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Published on: July 10, 2018
Exploring the role of intelectin-1 in modulating asthma through the gut-bone-lung axis
Shiyue He1,2,3, Xinyue Hu1,2,3,4,5, Xiaoxiao Gong1,2
1Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China.
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.
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