Exploring the role of intelectin-1 in modulating asthma through the gut-bone-lung axis.

BACKGROUND: The development of extra-intestinal diseases is often accompanied by disruptions in intestinal microbiota and its metabolites, yet the mechanistic link between the gut microbiota and asthma remains unclear. We investigated whether intelectin-1 (ITLN1) mitigates allergic asthma through the gut‒bone‒lung axis as a regulator of gut microbial homeostasis. METHODS: Serum samples from 53 asthmatic patients and 34 healthy subjects were analyzed to assess the association between asthma and ITLN1 levels. Mechanism studies were conducted using a house dust mite (HDM)-induced asthma model in Itln1-knockout and Itln1-overexpression mice. Fecal samples were subjected to 16S rRNA sequencing, while lung tissues were analyzed using metabolomics and mRNA sequencing. Butyrate and CCL8-neutralizing antibody were used in the intervention studies, and human serum CCL8 levels were evaluated for clinical relevance. RESULTS: Serum ITLN1 levels inversely correlated with blood eosinophils in asthmatic patients. Itln1 deficiency exacerbated HDM-induced allergic lung inflammation, particularly type 2 inflammation, while Itln1 overexpression attenuated these effects. Fecal 16S rRNA analysis revealed reduced levels of Bifidobacteriaceae, Erysipelotrichaceae, and Muribaculaceae in Itln1-deficient asthmatic mice, mainly due to the loss of agglutination effects of ITLN1. Moreover, Itln1 deficiency correlated with decreased lung butyrate levels, further enhanced macrophage-derived CCL8 production using the NF-κB pathway and then activated CCR3 expression in CD4+ T cells from bone marrow. Noteworthily, butyrate supplementation or CCL8 neutralization effectively attenuated type 2 inflammation, especially in Itln1 deficiency condition. Additionally, human serum CCL8 levels exhibited a negative correlation with FEV1/FVC, FEV1, and FVC and a positive correlation with neutrophils under asthmatic conditions. CONCLUSION: ITLN1 is a promising therapeutic target linking gut microbial metabolism to asthma immune regulation using the gut‒bone‒lung axis.