NOD1 sensing of house dust mite-derived microbiota promotes allergic experimental asthma.

ABSTRACT Background Asthma severity has been linked to exposure to Gram-negative bacteria from the environment, that are recognized by NOD1 receptor and are present in HDM extracts. NOD1 polymorphism has been associated with asthma. Objective To evaluate if either host or HDM-derived microbiota may contribute to NOD1-dependent disease severity. Methods A model of HDM-induced experimental asthma was used and the effect of NOD1 deficiency evaluated. Contribution of host microbiota was evaluated by fecal transplantation. Contribution of HDM-derived microbiota was assessed by 16S ribosomal RNA (rRNA) sequencing, mass spectrometry analysis, and peptidoglycan depletion of the extracts. Results In this model, loss of the bacterial sensor NOD1 and its adaptor receptor-interacting protein kinase 2 improved asthma features. Such inhibitory effect was not related to dysbiosis caused by NOD1 deficiency, as shown by fecal transplantation of Nod1-deficient microbiota to wild-type germ-free mice. 16S rRNA gene sequencing and mass spectrometry analysis of HDM allergen, revealed the presence of some muropeptides from Gram-negative bacteria that belong to the Bartonellaceae family. While such HDM-associated muropeptides were found to activate NOD1 signaling in epithelial cells, peptidoglycan-depleted HDM had a decreased ability to instigate asthma in vivo. Conclusion These data show that NOD1-dependent sensing of HDM-associated Gram-negative bacteria aggravates the severity of experimental asthma, suggesting that inhibiting NOD1 signaling pathway may be a therapeutic approach to treating asthma.