An intestinal factor intelectin-1 maintains anti-asthmatic environment via gut-bone-lung axis

The development of extra-intestinal diseases is often accompanied by disruptions in intestinal microbiota and their metabolites. Improvement of the intestinal microenvironment frequently results in amelioration of these diseases, highlighting the need to identify key regulatory intestinal factors. In our asthma study, we identified intelectin-1 (ITLN1), predominantly expressed in the intestine, as a critical factor in maintaining intestinal bacterial homeostasis to mitigate allergic asthma via gut-bone-lung axis. We observed that reduced serum ITLN1 levels in asthmatic patients were significantly associated with increased disease severity and airway inflammation. In house dust mite (HDM)-induced asthma mouse model, ITLN1 deficiency exacerbated allergic inflammation by disrupting gut microbial homeostasis, resulting in decreased production of the beneficial short-chain fatty acid butyrate due to reduced Erysipelotrichaceae, Muribaculaceae, and Bifidobacteriaceae levels. Butyrate reduction increased CCL8 secretion by lung macrophages, which facilitated the recruitment of CD4+ T cells from the bone marrow to the lungs through the CCL8-CCR3 axis and enhanced group 2 innate lymphoid cells immune response, thereby amplifying type 2 inflammation. Elevated CCL8 levels were detected in both asthmatic patients and ITLN1-deficient asthmatic mice. Notably, supplementation with either ITLN1 or butyrate, as well as neutralization of CCL8, effectively attenuated lung allergic inflammation and improved asthma outcomes. Our findings establish ITLN1 as a crucial mediator that links gut microbial metabolism to pulmonary immune regulation, providing insights into the gut-bone-lung axis as a regulatory mechanism in asthma pathogenesis. These results position ITLN1 as a promising therapeutic target for modulating the intestinal microenvironment and mitigating systemic inflammatory responses in asthma and related disorders. Overall design: To explore the genes that plays key roles in the asthma model with Itln1 deiffcient mice compared to asthma model with wild type mice, we processing RNA sequencing in lung tissues between these two types. We then performed gene expressing profiling analysis using data from RNA-seq of the above two models of lung tissue.