Lay Summary

The “hygiene hypothesis” suggests that the human immune system has adapted to a pathogen-replete environment, which has characterized most of human history, and that lower exposure to environmental pathogens (viruses, bacteria, protozoa, and parasitic worms) in the setting of industrialized countries results in unbalanced immune responses and eventually predisposes the system to inflammatory bowel diseases (IBD) and other autoimmune conditions. It is, therefore, conceivable that a portion of gene variants that predispose the system to autoimmune conditions, including IBD, has been subjected to natural selection by infectious agents. In line with this view, we have recently shown that some genetic risk factors for IBD have been subjected to pathogen-driven selective pressure.

 

In this project, we aim at using genetic variability and epidemiological data for 52 human populations distributed worldwide in order to verify the predictions of the hygiene hypothesis and to study the relative contribution of genetic and environmental risk factors in the development of IBD. Also, we will exploit the selection signatures left by pathogens on human genes to identify novel genetic susceptibility variants for IBD. These data will be integrated so that we will be able to have a picture of how genes involved in the development of IBD interact with one another and converge into common pathways. This is expected to improve our knowledge on the mechanisms underlying the etiology of IBD and holds the promise to develop more effective drugs. Moreover, we consider that testing the basis of the hygiene hypothesis not only addresses a general question about the possibility that cultural and technological changes have outpaced genetic adaptation, but rather harbors important medical and therapeutic/preventive implications. As an example, controlled exposure to worm antigens has been hypothesized to represent a potential prophylactic treatment for IBD. In general, a better understating of the complex interactions between genetic adaptation and environmental change is expected to provide clues as to how life-style modifications have affected the incidence of IBD and whether this trend can be reversed by adopting preventive strategies.