Abstract
Group 2 Innate lymphoid cells (ILC2) contribute significantly to allergic inflammation. However, the role of microbiota on ILC2s remains to be unraveled. Here we show that short chain fatty acids (SCFAs), such as butyrate, derived from fermentation of dietary fibers by the gut microbiota inhibit pulmonary ILC2 functions and subsequent development of airway hyperreactivity (AHR). We further show that SCFAs modulate GATA3, oxidative phosphorylation, and glycolytic metabolic pathways in pulmonary ILC2s. The observed phenotype is associated with increased IL-17a secretion by lung ILC2s and linked to enhanced neutrophil recruitment to the airways. Finally, we show that butyrate-producing gut bacteria in germ-free mice effectively suppress ILC2-driven AHR. Collectively, our results demonstrate a previously unrecognized role for microbial-derived SCFAs on pulmonary ILC2s in the context of AHR. The data suggest strategies aimed at modulating metabolomics and microbiota in the gut, not only to treat, but to prevent lung inflammation and asthma.
Highlights
Allergic disease affects 10–15% of people in the U.S reflecting dysregulated immunity toward otherwise harmless environmental antigens
RAG2−/− mice to a Normal 4.5% cellulose chow (Control Diet), or diets high in Cellulose (Hi-C) or Pectin (Hi-P) at 30% of dietary formula followed by allergic asthma challenge (Figure 1A)
Pectin is more fermentable than cellulose and leads to increased short chain fatty acids (SCFAs) production in vivo
Summary
Allergic disease affects 10–15% of people in the U.S reflecting dysregulated immunity toward otherwise harmless environmental antigens. Recent studies have shown increased ILC2 activity in asthma and allergic diseases [1, 2]. In murine models of asthma, ILC2s are sufficient to provoke eosinophilic inflammation accompanied by airway hyperreactivity (AHR) independent of adaptive immunity [3]. Finding negative regulators of ILC2 function remains an important clinical goal [1]. Both direct recognition of microbes as well as microbial metabolites have profound effects on immune system function including barrier defense, pathogen protection [4] and immune tolerance [5].
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