Date Published: September 20, 2018
Publisher: Public Library of Science
Author(s): Joseph H. Skalski, Jose J. Limon, Purnima Sharma, Matthew D. Gargus, Christopher Nguyen, Jie Tang, Ana Lucia Coelho, Cory M. Hogaboam, Timothy R. Crother, David M. Underhill, Tobias M. Hohl.
The gastrointestinal microbiota influences immune function throughout the body. The gut-lung axis refers to the concept that alterations of gut commensal microorganisms can have a distant effect on immune function in the lung. Overgrowth of intestinal Candida albicans has been previously observed to exacerbate allergic airways disease in mice, but whether subtler changes in intestinal fungal microbiota can affect allergic airways disease is less clear. In this study we have investigated the effects of the population expansion of commensal fungus Wallemia mellicola without overgrowth of the total fungal community. Wallemia spp. are commonly found as a minor component of the commensal gastrointestinal mycobiota in both humans and mice. Mice with an unaltered gut microbiota community resist population expansion when gavaged with W. mellicola; however, transient antibiotic depletion of gut microbiota creates a window of opportunity for expansion of W. mellicola following delivery of live spores to the gastrointestinal tract. This phenomenon is not universal as other commensal fungi (Aspergillus amstelodami, Epicoccum nigrum) do not expand when delivered to mice with antibiotic-depleted microbiota. Mice with Wallemia-expanded gut mycobiota experienced altered pulmonary immune responses to inhaled aeroallergens. Specifically, after induction of allergic airways disease with intratracheal house dust mite (HDM) antigen, mice demonstrated enhanced eosinophilic airway infiltration, airway hyperresponsiveness (AHR) to methacholine challenge, goblet cell hyperplasia, elevated bronchoalveolar lavage IL-5, and enhanced serum HDM IgG1. This phenomenon occurred with no detectable Wallemia in the lung. Targeted amplicon sequencing analysis of the gastrointestinal mycobiota revealed that expansion of W. mellicola in the gut was associated with additional alterations of bacterial and fungal commensal communities. We therefore colonized fungus-free Altered Schaedler Flora (ASF) mice with W. mellicola. ASF mice colonized with W. mellicola experienced enhanced severity of allergic airways disease compared to fungus-free control ASF mice without changes in bacterial community composition.
The gut microbiome is a dynamic ecosystem that profoundly influences immune function throughout the body [1–3]. Commensal microorganisms are recognized by the host immune system and can alter systemic immune response or produce bioactive metabolites which are absorbed into the bloodstream and have pharmacological effect on distant organ systems [4–7]. The commensal microbial composition of the gut can therefore have a distant effect on immune function in the lung and other organ systems; this is the concept of the gut-lung axis.
We have shown that altered composition of the gastrointestinal mycobiota enhances the severity of allergic airways disease with enhanced eosinophilic airway inflammation and increased IL-13 production by mediastinal lymphocytes in response to HDM allergen stimulation. Interestingly, these effects are not due to a fungal overgrowth state where bloom of a single organism results in exponential population expansion of the total gastrointestinal fungal burden. Rather, the W. mellicola dysbiosis described herein is a shift in the composition of the commensal fungal community that occurs without substantial increase in the total fungal burden yet still produces a significant change in pulmonary immune response to inhaled allergens. The term “dysbiosis” is generally used to describe altered gut microbial ecosystem that results in negative host effects but is not an infectious state. We believe that the dysbiosis state described in this manuscript is not unique to Wallemia mellicola. Rather Wallemia mellicola dysbiosis may just be one representative example of a gut microbial pattern that alters pulmonary and systemic immune response. Other alterations of the gastrointestinal mycobiota community characterized by expansion of different fungal species may have distinctive beneficial or harmful effects on respiratory immune function.