Contributions of the early-life microbiome to childhood atopy and asthma development

The rapid rise in atopy and asthma in industrialized nations has led to the identification of early life environmental factors that promote these conditions and spurred research into how such exposures may mediate the trajectory to childhood disease development. Over the past decade, the human microbiome has emerged as a key determinant of human health. This is largely due to the increasing appreciation for the myriad of non-mutually exclusive mechanisms by which microbes tune and train host immunity. Microbiomes, particularly those in early life, are shaped by extrinsic and intrinsic factors, including many of the exposures known to influence allergy and asthma risk. This has led to the over-arching hypothesis that such exposures mediate their effect on childhood atopy and asthma by altering the functions and metabolic productivity of microbiomes that shape immune function during this critical developmental period. The capacity to study microbiomes at the genetic and molecular level in humans from the pre-natal period into childhood with well-defined clinical outcomes, offers an unprecedented opportunity to identify early-life and inter-generational determinants of atopy and asthma outcomes. Moreover, such studies provide an integrative microbiome research framework that can be applied to other chronic inflammatory conditions. This review attempts to capture key studies in the field that offer insights into the developmental origins of childhood atopy and asthma, providing novel insights into microbial mediators of maladaptive immunity and chronic inflammatory disease in childhood.     

Multiple sclerosis,the microbiome,TLR2, and the hygiene hypothesis

The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the “Hygiene Hypothesis,” have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too “clean” lack the requisite exposure to “immune-tolerizing” microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS.Our central hypothesis is that the microbiome in MS represents a “defective environment” that fails to provide normal levels of “TLR2-tolerizing” bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.     

Protection against allergies: Microbes,immunity, and the farming effect

The prevalence of asthma and other allergic diseases has rapidly increased in “Westernized” countries over recent decades. This rapid increase suggests the involvement of environmental factors, behavioral changes or lifestyle, rather than genetic drift. It has become increasingly clear that the microbiome plays a key role in educating the host immune system and, thus, regulation of disease susceptibility. This review will focus on recent advances uncovering immunological and microbial mechanisms that protect against allergies, in particular, within the context of a farming environment. A whole body of epidemiological data disclosed the nature of the protective exposures in a farm. Current evidence points toward an important role of the host microbiome in setting an immunological equilibrium that determines progression toward, or protection against allergic diseases. Conclusive mechanistic insights on how microbial exposures prevent from developing allergic diseases in humans are still lacking but findings from experimental models reveal plausible immunological mechanisms. Gathering further knowledge on these mechanisms and confirming their relevance in humans is of great importance to develop preventive strategies for children at risk of developing allergies.     

Influences of environmental bacteria and their metabolites on allergies,asthma, and host microbiota

The prevalence of allergic diseases and asthma has dramatically increased over the last decades, resulting in a high burden for patients and healthcare systems. Thus, there is an unmet need to develop preventative strategies for these diseases. Epidemiological studies show that reduced exposure to environmental bacteria in early life (eg, birth by cesarean section, being formula‐fed, growing up in an urban environment or with less contact to various persons) is associated with an increased risk to develop allergies and asthma later in life. Conversely, a reduced risk for asthma is consistently found in children growing up on traditional farms, thereby being exposed to a wide spectrum of microbes. However, clinical studies with bacteria to prevent allergic diseases are still rare and to some extent contradicting. A detailed mechanistic understanding of how environmental microbes influence the development of the human microbiome and the immune system is important to enable the development of novel preventative approaches that are based on the early modulation of the host microbiota and immunity. In this mini‐review, we summarize current knowledge and experimental evidence for the potential of bacteria and their metabolites to be used for the prevention of asthma and allergic diseases.     

Microbial,environmental and anthropogenic factors influencing the indoor microbiome of the built environment

A built environment is a human-made environment providing surroundings for human occupancy, activities, and settlement. It is supposed to safeguard humans from all undesirable and harmful pollutants; however, indoor concentrations of some pollutants are much greater than that of the outdoors. Bioaerosols infiltrate from the outdoors in addition to many indoor sources of bioaerosols including the use of various chemicals as well as activities like cooking, smoking, cleaning, or even normal movement. They are also associated with a number of serious health concerns. Various ecological factors associated with the generation, the persistence as well as the dispersal of these microbial components of indoor bioaerosols, are discussed in this review, that have not been considered all together till now. The factors like microbial taxa, environmental factors, and anthropogenic activities (human occupancy, activities, and impact of urbanization) are addressed in the review. Effects of both indoor environmental factors like architectural design, lighting, ventilation, temperature, humidity, indoor/outdoor ratio, particulate matter, indoor chemistry as well as outdoor environmental factors like geography, seasons, and meteorology on the microbial concentrations have been discussed. Efforts are underway to design selective pressures for microbes to create a healthy symbiotic built microbiome as the “right” indoor microbiome is a “healthy” indoor microbiome.     

What can the gut microbiome teach us about the connections between child physical and mental health? A systematic review

A deeper understanding of the gut–brain axis is of significance in pediatrics, given the influential role of early childhood experiences and exposures in shaping the microbiome, and health, across the life course. This systematic review synthesized evidence on the connection between the gut microbiome and mental health in children with physical illness. Six electronic databases were systematically searched and data extracted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Of 1,476 identified articles, 11 articles reporting on nine unique studies (all randomized controlled trials) were included. Most studies examined the gut microbiome in infants with colic, while the remaining studies investigated outcomes in children aged 1 day to 18 years at risk for atopic dermatitis or irritable bowel syndrome. Baseline and postintervention gut microbiome differences varied across studies. Findings on psychological functioning also varied, with only half of the captured studies showing a positive effect of intervention on psychological well-being. Only two studies analyzed the association between the gut microbiome and psychological outcomes, each with a different pattern of results. As the field moves forward, it will be critical to gain a better understanding of the microbiome characteristics that influence mental health outcomes in pediatric populations.     

CD14 polymorphisms,microbial exposure and allergic diseases: a systematic review of gene–environment interactions

Asthma and allergy may develop as a result of interactions between environmental factors and the genetic characteristics of an individual. This review aims to summarize the available evidence for, and potential effects of, an interaction between polymorphisms of the CD14 gene and exposure to microbes on the risk of asthma and allergic diseases. We searched PubMed, MEDLINE and Global Health databases, finding 12 articles which met inclusion criteria. Most studies reported a significant interaction between CD14 polymorphisms and microbial exposure. When stratified by age at microbial exposure (early life vs adult life), there was evidence of a protective effect of gene–environment interaction against atopy in children, but not adults. We also found different effects of interaction depending on the type of microbial exposures. There was no strong evidence for asthma and eczema. Future studies should consider a three‐way interaction between CD14 gene polymorphisms, microbial exposures and the age of exposure.     

Microbiome and its impact on gastrointestinal atopy

The prevalence of allergic conditions has continuously increased in the last few decades in Westernized countries. A dysbiotic gut microbiome may play an important role in the development of allergic diseases. Genetic, environmental, and dietary factors may alter the commensal microbiota leading to inflammatory dysregulation of homeostasis. Murine and human studies have begun to elucidate the role of the microbiota in the pathogenesis of atopic diseases including asthma, atopic dermatitis, and food allergies. However, the role of the microbiome in most eosinophilic gastrointestinal diseases (EGIDs) is not yet known. This review provides an overview of what is currently known about the development of tolerance from both molecular and clinical standpoints. We also look at the gut‐specific microbiome and its role in atopic conditions with the hope of applying this knowledge to the understanding, prevention, and treatment of EGIDs, particularly EoE.     

Transient environmental exposures on the developing immune system: implications for allergy and asthma

PURPOSE OF REVIEW: Early environmental exposures have been extensively studied as potential causes of the observed increase in allergic disease over time. Transient fetal or neonatal exposures in particular are of interest in that they may occur during critical windows of immune system development. Due to the tremendous complexity of variables in early life, as well as the difficulty in randomizing many interventions, it is very difficult to properly study these exposures. Some progress, however, has been made and some more candidates for study may be emerging. Of particular interest are micronutrients, whose ever-changing use and immunomodulatory capabilities make them prime targets for study. RECENT FINDINGS: New risk factors for atopic disease have emerged from the pool of early life interventions, such as caesarian section, prolonged labor and infant multivitamin supplementation. Data are emerging regarding micronutrient status and supplementation and their effects on the developing immune system and risk for allergic disease. Clinical trials have yet to demonstrate much causality but, in some cases, it is too early to make any judgments. SUMMARY: The gold standard of randomized clinical trials has not borne out a number of proposed early-life allergic risk factors, while other trials are too incomplete to draw any conclusions so far. Properly designed studies for other risk factor interventions may still be achievable, provided that there is a proper understanding of the interventions, populations and outcomes.     

Antibiotic Treatment of Pregnant Non‐Obese Diabetic Mice Leads to Altered Gut Microbiota and Intestinal Immunological Changes in the Offspring

The intestinal microbiota is important for tolerance induction through mucosal immunological responses. The composition of the gut microbiota of an infant is affected by environmental factors such as diet, disease and antibiotic treatment. However, already in utero, these environmental factors can affect the immunological development of the foetus and influence the future gut microbiota of the infant. To investigate the effects of antibiotic treatment of pregnant mothers on the offspring's gut microbiome and diabetes development, we treated non‐obese diabetic (NOD) mice with a cocktail of antibiotics during gestation and the composition of the gut microbiota, diabetes incidence and major gut‐related T lymphocyte populations were investigated in the offspring. We observed a persistent reduction in the general diversity of the gut microbiota in the offspring from NOD mothers treated with antibiotics during gestation compared with offspring from control mothers. In addition, by clustering the present bacterial taxa with principal component analysis, we found a differential clustering of gut microbiota in the offspring from NOD mothers treated with antibiotics during gestation compared with offspring from control mothers. Offspring from NOD mothers treated with antibiotics during gestation also showed some immunological alterations in the gut immune system, which could be related to the diversity of the gut microbiome and influence modulation of diabetes development at 20 weeks. Our data point out maternal derangement of the intestinal microbiota as a potential environmental risk factor for T1D development.     

Maternal diet and its influence on the development of allergic disease

The early presentation of childhood allergies and the rise in their prevalence suggest that changes in early‐life exposures may increase the predisposition. Very early‐life exposures may act upon the developing foetal immune system and include infection, environmental tobacco smoke, other pollutants and nutrients provided via the mother. Three nutrients have come under close scrutiny: vitamin D, omega 3 polyunsaturated fatty acids (PUFAs) and folate (or the synthetic form, folic acid). Much of the data on these nutrients are observational although some randomised, placebo‐controlled trials have been conducted with omega 3 PUFAs and one with vitamin D. Some studies with omega 3 PUFA supplements in pregnancy have demonstrated immunomodulatory effects on the neonate and a reduction in risk of early sensitisation to allergens. A few studies with omega 3 polyunsaturated fatty acid supplements in pregnancy have shown a reduction in proportion of children affected by allergic symptoms (food allergy) or in symptom severity (atopic dermatitis). Observational studies investigating the association of maternal vitamin D intake or maternal or neonatal vitamin D status have been inconsistent. One randomised, controlled trial of vitamin D supplementation during pregnancy did not show any significant effect on allergic outcome in the offspring. Studies investigating the association between maternal folic acid or folate intake or maternal or neonatal folate status and offspring risk of allergic disease have been equivocal. Further evidence is required to clarify whether increased intake of these nutrients during pregnancy influences allergic disease in the offspring. In the light of current evidence, mothers should not either increase or avoid consuming these nutrients to prevent or ameliorate allergic disease in their offspring. However, these essential nutrients each have important roles in foetal development. This is reflected in current government recommendations for intake of these nutrients by pregnant women.     

Diet-microbiome-immune interplay in multiple sclerosis: Understanding the impact of phytoestrogen metabolizing gut bacteria

Multiple sclerosis (MS) is a chronic and progressive autoimmune disease of the central nervous system (CNS), with both genetic and environmental factors contributing to the pathobiology of the disease. Although HLA genes have emerged as the strongest genetic factor linked to MS, consensus on the environmental risk factors is lacking. Recently, the gut microbiota has garnered increasing attention as a potential environmental factor in MS, as mounting evidence suggests that individuals with MS exhibit microbial dysbiosis (changes in the gut microbiome). Thus, there has been a strong emphasis on understanding the role of the gut microbiome in the pathobiology of MS, specifically, factors regulating the gut microbiota and the mechanism(s) through which gut microbes may contribute to MS. Among all factors, diet has emerged to have the strongest influence on the composition and function of gut microbiota. As MS patients lack gut bacteria capable of metabolizing dietary phytoestrogen, we will specifically discuss the role of a phytoestrogen diet and phytoestrogen metabolizing gut bacteria in the pathobiology of MS. A better understanding of these mechanisms will help to harness the enormous potential of the gut microbiota as potential therapeutics to treat MS and other autoimmune diseases.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Farm lifestyles and the hygiene hypothesis

About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact may confer protection from the development of allergic illnesses. The so‐called ‘hygiene hypothesis’ has since undergone numerous modifications in the field of epidemiology, clinical science and immunology. Three main areas of research have been brought forward: to explore the role of overt viral and bacterial infections for the inception of allergic diseases; to investigate the significance of environmental exposure to microbial compounds on the development of allergies; and to study the effect of both exposures on underlying innate and adaptive immune responses. A concept unifying these various aspects has not been found, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure and the interactions between an exposed subject's genetic background and the environmental exposures becomes apparent. A natural experiment relating to the hygiene hypothesis is the recurrent observation of a protective effect of growing up on a farm for asthma and allergies. This has been shown in a large number of epidemiological studies across the world among children and adults. The timing and duration of exposure are likely to play a critical role. The largest reduction in risk has been demonstrated for those exposed prenatally and continuously thereafter until adulthood. The protective factors in these farming environments have not been unravelled completely. Findings from various studies suggest that the contact with farm animals, at least in childhood, confers protection. Also the consumption of unprocessed cow's milk directly from the farm has been shown to protect from childhood asthma and allergies. Increased levels of microbial substances may, at least in part, contribute to the ‘farm effect’. However, only few studies have measured microbial exposures in these environments and the results obtained so far suggest that the underlying protective microbial exposure(s) have not been identified, but a number of studies using metagenomic approaches are currently under way. The mechanisms by which such environmental exposures confer protection from respiratory allergies are also not well understood. There is good evidence for the involvement of innate immune responses, but translation into protective mechanisms for asthma and allergies is lacking. Furthermore, a number of gene × environment interactions have been observed.     

Effects of intestinal microflora and the environment on the development of asthma and allergy

The aim of previous research into the causes of allergic diseases, including asthma was mostly to identify potential risk factors in the environment. No major risk factors have been identified, however. Over the past 10 years, focus has, therefore, more been directed towards protective factors that could enhance the development of tolerance to allergens which were previously encountered early in life, but are now lost in modern affluent societies. In particular, the role of childhood infections has been discussed, but so far these studies have not been conclusive. Recent epidemiological studies and experimental research suggest that the microbial environment and exposure to microbial products in infancy modifies immune responses and enhances the development of tolerance to ubiquitous allergens. The intestinal microflora may play a particular role in this respect, as it is the major external driving force in the maturation of the immune system after birth, and animal experiments have shown it to be a prerequisite for normal development of oral tolerance. Recent studies have shown differences in the composition of the microflora between healthy and allergic infants in countries with a high and low prevalence of allergies and between healthy and allergic infants within such countries. These differences are apparent within the first week of life and thus precede clinical symptoms. The use of live microorganisms that might be beneficial to health has a long tradition and the safety is well documented. Very recently, several prospective intervention studies, modifying the gut flora from birth have yielded encouraging results and may suggest a new mode of primary prevention of allergy in the future.     

Teratogenic IgG From Sera of Women With Spontaneous Abortions Seem to Induce Anomalies and Yolk Sac Damage in Rat Embryos. A Possible Method to Detect Abortions of Immunologic Origin

PROBLEM: Spontaneous abortions due to immunological rejection of the embryo may be avoided by immunotherapy with paternal allogeneic leukocytes but there is no appropriate method to detect and differentiate this group of aborters from other groups. METHODS: In previous studies we have demonstrated that in about two-thirds of sera from women with spontaneous abortions the IgG antibodies are responsible (alone or in combination with other factors) for the embryotoxic effects of these sera on cultured rat embryos. We presently cultured 10.5-day-old rat embryos on highly teratogenic serum (“high risk” serum that induced anomalies in more than 50% of the embryos) from women with spontaneous abortions, where the IgG fraction was exchanged with IgG from control sera and vice-versa. We studied by Transmission Electron Microscopy (TEM) the extent of yolk sac damage in comparison to the rate of embryonic anomalies. RESULTS: In cases where IgG antibodies were teratogenic, embryos cultured in control sera with IgG from “high risk” sera exhibited ultrastructural yolk sac damage as well as embryonic anomalies, and the yolk sacs cultured in “high risk” sera with control IgG were normal. In cases in which the IgG exchange did not change the rate of anomalies, as IgG was not teratogenic, yolk sacs from embryos cultured in “high risk” sera remained damaged, while yolk sacs from embryos cultured in control sera after IgG exchange stayed normal. Although no significant difference in total IgG levels was found between the groups, a higher IgG1 level in sera from women with teratogenic IgG was observed in comparison to control women's sera. The obstetrical history of the women with two or more abortions who took part in our study showed that there were more cases of unknown etiology of the abortion in the women from the “high risk” group. CONCLUSIONS: The serum and the IgG fraction from women with habitual abortions can be tested in whole embryo culture to evaluate the embryonic and yolk sac damage. On this basis it may be possible to detect the women in whom the habitual abortions result from immunological rejection.     

Immune recognition and response to the intestinal microbiome in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell-mediated destruction of the insulin-secreting pancreatic beta cells. During the past 50 years T1D incidence has increased dramatically in many countries accompanied by an earlier age of onset especially in persons with lower genetic risk. These observations have prompted investigations of dynamic environmental factors that may contributor to risk for anti-pancreatic immunity. The gut and pancreas are anatomically and biochemically linked through the enteroinsular axis, a system in which gut-derived immune and metabolic signals have the potential to evoke effects in the pancreas. The gut microbiome (i.e. the 100 trillion symbiotic microorganisms which inhabit the mammalian gastrointestinal tract) influences numerous aspects of host metabolism, development and immunity. Here we examine recent evidence linking gut microbiome composition and function to pancreatic autoimmunity. Studies in children with genetic risk factors for T1D and analyses of the microbiome in rodent models have begun to associations between an altered microbiome composition potentially favoring a pro-inflammatory intestinal metabolic milieu and T1D. We discuss how environmental factors during critical developmental windows – gestation, birth, weaning and puberty may contribute to T1D risk. For example mode of delivery (vaginal or C-section) and exposure to antibiotics (pre- or post-natally) are two factors that modulate the maternal and/or offspring microbiome and can impact T1D development. Taken together, these emerging data underscore the requirement for longitudinal studies and mechanistic investigations in human subjects and rodent models to identify the basis for microbiome modulation of T1D and to identify biomarkers and therapeutics to improve the delayed onset and prevention of the disease.     

Microbiome-based interventions to modulate gut ecology and the immune system

The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.     

Early life precursors, epigenetics, and the development of food allergy

Food allergy (FA), a major clinical and public health concern worldwide, is caused by a complex interplay of environmental exposures, genetic variants, gene-environment interactions, and epigenetic alterations. This review summarizes recent advances surrounding these key factors, with a particular focus on the potential role of epigenetics in the development of FA. Epidemiologic studies have reported a number of nongenetic factors that may influence the risk of FA, such as timing of food introduction and feeding pattern, diet/nutrition, exposure to environmental tobacco smoking, prematurity and low birth weight, microbial exposure, and race/ethnicity. Current studies on the genetics of FA are mainly conducted using candidate gene approaches, which have linked more than 10 genes to the genetic susceptibility of FA. Studies on gene-environment interactions of FA are very limited. Epigenetic alteration has been proposed as one of the mechanisms to mediate the influence of early life environmental exposures and gene-environment interactions on the development of diseases later in life. The role of epigenetics in the regulation of the immune system and the epigenetic effects of some FA-associated environmental exposures are discussed in this review. There is a particular lack of large-scale prospective birth cohort studies that simultaneously assess the interrelationships of early life exposures, genetic susceptibility, epigenomic alterations, and the development of FA. The identification of these key factors and their independent and joint contributions to FA will allow us to gain important insight into the biological mechanisms by which environmental exposures and genetic susceptibility affect the risk of FA and will provide essential information to develop more effective new paradigms in the diagnosis, prevention, and management of FA.     

Infectome: A platform to trace infectious triggers of autoimmunity

The “exposome” is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the “infectome”, which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regard to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the “immunome” and “microbiome” projects.     

Childhood asthma and early life exposure to indoor allergens,endotoxin and β(1,3)‐glucans

Background Divergent results have been reported regarding early life exposure to indoor environmental agents and the risk of asthma and allergic sensitization later in life. Objective To assess whether early exposure to indoor allergens, β(1,3)‐glucans and endotoxin modifies the risk of allergic diseases at 10 years of age. Methods The concentrations of mite, cat and dog allergens, endotoxin and β(1,3)‐glucans were determined in dust from the homes of 260 two‐year‐old children with lung function measured at birth (tidal flow volume loops) in the Environment and Childhood Asthma study in Oslo. At 10 years, the health status was assessed in a follow‐up study including a structured interview of the parents and an extended clinical examination. Results Cat and dog keeping at 2 years of age was reported in 6.5% and 5.5% of the families, respectively. Mite allergens were detected in only 4/260 dust samples. The adjusted odds ratio for asthma at age 10 was 1.20 (95% confidence interval: 1.01–1.43) and 1.22 (1.02–1.46) for bronchial hyperresponsiveness (BHR) per 10 μg/g dust increase in cat allergen exposure at 2 years of age. No association was seen with allergic sensitization. Moreover, endotoxin and β(1,3)‐glucan exposure did not modify the risk of asthma or allergic sensitization. None of the measured environmental factors were associated with lung function at 10 years of age or a relative change in lung function from birth. Conclusion In a community with a low prevalence of pet keeping and low mite allergen levels, exposure to cat allergens early in life increased the risk of late childhood asthma and BHR, but not the risk of allergic sensitization. No risk modification was seen for dog allergens, endotoxin and β(1,3)‐glucans. Cite this as: R. J. Bertelsen, K. C. Lødrup CarlsenK.‐H. Carlsen, B. Granum, G. Doekes, G. Håland, P. Mowinckel and M. Løvik, Clinical & Experimental Allergy, 2010 (40) 307– 316.