Dysbiosis of the intestinal fungal microbiota increases lung resident group 2 innate lymphoid cells and is associated with enhanced asthma severity in mice and humans

Abstract

Background: The gut-lung axis is the concept that alterations of gut microbiota communities can influence immune function in the lungs. While studies have explored the relationship between intestinal bacterial dysbiosis and asthma development, less is understood about the impact of commensal intestinal fungi on asthma severity and control and underlying mechanisms by which this occurs.

Methods: Wild-type mice were treated with Cefoperazone to deplete gut bacteria and administered Candida albicans or water through gavage. Mice were then sensitized to house dust mite (HDM) and their lungs were analyzed for changes in immune response. Humans with asthma were recruited and stool samples were analyzed for Candida abundance and associations with asthma severity and control.

Results: Mice with intestinal Candida dysbiosis had enhanced Th2 response after airway sensitization with HDM, manifesting with greater total white cell and eosinophil counts in the airway, and total IgE concentrations in the serum. Group 2 innate lymphoid cells (ILC2) were more abundant in the lungs of mice with Candida gut dysbiosis, even when not sensitized to HDM, suggesting that ILC2 may be important mediators of the enhanced Th2 response. These effects occurred with no detectable increased Candida in the lung by culture or rtPCR suggesting gut-lung axis interactions were responsible. In humans with asthma, enhanced intestinal Candida burden was associated with the risk of severe asthma exacerbation in the past year, independent of systemic antibiotic and glucocorticoid use.

Conclusions: Candida gut dysbiosis may worsen asthma control and enhance allergic airway inflammation, potentially mediated by ILC2. Further studies are necessary to examine whether microbial dysbiosis can drive difficult-to-control asthma in humans and to better understand the underlying mechanisms.

Keywords: Asthma; Candida; Gut; ILC2; Mycobiota.

Fig. 1

Mice were provided with cefoperazone-medicated water as the only source of water for an entire week. This was followed by a single gavage of live C. albicans or water (control), and intranasal challenge with house dust mite (HDM). The gavage of C. albicans to antibiotic depleted mice resulted in an intestinal dysbiosis state characterized by an enhanced intestinal Candida population that persisted weeks after discontinuation of the antibiotic. Mice with Candida gut dysbiosis were phenotypically normal and Candida was not detected in the lungs of mice with dysbiosis above control baseline by PCR.

Fig. 2

Mice with Candida intestinal dysbiosis demonstrated enhanced airway inflammation after challenge with HDM, characterized by higher total cell and eosinophil counts on bronchoalveolar lavage, higher serum total IgE and higher percent (%) of lung ILC2 cells compared to controls

Fig. 3

The increase in %ILC2 population in the lungs was also observed without HDM challenge suggesting ILC2 may be key mediators of observed gut-lung axis effects. ILC2 were defined as Lin- CD25 + CD44+.

Fig. 4

To investigate whether Candida gut dysbiosis might be observed in humans with difficult to control asthma, 24 patients with asthma were recruited. There was no significant association between either antibiotic (n = 14; 58%) or systemic glucocorticoid (n = 16; 67%) use in the past year and Candida-to-bacteria DNA in stools. Patients with severe asthma exacerbation (defined as any asthma-related emergency department visit or hospitalization) in the past year (n = 8; 33%) had a higher median Candida-to-bacteria DNA ratio in stools