Osteopontin protects from ovalbumin-induced asthma by preserving the microbiome and the intestinal barrier function.

Abstract

The gut and lung microbiota are associated with asthma. Osteopontin (OPN) is an important cytokine associated with several inflammatory diseases. The potential role of OPN in the asthma-associated microbiome remains poorly understood. Here, we investigated whether OPN could moderate asthma by affecting the gut and lung microbiota. Our results showed that compared with wild-type (WT) mice, Spp1^-/- mice exhibited immune cell infiltration in the lung, OVA-specific IgG1, increased levels of Th2- and Th17-related inflammatory factors, and decreased levels of Th1-related inflammatory factors and forkhead box P3 (FOXP3) expression, resulting in a Th1/Th2 and Th17/Treg imbalance. In addition, gut structure was impaired, and expression of tight junction-related proteins was reduced in Spp1^-/- mice, which disrupted gut barrier function. Importantly, OPN-deficient significantly aggravated gut and lung microbiota dysbiosis in OVA-induced asthmatic mice. The results of high-throughput 16S rRNA sequencing demonstrated that OPN-deficient mice showed a substantial reduction in beneficial gut and lung bacteria (Bacteroidetes, Lactobacillus, Allobaculum), and an OVA-induced increase in the abundance of bacteria associated with potentially pathogenic gut and lung (Epsilonbacteraeota, Helicobacter, Desulfovibrio, Oscillibacter)-associated bacteria was elevated in abundance. Allobaculum was negatively correlated with interleukin-4 and GATA-3 and was positively correlated with interferon gamma and FOXP3. Moreover, through fecal microbiota transplantation, we found that OVA-induced IgE and IgG1 levels were reduced in OPN-deficient asthmatic mice, Th1/Th2 and Th17/Treg balance was maintained, gut barrier function was improved, and microbiome changes in OPN-deficient mice were compensated for, with an elevated abundance of Allobaculum and reduced abundance of Desulfovibrio and Oscillibacter. We further discovered that OPN deficiency reduces FOXP3 expression and decreases Lactobacillus colonization through activation of the PD-1/PD-L1 pathway in the intestine and lung. The present study suggests that OPN may moderate OVA-induced asthma by modulating the gut and lung microbiota.

Importance: Osteopontin deficiency exacerbated asthmatic airway inflammation, an effect associated with microbiota dysbiosis, impaired intestinal barrier function, and increased PD-1/PD-L1 expression and thus decreased Treg cell function. The study provides clinicians with new insights into asthma mechanisms and can also lead to new ideas for asthma treatment.