Causality and gastrointestinal infections: Koch, Hill, and Crohn's

The gastrointestinal tract contains a complex mix of microorganisms. Therefore, the finding of a particular microbe in the gastrointestinal tract or stools of a patient with intestinal disease does not necessarily indicate that the clinical state resulted from the presence of this organism. For this reason, extending from epidemiological association to causality is particularly challenging for gastrointestinal diseases. Most established agents of acute bacterial gastroenteritis (eg, Escherichia coli, Campylobacter jejuni) have been shown to fulfil Koch's postulates of causality in human volunteer studies. For Helicobacter pylori, which can cause both acute and chronic disease, the organism was first linked to an acute syndrome through volunteer studies and then later assessed for a role in chronic disease by use of Hill's epidemiological criteria of causation. However, for agents of chronic intestinal disease, this approach is not ethical and risks overlooking events occurring long after the exposure. We examine the criteria used to judge causality (Koch's postulates and Hill's criteria) and their applicability for chronic gastrointestinal diseases (eg, Whipple's disease and Crohn's disease). We also identify crucial research questions required to advance towards assessing the causal role of candidate microbes in the aetiopathogenesis of Crohn's disease.