Expansion of commensal fungus Wallemia mellicola in the gastrointestinal mycobiota enhances the severity of allergic airway disease in mice

Abstract

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-Lung Axis in Health and Respiratory Diseases: A Place for Inter-Organ and Inter-Kingdom Crosstalks

“…In summary, GLA results from complex interactions between the different microbial components of both the gut and lung microbiotas combined with local and long-reaching immune effects. All these interactions strongly suggest a major role for the GLA in respiratory diseases, as recently documented in a mice model (Skalski et al, 2018).…”

“…Nevertheless, it is still not fully deciphered, as some studies conversely found that an early colonization with Bacteroides, including B. fragilis, could be an early indicator of asthma later in life (Vael et al, 2008). Regarding fungi, gut fungal overgrowth (after antibiotic administration or a gut colonization protocol with Candida or Wallemia mellicola) increases the occurrence of asthma via IL-13 without any fungal expansion in the lungs (Noverr et al, 2005;Wheeler et al, 2016;Skalski et al, 2018). The prostaglandin E2 produced in the gut by Candida can reach the lungs and promotes lung M2 macrophage polarization and allergic airway inflammation (Kim et al, 2014).…”

The Role of Lung and Gut Microbiota in the Pathology of Asthma

“…In addition to antibiotic treatment, antifungal treatment induces changes to both the bacterial and fungal communities in the gut of specific pathogen-free (SPF) mice and has been shown to exacerbate type 2 allergic airway inflammation and eosinophilia in a HDM model of AAD (Wheeler et al, 2016;Li et al, 2018). Continuous supplementation with three fungal species identified in this model to be overrepresented in the gut following antifungal treatment (Aspergillus amstelodami, Wallemia mellicola [sebi], and Epicoccum nigrum) (Wheeler et al, 2016;Li et al, 2018) or with Wallemia mellicola alone following antibiotic treatment (Skalski et al, 2018) similarly increases asthma severity (Figure 3) (Wheeler et al, 2016;Skalski et al, 2018). Antifungal treatment and the introduction of dysbiotic fungal communities to SPF mice in these studies results in changes to gut bacterial communities, including depletions of bacteria from the Lactobacillaceae family Skalski et al, 2018).…”

“…Continuous supplementation with three fungal species identified in this model to be overrepresented in the gut following antifungal treatment (Aspergillus amstelodami, Wallemia mellicola [sebi], and Epicoccum nigrum) (Wheeler et al, 2016;Li et al, 2018) or with Wallemia mellicola alone following antibiotic treatment (Skalski et al, 2018) similarly increases asthma severity (Figure 3) (Wheeler et al, 2016;Skalski et al, 2018). Antifungal treatment and the introduction of dysbiotic fungal communities to SPF mice in these studies results in changes to gut bacterial communities, including depletions of bacteria from the Lactobacillaceae family Skalski et al, 2018). However, the AAD-exacerbating effects of supplementation with a dysbiotic fungal community can be recapitulated in altered Schaedler flora mice without pre-treatment with antibiotics and in the absence of substantial changes to the bacterial microbiota Skalski et al, 2018).…”

“…Antifungal treatment and the introduction of dysbiotic fungal communities to SPF mice in these studies results in changes to gut bacterial communities, including depletions of bacteria from the Lactobacillaceae family Skalski et al, 2018). However, the AAD-exacerbating effects of supplementation with a dysbiotic fungal community can be recapitulated in altered Schaedler flora mice without pre-treatment with antibiotics and in the absence of substantial changes to the bacterial microbiota Skalski et al, 2018). Furthermore, Li et al (2018) recently demonstrated that direct sensing of antifungal-induced fungal dysbiosis by gut-resident CX3CR1 + mononuclear phagocytes increases numbers of Th2 cells in the lamina propria and is responsible for fungal dysbiosis-associated increased airway inflammation in a HDM model of AAD, independent of antifungal-associated changes to the bacterial communities .…”