Hygiene hypothesis in inflammatory bowel disease: A criticalreview of the literature

The hygiene hypothesis is thought to be a significant contributor to the growing incidence of inflammatory bowel disease (IBD) around the world, although the evidence for specific factors that underlie the hygiene hypothesis in IBD is unclear. We aimed to systematically review the literature to determine which hygiene-related factors are associated with the development of IBD. Publications identified from a broad based MEDLINE and Current Contents search between 1966 and 2007 on key terms relevant to the 'hygiene hypothesis' and IBD including H pylori exposure, helminths, cold chain hypothesis, measles infection and vaccination, antibiotic use, breastfeeding, family size, sibship, urban upbringing, day care attendance and domestic hygiene were reviewed. The literature suggests that the hygiene hypothesis and its association with decreased microbial exposure in childhood probably plays an important role in the development of IBD, although the strength of the supporting data for each of the factors varies considerably. The most promising factors that may potentially be associated with development of IBD include H pylori exposure, helminths, breastfeeding and sibship. However, the vast majority of studies in this area are plagued by serious methodological shortcomings, particularly the reliance on retrospective recall of information making it difficult to truly ascertain the importance of a 'hygiene hypothesis' in IBD. The 'hygiene hypothesis' in IBD is an important area of research that may give clues to the aetiology of this disease. Directions for future research are recommended.

Role of dendritic cells:a step forward for the hygiene hypothesis

The hygiene hypothesis was proposed more than two decades ago,but its mechanism remains unclear.This review focuses on recent advances in the field,especially on the role played by dendritic cells(DCs)and their modulating effects on various infections and allergic diseases,including allergic asthma.DCs isolated from mice long after the resolution of an infection were reported to have a significant modulating effect on allergen-specific Th2 responses in both in vitro and in vivo systems.These DCs showed DC1-like and/or tolerogenic DC capacity,which allowed for the inhibition of allergic responses by immune deviation(enhancing Th1 response)and immune regulation(through regulatory T-cell and Th2 hyporesponsiveness)mechanisms.These findings represented a significant advance in the elucidation of the mechanisms underlying the hygiene hypothesis.Further investigation on the mechanisms by which DCs are‘educated’by infectious agents and the influence of the type,time,and extent of infections on this‘education’process will help us understand immune regulation in disease settings and in the rational design of preventive/therapeutic approaches to allergy/asthma and infections.

What caused the increase of autoimmune and allergic diseases:A decreased or an increased exposure to luminal microbial components?

The dramatic increase of allergic and autoimmune diseases such as asthma, atopic dermatitis （eczema）, allergic rhinitis, inflammatory bowel disease （IBD, including both Crohn＇s disease and ulcerative colitis）, multiple sclerosis, and insulin-dependent diabetes mellitus （type Ⅰ diabetes） in the developed countries in the last century is a big puzle. ＂Hygiene Hypothesis＂ was proposed more than two decades ago and it suggested that the increase in these allergic and autoimmune diseases is caused by the aberrant development and response of the immune system due to a reduced exposure to microorganisms along with the improved hygiene. Interestingly, recent studies revealed that these allergic and autoimmune diseases are closely related to the microbes in the gut. For instance, even asthma, an allergic reaction of the lung to inhaled antigens, is closely related to a reduced exposure to foodborne and orofaecal microbes, rather than the amount of allergens in the air or the exposure to airborne microbes. It is known that bacteria in the gut could be 10 times in number of the eukaryotic cells of the body. Therefore, it would be not too surprising that microbes in the gut may have a great impact on these autoimmune and allergic diseases.

Helicobacter pylori infection and atopic diseases:Is there a relationship? A systematic review and meta-analysis

AIM: To review and conduct a meta-analysis of the existing literature on the relationship between Helicobacter pylori (H. pylori), atopy and allergic diseases.

Epidemiological studies of migration and environmental risk factors in the inflammatory bowel diseases

Inflammatory bowel diseases(IBD)are idiopathic chronic diseases of the gastrointestinal tract well known to be associated with both genetic and environmental risk factors.Permissive genotypes may manifest into clinical phenotypes under certain environmental influences and these may be best studied from migratory studies.Exploring differences between first and second generation migrants may further highlight the contribution of environmental factors towards the development of IBD.There are few opportunities that have been offered so far.We aim to review the available migration studies on IBD,evaluate the known environmental factors associated with IBD,and explore modern migration patterns to identify new opportunities and candidate migrant groups in IBD migration research.

Crohn's disease environmental factors in the developing world: A case-control study in a statewide catchment area in Brazil

To identify environmental risk factors associated with the development of Crohn’s disease (CD) in order to re-assess the hygiene hypothesis. METHODSA hospital-based, case-control study was carried out with CD patients (n = 145) and controls (n = 163) representing a socioeconomically diverse statewide catchment area in Brazil. Controls were recruited from caregivers of patients seen in different outpatient clinics at the same hospital. A multi-item survey with 94 questions regarding family history of CD, perinatal and childhood circumstances, living conditions, tobacco use and familial socioeconomic status was carried out by interviewers. RESULTSOn the univariate analysis, predictive variables for CD included being male, under age of 40, a high education level, urban dweller, smaller family size, exposure to enteric pathogens and user of treated water (P < 0.005). On the multivariate analysis, variables significantly associated with CD were male gender (OR = 2.09), under age 40 (OR = 3.10), white (OR = 2.32), from a small family in childhood (OR = 2.34) and adulthood (OR = 3.02), absence of viral infections in childhood (OR = 2.23), exposure to enteric pathogens (OR = 2.41), having had an appendectomy (OR = 2.47) and prior or current smoker (OR = 2.83/1.12). CONCLUSIONMost variables supporting the “hygiene hypothesis” are associated with the development of CD but are not independent predictors of the diagnosis.

Risk factors associated with inflammatory bowel disease: A multicenter case-control study in Brazil

BACKGROUND The etiology of inflammatory bowel disease(IBD)is unknown,but it is believed to be multifactorial.The hygiene hypothesis proposes that better hygiene conditions would lead to less infectious disease during childhood and favor the development of immune-mediated diseases.AIM To test the hygiene hypothesis in IBD by assessing the environmental risk factors associated with IBD development in different regions of Brazil with diverse socioeconomic development indices.METHODS A multicenter case-control study was carried out with 548 Crohn’s disease(CD)and 492 ulcerative colitis(UC)outpatients and 416 healthy controls,from six IBD centers within different Brazilian states at diverse socioeconomic development stages.A semi-structured questionnaire with 87 socioeconomic and environmental questions was applied.Logistic regression model was created to assess the odds ratio(OR)with P value and 95%confidence intervals(CI).RESULTS Predictive variables for both diseases(CD and UC)were women[odd ratios(OR)=1.31;OR=1.69],low monthly family income(OR=1.78;OR=1.57),lower number of cohabitants(OR=1.70;OR=1.60),absence of vaccination(OR=3.11;OR=2.51),previous history of bowel infections(OR=1.78;OR=1.49),and family history of IBD(OR=5.26;OR=3.33).Associated risk factors for CD were age(18-39 years)(OR=1.73),higher educational level(OR=2.22),absence of infectious childhood diseases(OR=1.99).The UC predictive variables were living in an urban area(OR=1.62),inadequate living conditions(OR=1.48)and former smokers(OR=3.36).Appendectomy was a risk factor for CD(OR=1.58)with inverse association with UC(OR=4.79).Consumption of treated and untreated water was associated with risk of CD(OR=1.38)and UC(OR=1.53),respectively.CONCLUSION This is the first examining environmental exposures as risk factors for inflammatory bowel disease in Brazil.Most of the variables associated with disease risk support the role of the hygiene hypothesis in IBD development.

Is sibship composition a risk factor for childhood asthma? Systematic review and meta‑analysis

Background Following the“hygiene hypothesis”,the role of sibship composition in asthma and wheezing has been extensively studied,but the fndings are inconsistent.For the frst time,this systematic review and meta-analysis synthesized evidences from studies investigating the association of sibship size and birth order with risk of asthma and wheezing.Methods Fifteen databases were searched to identify eligible studies.Study selection and data extraction were performed independently by pairs of reviewers.Meta-analysis with robust variance estimation(RVE)was used to produce pooled risk ratio(RR)efect estimates from comparable numerical data.Results From 17,466 identifed records,158 reports of 134 studies(>3 million subjects)were included.Any wheezing in the last≤1.5 years occurred more frequently in infants with≥1 sibling[pooled RR 1.10,95%confdence interval(CI)1.02–1.19]and≥1 older sibling(pooled RR 1.16,95%CI 1.04–1.29).The pooled efect sizes for asthma were overall statistically nonsignifcant,although having≥1 older sibling was marginally protective for subjects aged≥6 years(pooled RR 0.93,95%CI 0.88–0.99).The efect estimates weakened in studies published after 2000 compared with earlier studies.Conclusions Being second-born or later and having at least one sibling is associated with a slightly increased risk of temporary wheezing in infancy.In contrast,being second-born or later is associated with marginal protection against asthma.These associations appear to have weakened since the turn of the millennium,possibly due to lifestyle changes and socioeconomic development.

Alzheimer's disease and gut microbiota

Alzheimer＇s disease （AD） is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut rnicrobiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the ＂hygiene hypothesis＂. All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.

The role of gut microbiota(commensal bacteria)and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer:contribution of germ-free and gnotobiotic animal models of human diseases

Metagenomic approaches are currently being used to decipher the genome of the microbiota(microbiome),and,in parallel,functional studies are being performed to analyze the effects of the microbiota on the host.Gnotobiological methods are an indispensable tool for studying the consequences of bacterial colonization.Animals used as models of human diseases can be maintained in sterile conditions(isolators used for germ-free rearing)and specifically colonized with defined microbes(including non-cultivable commensal bacteria).The effects of the germ-free state or the effects of colonization on disease initiation and maintenance can be observed in these models.Using this approach we demonstrated direct involvement of components of the microbiota in chronic intestinal inflammation and development of colonic neoplasia(i.e.,using models of human inflammatory bowel disease and colorectal carcinoma).In contrast,a protective effect of microbiota colonization was demonstrated for the development of autoimmune diabetes in non-obese diabetic(NOD)mice.Interestingly,the development of atherosclerosis in germ-free apolipoprotein E(ApoE)-deficient mice fed by a standard low-cholesterol diet is accelerated compared with conventionally reared animals.Mucosal induction of tolerance to allergen Bet v1 was not influenced by the presence or absence of microbiota.Identification of components of the microbiota and elucidation of the molecular mechanisms of their action in inducing pathological changes or exerting beneficial,disease-protective activities could aid in our ability to influence the composition of the microbiota and to find bacterial strains and components(e.g.,probiotics and prebiotics)whose administration may aid in disease prevention and treatment.

Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference?

Virus infections have been implicated in both initiation of and protection from autoimmune diseases,such as type 1 diabetes(T1D).In this review we intend to reflect on recent evidence how viruses might on the one hand be involved in the pathogenesis of T1D and on the other hand induce a state of protection from autoimmune-mediated damage.It is important to acknowledge that human individuals encounter more than just one virus infection in their lifetime.Therefore,it is important to integrate more than just one possible environmental triggering factor for autoimmune diseases to occur.

New insights into the effects of Mycobacterium bovis Bacillus Calmette-Guérin on asthma

Allergic asthma has been defined as a disease of immunodysregulation, where the pathology is a direct consequence of excessive T-helper type 2 immune responses （Th2） to allergens in the lungs. Disease is associated with increased secretion of type-2 cytokines such as interleukin （IL）-4, IL-5 and IL-13 which, among other things,