse causation: stress caused ulcers first, and bacteria merely colonized the dead tissue afterward. When laboratory piglets refused to catch the human-adapted strain, preventing fulfillment of Koch's postulates in animals, Marshall ran the test on himself at Fremantle Hospital.

After undergoing a baseline endoscopy by Dr. Ian Hislop confirming a healthy pink gastric lining free of bacteria, Marshall isolated a pure H. pylori strain from a gastritis patient, verified in vitro that it was sensitive to metronidazole and bismuth, and cured the donor patient first. One morning in July 1984, Marshall scraped a three-day culture of H. pylori off an agar petri dish into twenty milliliters of warm alkaline peptone beef broth and drank the cloudy suspension.

On day five, Marshall woke before dawn vomiting a pint of clear, acid-free mucus; acute infection had paralyzed his acid-secreting parietal cells. By day six, colleagues and his wife Adrienne noticed putrid halitosis emanating from his bacteria-filled stomach, accompanied by headaches and epigastric pain. On day eight and day ten, Marshall swallowed the fiber-optic endoscope tube again. His previously smooth pink mucosa was swollen, fiery red, and bleeding on contact, and Robin Warren's blind microscopic examination of the biopsy forceps samples confirmed severe acute gastritis packed with neutrophils and dense colonies of spiral H. pylori. On day fourteen, Marshall eradicated his infection with a two-week course of bismuth subcitrate and metronidazole. Ten years later, in February 1994, an NIH Consensus Development Conference officially declared peptic ulcers an infectious bacterial disease curable with antibiotics, and in October 2005 Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine.