ITIH4 alleviates OVA-induced asthma by regulating lung-gut microbiota

Area of Science:

• Immunology
• Microbiology
• Pulmonology

Background:

• Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a Type 2 acute phase protein involved in inflammation resolution and tissue repair.
• Its role in chronic respiratory diseases is known, but its specific effects on asthma are not well understood.

Purpose of the Study:

• To investigate the effects of ITIH4 on lung and gut microbiota.
• To assess ITIH4's ability to attenuate allergic inflammation and improve respiratory outcomes in a mouse model of asthma.

Main Methods:

• Mice were divided into control, ITIH4, ovalbumin (OVA), and OVA + ITIH4 groups.
• Lung function, oxygen saturation, bronchoalveolar lavage fluid (BALF) cytokines, and white blood cell counts were analyzed.
• 16S rRNA gene sequencing was used for microbiome profiling, and gas chromatography-mass spectrometry (GC-MS) measured short-chain fatty acids (SCFAs).
• Proteomic profiling identified ITIH4-associated signaling pathways in intestinal tissues.

Main Results:

• ITIH4 significantly reduced asthma symptoms, including weight loss and airway resistance, and improved lung histology.
• ITIH4 decreased BALF eosinophils, lymphocytes, IgE, and Th2 cytokines (IL-4, IL-5, IL-13).
• Microbiome analysis showed ITIH4 enriched Gram-positive taxa and depleted Gram-negative Helicobacteraceae, correlating with altered SCFA levels.
• Proteomics revealed dose-dependent activation of granzyme A signaling and suppression of metabolic pathways.

Conclusions:

• ITIH4 ameliorates asthma symptoms by modulating lung and gut microbiota, reducing Th2 inflammation, and restoring immune balance.
• These findings highlight ITIH4 as a potential therapeutic agent for microbiome-targeted asthma treatment.