Hygiene hypothesis in infl ammatory bowel disease

Th e word “hygiene” is defi ned as “conditions or practices conducive to maintaining health and preventing disease, especially through cleanliness” [1]. Th e etiology of infl ammatory bowel diseases like ulcerative colitis (UC) and Crohn’s disease is unknown. We will focus on UC. Th e lack of complete penetrance of UC among monozygotic twins and the absence of a family history in the majority of UC cases has always implied that factors in the environment must play an important causative role. Furthermore, the disease has always been more common in the developed than in the developing countries. Th is geographic diff erence in the prevalence of UC has spurred the hypothesis that reduced exposure to childhood infections (enteric antigens) might lead to improper development of the immune system in those residing in developed countries. It is believed that modern living conditions cause defective maturation of regulatory T cells and regulatory antigen-presenting cells. Subsequently, chronic intestinal infl ammation evolves aft er an alleged microbiological insult in genetically susceptible individuals [2]. Various proxy markers of hygiene have been proposed to explain the geographical diff erence of UC incidence. Controlled studies in UC patients over the last twenty years have examined possible associations with such interrelated factors as access to running water, hot water taps, sanitation, overcrowded living conditions, family size, pregnancy and perinatal factors, lack of breast-feeding, sibship birth order, sharing of bedrooms, rural environment, childhood bacterial infections and parasites, household pets, swimming, diet (including fast food), exposure to antibiotics, immunization, medications, dental care, income, education, industrialization, indoor occupation, and so on, with varying results. Nonetheless, the increased presence in Crohn’s disease patients of NOD2/CARD15 that codes for a protein involved in innate immunity responses to bowel bacteria, and the inability to provoke infl ammatory bowel disease in sterile animal models, does strengthen the possibility of the hygiene hypothesis being in operation, also in UC patients. Several detailed reviews of studies of the hygiene hypothesis have been published in recent years [2-4]. Th e studies have recurring limitations. Cross-sectional studies of this subject are inherently retrospective over many years or decades, and are thus subject to a strong recall bias. Furthermore, lack of accessible medical documentation can mask important diff erences between subjects and controls, and this is quite likely in third world countries with limited budgets. Many of the factors studied are interrelated and impossible to separate. Sample size may be a major problem where UC is uncommon or where access to specifi c populations is limited. For example, an impressive Israeli study of a 400,000-strong cohort of army recruits showing that male gender, urban upbringing, and small family size were signifi cantly associated with a higher incidence rate of UC eschewed the inclusion of a large population of orthodox women likely raised in more crowded conditions from the studied population [5]. Th e evidence for a causal link between diet and UC is tenuous since dietary histories from the childhood years are oft en inaccurate [3]. Breastfeeding however protected against UC onset in most studies, possibly through the antibacterial eff ect of lactoferrin on gut Escherichia coli [4]. Birth order hierarchy associated with UC has given confl icting results [5,6]. Early-life exposure to respiratory and gastrointestinal infections had a strong negative association with UC development in a Spanish cohort [7]. However, in a nine-country case study with 197 UC cases where childhood respiratory infections were more common, it was not clear whether the infections preceded the onset of UC [8]. Helicobacter pylori (H. pylori) infection is rife in crowded communities. Th e low seroprevalence of H. pylori of 18% in UC cases compared with 43% in controls was suggestive evidence for a protective role of exposure to childhood infections [9]. Th e fault in this theory is that H. pylori is not a microbe of the intestines and its association with other infections was not determined. Nonetheless, H. pylori DNA was found in tissues from UC patients [10]. A comprehensive retrospective population-based controlled study from Manitoba in Canada compared 217 UC patients with 433 healthy controls but yielded negative results [11]. Th us, it was found that UC patients had a similar birth order to controls, family size was smaller than controls, and a history of having quit smoking did not reach statistical signifi cance. In a diff erent theme, attention has been focused on soilborne helminths that play an immunoregulatory role in the intestinal microbiota in animal models. Of note, helminths were postulated to have a protective role in the development of UC, that disease being more common in societies where helminth infestation has become rare. Indeed, administration of Trichuris suis (pig whipworm) ova has been proposed as a therapy for UC patients [12], but its effi cacy is debatable and much further study is indicated. Taken together, the many works on the hygiene hypothesis in UC give suggestive but aInfectious Diseases Institute, Soroka University Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev (Lisa Saidel-Odes); bInfl ammatory Bowel Diseases Unit, Department of Gastroenterology and Hepatology, Soroka University Medical Center and Ben-Gurion University of the Negev, (Selwyn Odes), Beer Sheva, Israel