Journal of Gastrointestinal Disorders and Liver Function

Robert Koch received the Nobel Prize in Physiology or Medicine in the year 1905 for his discoveries in relation to tuberculosis, which at that time was one of the most important diseases and was responsible for numerous deaths. For Mycobacterium tuberculosis, Koch was able to show that the bacterium follow his postulates, which means that the pathogen can be found only in diseased animals and not in healthy animals, can be isolated in pure form from the diseased animals, has the potential to cause disease when introduced in healthy animals and can be re-isolated from the diseased animals[2]. Exactly 100 years after Koch’s Nobel Prize, in 2005, Barry Marshall and Robin Warren received the Noble Prize in Physiology or Medicine for the identification and culture of the curved bacilli, Helicobacter pylori, the most important infectious etiologic agent for gastritis, duodenal and gastric ulcer as well as gastric adenocarcinoma[3]. To prove Koch’s postulates Barry Marshall consumed H. pylori and he had massive gastritis, achlorhydria and vomiting before he took antibiotics for the eradication of the introduced H. pylori[4]. Later, when the animal models for H. pylori became available, the contributions of the bacterium and its virulence factors in developing peptic ulcer and gastric cancer have been firmly established[5,6]. Thus, for H. pylori, the second and the third postulates of Robert Koch has been demonstrated. Interestingly, however, it is well known that approximately 50% of the world population carry this bacterium in their stomach and only 10-20% of them develop the above mentioned gastric and duodenal disorders[7]. Why ~80% of the H. pylori infected population does not become sick? In other words, why the very first postulate of Koch, which says that the infectious agent must be present only in diseased animals and not in healthy animals, is not valid for H. pylori? H. pylori infection and clinical outcomes depend on several complicated and not fully understood factors. Prevalence of H. pylori infection and its virulence markers as well as the diseases vary with geography. Some of the virulence genes of H. pylori, like cagA and vacA have been linked with cancer and ulcer for some countries, but not for other countries[8]. Also, H. pylori is naturally competent, extremely efficient in horizontal gene transfer, causes long-term colonization and is believed to be co-evolved with human[9]. Therefore, the host genetic background should play a critical role in determining the disease outcome. Indeed, polymorphisms in several of the genes that encode cytokines like IL-1β and TNFα are connected with H. pylori related diseases[10]. But, is H. pylori the only pathogen that fails to show any direct manifestation of Koch’s first postulate? Many viral infections, like hepatitis B virus or herpes virus, show no clinical manifestations for many individuals and the infections may remain benign for decades. But, let’s take the most dramatic example of Vibrio cholerae, another microbe that was isolated by Robert Koch. Unlike H. pylori, it is fast growing, infections are acute and self-limiting. Moreover, this bacterium secretes an extremely potent toxin, the cholera toxin. Seven pandemics and numerous epidemics have been caused by the serotypes of V. cholerae that produce this toxin. But in the recent past, presence of Vibrio cholerae/mimicus infection has been shown in healthy children in Kolkata, India[11]. These children live in hygienic condition and therefore, infection with V. cholerae is not impossible. But why did they not become sick? Importantly, isolation of V. cholerae from healthy subjects was reported also in the past[2,12]. But quite fascinatingly, many