Microbes and man: an evolving story in asthma

The notion that microbes can influence the development of atopy and the course of asthma is not new. In 1932, Cooke proposed a role for bacteria in initiating and sustaining asthma, and this subject remains an area of intense debate today [1]. Bacteria may impact allergic disease through an array of immune pathways that are as divergent as bacteria themselves. In considering the mode of exposure, these can be broadly classified as occurring through (1) environmental bacteria; (2) non-pathogenic microbes that constitute the human microflora; and (3) pathogenic bacteria that infect the host. If we first consider how environmental exposure may impact allergic disease, perhaps the most frequently cited example is the report of decreased atopy among children exposed to high levels of endotoxin living in rural farming areas in Europe [2]. The implication was that an environment rich in microbes, was protective. Based on subsequent studies of animal models of asthma, the assumption has been that inhalation of environmental pathogen-associated molecular patterns such as lipopolysaccharide, activate dendritic cells to prime Th1 responses. This process could, in theory, inhibit the generation or persistence of Th2 responses directed against allergens in early life. In contrast to this scenario, the microorganisms that live inside and on humans (known as the microbiota) constitute a distinct source of bacteria that could also influence allergic disease. Considerable attention has been focused on how microbial colonization of the gut in the neonatal period relates to allergic status [3]. While the gastrointestinal tract of the newborn baby is sterile, it is rapidly colonized by microorganisms within the first week of life. Commensal microbes present in the gut may play a key role in priming the immune system in early life by ‘educating’ discrete T cell types and thus, influencing the development of Th2-driven allergic disease. Differences in the composition of intestinal microflora have been reported among infants in geographically disparate regions with a different prevalence of allergy, as well as between allergic and non-allergic children [3]. One interpretation of these findings is that increased colonization with specific bacterial species (e.g. Bifidobacteria and Lactobacilli) is protective; however, this theory remains to be proven. What is clear is that the relationship between the microbiota and humans constitutes a highly complex and dynamic interaction. Infections with diverse pathogenic microbes such as fungi, bacteria, and viruses that colonize incongruent anatomical sites have been linked to the development of asthma. For example, chronic toe and nail infections with Trichophyton spp. have been associated with late-onset asthma in adults who exhibit immediate hypersensitivity skin tests and IgE responses to this dermatophyte fungus [4, 5]. Similarly, colonization of the hypopharyngeal region by respiratory pathogens including Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella cattharalis, has been linked to childhood asthma [6]. A key question is: does infection lead to asthma or does asthma lead to infection, or are these two options inextricably linked? It has been proposed that bacterial colonization reflects a defective innate immune response that promotes the development of asthma [7]. This could culminate in a diminished Th1 response to bacteria in susceptible individuals. An alternative, though not a mutually exclusive viewpoint, is that microbial products secreted by colonizing bacteria actively promote asthma through ‘proallergic’ pathways. Approaching this from a different angle, bacterial colonization may simply reflect an epiphenomenon associated with the asthma phenotype and as such, it may not play a direct role in disease pathogenesis. If we are to understand these arguments, we must consider immune events at the molecular level. Asthma is a complex disease that has been associated with numerous genes and the list will no doubt grow longer now Correspondence: Judith A. Woodfolk, Allergy Division, PO Box 801355, University of Virginia Health System, Charlottesville, VA 22908-1355, USA. E-mail: jaw4m@virginia.edu Cite this as: J. A. Woodfolk, Clinical & Experimental Allergy, 2009 (39) 1112–1114. doi: 10.1111/j.1365-2222.2009. 03285.x Clinical & Experimental Allergy, 39, 1112–1114