Leena von Hertzen

Environmental biodiversity, human microbiota, and allergy are interrelated

Rapidly declining biodiversity may be a contributing factor to another global megatrend—the rapidly increasing prevalence of allergies and other chronic inflammatory diseases among urban populations worldwide. According to the “biodiversity hypothesis,” reduced contact of people with natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity. Analyzing atopic sensitization (i.e., allergic disposition) in a random sample of adolescents living in a heterogeneous region of 100 × 150 km, we show that environmental biodiversity in the surroundings of the study subjects’ homes influenced the composition of the bacterial classes on their skin. Compared with healthy individuals, atopic individuals had lower environmental biodiversity in the surroundings of their homes and significantly lower generic diversity of gammaproteobacteria on their skin. The functional role of the Gram-negative gammaproteobacteria is supported by in vitro measurements of expression of IL-10, a key anti-inflammatory cytokine in immunologic tolerance, in peripheral blood mononuclear cells. In healthy, but not in atopic, individuals, IL-10 expression was positively correlated with the abundance of the gammaproteobacterial genus Acinetobacter on the skin. These results raise fundamental questions about the consequences of biodiversity loss for both allergic conditions and public health in general.

The biodiversity hypothesis and allergic disease: world allergy organization position statement

Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro-levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live.

Trends in prevalence of asthma and allergy in Finnish young men: nationwide study, 1966-2003.

Recent reports on time trends in atopic disease suggest that the prevalence of asthma and allergic rhinitis has levelled off in some European countries after several decades of increasing.1 2 We reported earlier that the prevalence of asthma in young Finnish men remained stable from 1926 to 1961 but started to rise steeply during the 1960s; a sixfold, virtually linear increase in asthma prevalence was found between 1966 and 1989, in parallel with increases in indicators of disabling asthma (on the basis of the percentage of men exempted from military service at call-up owing to asthma and of men discharged during service as a result of asthma).3 We examined whether similar trends have continued during the subsequent 13 years (1990-2003). As data on current trends in prevalence of allergic conditions are scarce, we also examined the trends in prevalence of allergic rhinitis and eczema from 1966 to 2003 among these young men. In Finland, about 98% of all men aged 18-19 are examined to establish their fitness for …

Predominance of Gram-positive bacteria in house dust in the low-allergy risk Russian Karelia

Simple living conditions and farming environment have been associated with reduced risk for allergic diseases such as atopy and asthma but the factors responsible for this effect remain unresolved. We examined the bacterial composition of house dusts obtained from Finnish and Russian Karelia, two adjacent areas with high and low occurrence of atopic diseases respectively. Two dust mixes, both composed of 10 randomly selected dust samples from 349 Finnish and 417 Russian Karelian households were studied for bacterial biomarkers (DNA, Limulus-active endotoxin, 3-OH fatty acids, muramic acid) and for 16S rRNA gene sequences. Overall, the DNA cloning revealed more taxons (94 different genera) of dustborne bacteria than seen in any previous study on residential environments. Majority (67%) of the bacterial DNA clones in house dust from the low-allergy Russian Kareliarepresented Gram-positive bacteria (Firmicutes and Actinobacteria), predominantly Staphylococcaceae and Corynebacteriaceae. Russian Karelian dust showed up to 20-fold higher contents of muramic acid (marker of Gram-positive bacteria) and a sevenfold higher number of clones of animal-associated species, whereas in Finnish Karelian dust Gram-negatives (mainly Proteobacteria) predominated. Clones of plant-associated bacterial species and of chloroplast, indicating plant biomass, were more numerous in Finnish than in Russian Karelian dust. In conclusion, this study revealed major disparities between Finnish and Russian house dusts. The higher bacterial content and the predominance of Gram-positive bacteria in Russian dust may have implications for occurrence of atopy.

Mycobacterium tuberculosis infection and the subsequent development of asthma and allergic conditions

BACKGROUND Epidemiologic studies have suggested that certain viral infections, as well as exposure to Mycobacterium tuberculosis in early life, could, at least to some extent, prevent the subsequent development of atopic disease. OBJECTIVE We investigated whether M tuberculosis infection in childhood or adolescence has any effect on the development of asthma and allergic conditions in later life. METHODS The study subjects (n = 1162) were individuals notified to the National Tuberculosis Registry between January 1, 1966, and December 31, 1969, who were 20 years of age or younger and had verified or justifiably probable new active tuberculosis of respiratory or other organs. The control subjects were age-matched, sex-matched, and geographically matched control pairs from the Population Registry of the Social Insurance Institution in Finland. The subjects were followed for 28 to 32 years. The prevalence of persistent asthma and allergic conditions among men and women at the end of 1997 were calculated on the basis of the Drug Reimbursement Registry of the Social Insurance Institution in the whole study population and in the subgroup of subjects aged 16 years or younger at the time of M tuberculosis infection. RESULTS In women a significantly lower prevalence of persistent asthma was found among those aged 16 years or younger at the time of M tuberculosis infection than among the control subjects (3.7% vs 8.3%, respectively; P =.035). The women with a history of tuberculosis also showed a significantly lower prevalence of allergic conditions than the control subjects (8.3% vs 14.0%, respectively; P =.003) when the whole study population of women was considered. In men, however, the only significant difference between the cases and control subjects was found for persistent asthma, with the cases showing a significantly higher prevalence than the control subjects (4.4% and 1.8%, respectively; P =.008). CONCLUSION M tuberculosis infection in childhood significantly reduced the occurrence of subsequent asthma in women. Moreover, this infection was also found to reduce the occurrence of allergic conditions in later life in women. By contrast, no suppressive effect of M tuberculosis infection in childhood or adolescence on the later development of asthma or allergic conditions could be observed in men. The differences in the natural history of atopic disease between the sexes and the occurrence of tuberculosis mostly in later childhood and adolescence may largely explain our findings.

Natural immunity: Biodiversity loss and inflammatory diseases are two global megatrends that might be related

We are witnessing two global and deeply worrying trends that, at first glance, seem unrelated. The first trend is the ongoing decline in biodiversity, which is caused by human actions. It could well become the sixth mass extinction of animal and plant species on Earth, comparable in magnitude with the fifth mass extinction at the end of the Cretaceous, 65 million years ago. The second trend is a rapid increase in chronic diseases that are associated with inflammation, especially in developed countries (Fig 1). Inflammation is a key attribute in asthma and allergic diseases, autoimmune diseases and many cancers; even depression has been associated with the presence of inflammatory markers. In this article, we argue that these two phenomena are more closely related than commonly thought: declining biodiversity might actually increase the risk to humanity from chronic diseases and thereby cause a major public health problem. > We thereby extend the hygiene and microbial deprivation hypotheses to a biodiversity hypothesis, with inevitable consequences for public health Figure 1. Two global megatrends in biodiversity and public health. ( A ) Declining biodiversity since 1970 as measured by three indices. LPI, Living Planet Index; WBI, World Bird Index; WPSI, Waterbird Population Status Index (Butchart et al , 2010). ( B ) Increasing trends in the prevalence of inflammatory diseases. Asthma and allergic rhinitis among military conscripts from 1966 to 2003 (Latvala et al , 2005) are shown as an example. The underappreciated link between biodiversity and human health are microbes, which inhabit all ecosystems, including the human body. Although microbial life on Earth as such is not threatened—unlike many plant and animal species—the diversity and abundance of microorganisms in affluent urban environments has clearly declined (Alenius et al , 2008), which raises intriguing questions. What are the effects of the loss of biodiversity of plants, animals and their habitats on the environmental …

Puzzling associations between childhood infections and the later occurrence of asthma and atopy

The current unfavourable trends in asthma and atopy prevalences have raised great concern and have challenged investigators to accelerate search for new risk factors for atopic diseases. The lack or scarcity of intense, systemic infections in early life has been postulated to increase susceptibility of becoming sensitized to otherwise harmless allergens in later life. This hygiene hypothesis is considered one of the most plausible explanations for the current trends in atopic diseases to date. There are data to suggest that measles, hepatitis A, and Mycobacterium tuberculosis infection in early life may prevent the subsequent development of atopic diseases. The hypothesis is based on the concept that certain viral and bacterial infections, which induce a strongly polarized T helper (Th)-1 type response and a long-lasting memory immunity, are in early life able to reverse or prevent the biased Th1/Th2 balance in individuals prone to atopy and asthma. Evidence for the ability of mycobacterial infections to alter the Th1/Th2 balance has also been obtained from murine models. In humans, the critical time period during which immunomodulation with long-lasting effects is considered most successful is within the first two years of life. Possibly also nonpathogenic residents of the intestinal mucosa are involved in the proper maturation of the immune system. The use of antibiotics has been shown to be positively associated with the development of asthma and atopy. The mechanisms underlying these associations remain largely unknown.The current unfavourable trends in asthma and atopy prevalences have raised great concern and have challenged investigators to accelerate search for new risk factors for atopic diseases. The lack or scarcity of intense, systemic infections in early life has been postulated to increase susceptibility of becoming sensitized to otherwise harmless allergens in later life. This hygiene hypothesis is considered one of the most plausible explanations for the current trends in atopic diseases to date. There are data to suggest that measles, hepatitis A, and Mycobacterium tuberculosis infection in early life may prevent the subsequent development of atopic diseases. The hypothesis is based on the concept that certain viral and bacterial infections, which induce a strongly polarized T helper (Th)-1 type response and a long-lasting memory immunity, are in early life able to reverse or prevent the biased Th1/Th2 balance in individuals prone to atopy and asthma. Evidence for the ability of mycobacterial infections to alter the Th1/Th2 balance has also been obtained from murine models. In humans, the critical time period during which immunomodulation with long-lasting effects is considered most successful is within the first two years of life. Possibly also nonpathogenic residents of the intestinal mucosa are involved in the proper maturation of the immune system. The use of antibiotics has been shown to be positively associated with the development of asthma and atopy. The mechanisms underlying these associations remain largely unknown.

Infectious burden as a determinant of atopy-- a comparison between adults in Finnish and Russian Karelia.

Background: Evidence of the influence of pathogen exposure on the development of atopy and atopic disease is not unequivocal. We investigated the association between markers of infections and occurrence of atopy among adults in eastern Finland and western Russia, two adjacent areas with profound differences in living conditions and lifestyles. Methods: Randomly selected adults aged 25–54 years from Finland (n = 790) and from Russia (n = 387) participated in the study. Skin prick tests were performed to 11 common airborne allergens, and at least one positive prick reaction was considered to indicate atopy. Antibodies to different pathogens including hepatitis A virus (HAV), Helicobacter pylori, Toxoplasma gondii, herpes simplex virus (HSV), Chlamydia pneumoniae and the periodontal pathogens Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were measured. Results: In Finland 34.3% and in Russia 23.3% of the study population was atopic (p < 0.001). Seroprevalences to all these pathogens were significantly higher among the Russians. In multivariate logistic regression analysis, only H. pylori was inversely associated with atopy in Russia. A further stepwise analysis revealed that H. pylori alone can explain 32% of the difference in atopy between the countries, and T. gondii, A. actinomycetemcomitans, HSV and C. pneumoniae had a slightly additive effect, whereas, unexpectedly, seropositivity to HAV and, to a lesser extent, P. gingivalis had an opposite effect. The net result of the stepwise analysis showed that 44% of the difference in atopy between the countries could be explained by seropositivity to these seven pathogens. Conclusions: Seropositivity to select pathogens, particularly to H. pylori, could explain a substantial part of the difference in atopy prevalence between Finland and Russia. Exposure to HAV was not associated with protection against atopy in this adult population.

Chlamydia pneumoniae and its role in chronic obstructive pulmonary disease

The diverging of T-helper (Th) cells into predominantly Thl and Th2 subsets on the basis of their cytokine profiles has decisively improved our understanding of the pathogenesis of many chronic infectious diseases. Recent data suggest that the presence of interferon-γ and the subsequent suppression of interleukin-4 production leads to a Thl-type reponse that is required for the resolution of infections caused by intracellular pathogens. The ability of the macrophages to respond aggressively during early antigen contact seems to be one crucial factor in the development of an appropriate Th-cell response. Several host-related factors can affect macrophage function and the polarization of T-cell responses, ie the shift from a Thl response to a Th2 one, and thus dramatically deteriorate the resolution of infections caused by intracellular agents such as Chlamydia pneumoniae. Chronic C. pneumoniae infection has been associated with several common chronic diseases, quite recently with chronic obstructive pulmon...

Helsinki alert of biodiversity and health

Abstract Urban living in built environments, combined with the use of processed water and food, may not provide the microbial stimulation necessary for a balanced development of immune function. Many chronic inflammatory disorders, including allergic, autoimmune, metabolic, and even some behavioural disorders, are linked to alteration in the human commensal microbiota. Sedentary lifestyle is associated with reduced exposure to a broad spectrum of environmental micro-organisms and surplus energy balance, both risk factors of chronic inflammatory disorders. According to the Biodiversity Hypothesis, an environment with diverse macrobiota and microbiota modifies and enriches the human microbiota, which in turn is crucial in the development and maintenance of appropriate immune function. These issues were discussed in the symposium ‘Chronic Inflammation, Lifestyle and Environment’, held in Helsinki, 20–22 August 2014, under the sponsorship of the Yrjö Jahnsson Foundation. This paper briefly outlines the recent findings in the context of the environment, lifestyle, and health; discusses the forces that undermine immune tolerance in urban environments; and highlights the possibilities to restore broken immune tolerance among urban dwellers, summarizing the main messages in four statements and calling for actions to combat major public health threats.