P100 Salivary exosomes aggravate colitis via oral-gut axis

Abstract Background Inflammatory bowel disease (IBD) is a chronic intestinal immune-dysfunctional disease, while the presence of persistent triggering factors leading to relapsing and remitting inflammation in IBD remains undetermined. The oral cavity is one of the most frequently affected extraintestinal organ in IBD, and literature highlights the oral cavity's influence on gastrointestinal conditions. The understanding of alternative mechanisms in the long-distance interaction between the oral cavity and gut is limited. Exosomes exist in various bodily fluids and facilitate intercellular communication. Thus, we aimed to further explore the role of salivary exosomes in aggravating colitis via bridging oral cavity and gut. Methods Salivary exosomes were obtained from active IBD patients, remission IBD patients, and healthy donors using ultracentrifugation. In vivo, we established a dextran sulfate sodium (DSS)-induced colitis model to investigate the possible role and mechanisms of salivary exosomes. In vitro, THP-1 cells and Caco-2 cells were stimulated with salivary exosomes respectively and the expression of related inflammatory factors was detected. Moreover, our investigated the immune regulatory mechanism of salivary exosomes by analyzing their microRNA profiles. Results DIL-labeled salivary exosomes accumulated in mouse colon at 6 hours post-gavage, indicating their ability to reach and accumulate in the colon through the "oral-gut axis" (Figure 1A). Salivary exosomes of active IBD patients (active IBD-Sexos) exacerbated colitis in DSS mouse, while salivary exosomes derived from remission IBD patients or healthy donors not (Figure1B). The potential mechanisms may include remodeling of macrophage phenotypes by activating the NF-κB signaling pathway (Figure1D-F), impairment of intestinal mucosal barrier function (Figure1C), and modulation of the intestinal microbiota. Co-culture of THP-1 cells and Caco-2 cells with active IBD-Sexos were shown to raise inflammation in macrophages, which lead to increased release of inflammatory factors and promoted macrophage M1 polarization(Figure1G-K). We found 35 differentially expressed microRNAs in active IBD-Sexos compared to exosomes from both remission IBD patients and healthy donors (Figure1L). Specifically, miR-223 regulates the inflammatory response of IBD. MiR-119b-5p and miR-203-5p impact the NF-κB signaling pathway.These microRNAs promote inflammation, suggesting a possible role of salivary exosome delivery in IBD pathogenesis. Conclusion In conclusion, our study provides evidence that salivary exosomes play a significant role in the communication between the oral cavity and gut, beyond microorganisms or immune cells, with the potential to exacerbate intestinal inflammation in IBD (Figure1M).