Abstract Background The long-term triggers of recurrent inflammatory bowel disease (IBD) remain unclear. The oral microenvironment may contribute to IBD progression by regulating mucosal immunity and microbiota-host interactions. Our prior research identified salivary exosomes (SEXOs) from active-phase IBD patients (but not remission-phase or healthy controls) exacerbate intestinal inflammation, though the mechanisms are unknown. This study aims to elucidate the disease activity-dependent mechanisms by which active IBD SEXOs (IBDA-SEXOs) mediate intestinal inflammation, focusing on identifying and functionally validating key effector proteins. Methods Salivary exosomes were isolated from active-phase IBD patients, remission-phase IBD patients, and healthy controls using ultra-gradient centrifugation. Candidate proteins were screened through 4D-DIA proteomics. Epithelial-macrophage co-culture systems and T cell stimulation with macrophage-conditioned medium (Mø-CM) were employed to dissect cellular crosstalk. Mechanistic confirmation employed macrophage transfer models stimulated with SAA1 protein and exosomes derived from lentiviral-transduced SAA1overexpressing oral epithelial cells. Results Through proteomic analysis, we first identified and validated serum amyloid A1 (SAA1) as a key pro-inflammatory protein specifically enriched in salivary exosomes (IBDA-SEXOs) from patients with active inflammatory bowel disease (IBD). Functionally, SAA1 acts as a core effector molecule of IBDA-SEXOs, driving macrophage polarization toward the M1 phenotype via the TLR4–NF-κB/JNK signaling pathway, thereby exacerbating colitis in DSS-treated mice. Further investigation revealed that although IBDA-SEXOs alone do not directly induce Th17 differentiation, macrophages activated by these exosomes secrete IL-6 through the SAA1–TLR4–JNK axis. This, in cooperation with SAA1 carried by the exosomes, activates the STAT3 signaling pathway in T cells, ultimately driving pathogenic Th17 cell differentiation. Mechanistic intervention experiments demonstrated that a synthetic SAA1-inhibitory peptide (IP) effectively attenuated IBDA-SEXO-induced M1 macrophage polarization and associated pro-inflammatory effects in vivo. Finally, gain-of-function studies confirmed that exosomes derived from lentivirus-mediated SAA1-overexpressing oral epithelial cells were enriched in SAA1 and recapitulated the pro-inflammatory effects of IBDA-SEXOs in vivo—effects that were similarly blocked by the SAA1-inhibitory peptide. Conclusion SAA1functions as a key effector protein in active-phase IBD salivary exosomes, driving intestinal inflammation via oral-gut axis transmission. This finding identifies novel mechanistic and therapeutic targets for IBD. Conflict of interest: Dr. Yang, Congyi: No conflict of interest Chen, Ning: No conflict of interest
Yang et al. (2026) studied this question.