Fig. 4

Reprogramming metabolism by respiratory tract microbiota and MIS. The respiratory microbiota interacts with host immunity through metabolic modulation, influencing immune-metabolic reprogramming via three core pathways:I. Glycolysis: Staphylococcus epidermidis AIT01 enhances TNF-α production in neutrophils via secreted GAPDH. β-glucan activates the Akt-mTOR-HIF-1α axis, boosting glycolytic intermediates that drive epigenetic immune regulation. Conversely, Senecavirus exploits glycolysis-derived lactate to disrupt MAVS-RIG-I interactions, suppressing type I interferon responses for immune evasion. II. Amino Acid Metabolism: SARS-CoV-2 alters airway microbiota composition and induces distinct amino acid metabolic disorders in COVID-19 patients. Targeting amino acid metabolism reduces inflammatory cytokine release in PBMCs, suggesting therapeutic potential for mitigating hyperinflammation. III. Fatty Acid Metabolism: In COPD, Lactobacillus salivarius and Lactobacillus oris elevate IAA by modulating K01426 gene abundance, reducing airway IL-1β, IL-6, and IL-17A. Gut-derived SCFAs further mediate lung immunoprotection via the gut-lung axis, highlighting cross-organ metabolic-immune regulation. Collectively, microbiota-derived metabolites dynamically reshape immune responses through metabolic intermediates, offering insights into host-microbe synergy in health and disease. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RIG-I, retinoic acid-inducing gene I; MAVS, mitochondrial antiviral-signaling protein; ISGs, interferon-stimulated genes; PBMC, peripheral blood mononuclear cells; SCFAs, short chain fatty acids; IAA, indole-3-acetic acid