Early origins of asthma. Role of microbial dysbiosis and
metabolic dysfunction

Asthma is a developmental disease that affects airway growth and is characterized by inappropriate responses to a variety of environmental stimuli. Recent advances point to two altered early life pathways as major determinants of asthma risk. In the ``microbial'' pathway, pre- and post-natal exposures to microbiota-loaded farm environments block gene-virus interactions (e.g., interactions between risk alleles in chromosome 17q21 and lower respiratory illnesses [LRI] by rhinovirus) that are associated with asthma development. Early colonization of the airway by pathogenic bacteria such as Streptococci and Moraxella may predispose for recurrent wheezing LRIs and subsequent asthma. Abnormal patterns of gut microbial colonization (dysbiosis) in the first months of life are associated with production of deleterious metabolic products that predispose for the development of asthma and reduction of beneficial metabolites, such as short-chain fatty acids, that may protect from the disease. The ``metabolic'' pathway is triggered by maternal obesity, excessive weight gain during pregnancy, and accelerated body mass index growth in the first years of life, which in turn predispose for early development of both metabolic alterations and asthma phenotypes. Notably, early gut dysbiosis is also associated with subsequent development of obesity, although it is currently unknown whether there are common intestinal microbial patterns in obesity- and asthma-associated dysbiosis. Promising avenues for asthma prevention could entail manipulating these two pathways with microbes, surrogates of animal farm exposures, or dietary supplements such as n-3 long-chain polyunsaturated fatty acids.