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Mechanistic study on the effects of 2'-fucosyllactose in alleviating immune checkpoint inhibitor-induced colitis in mice
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Abstract:
[Abstract] Objective: To investigate the effect of 2'-fucosyllactose (2'-FL) on immune checkpoint inhibitor-induced colitis (ICIC) in mice and its possible mechanisms. Methods: BALB/c mice were randomly assigned into the normal control (NC) group, dextran sulfate sodium (DSS) group, ICIC group, and ICIC + 2'-FL group, using a random number table method. Mice in the DSS group were provided with 3.5% DSS-containing drinking water for seven days to induce colonic inflammation. The ICIC group was intraperitoneally injected of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; dose: 150 μg) on day 0 and day 4, while simultaneously consuming 3.5% DSS-containing drinking water. The ICIC + 2'-FL group received daily intragastric administration of 2'-FL (150 mg/[kg·d]) concurrently with the establishment of ICIC model. Changes in body weight and disease activity index (DAI) were statistically analyzed. On day 7, all mice were sacrificed, and the colon length was measured. Hematoxylin and eosin (H&E) staining was performed to observe histomorphological changes in colon tissues across groups. Immunohistochemistry (IHC) was conducted to assess the infiltration of CD3+ T cells and CD19+ B cells in colonic tissues. RNA sequencing (RNA-seq) was performed on colon tissues. The differentially expressed genes (DEGs) were subjected to Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: Compared with the NC and DSS groups, the ICIC group showed significant body weight loss, elevated DAI scores, and shorter colon length (all P <0.05); besides, the colon mucosal integrity was damaged, with typical ulcerative lesions. Compared with the ICIC group, ICIC + 2'-FL group demonstrated significantly alleviated body weight loss, reduced DAI score, and restored colon length (all P < 0.05). Transcriptomic results revealed 51 DEGs in the ICIC + 2'-FL group (vs ICIC group). GO functional annotation and KEGG enrichment analysis suggested that the protective effect of 2'-FL against ICIC-like symptoms might be associated with upregulation of signaling pathways related to B cell receptor, B cell proliferation regulation, inflammatory responses, and tissue repair. Conclusion: Human milk oligosaccharide 2'-FL significantly alleviates the pathological progression of ICIC by modulating B-cell receptor-related signaling pathways and pathways associated with inflammation responses and tissue repair, thereby reducing colonic damage in ICIC mice.
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