IDDF2024-ABS-0459 Berberine improves the immunotherapy efficacy and alleviates colitis induced by ICIS through restoring gut microbiota and metabolites in colorectal cancer

<h3>Background and Aim</h3> The therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either resistance mechanisms or ICIs-related toxic effects, including gastrointestinal toxicity. Berberine was believed to prevent colon adenoma recurrence and alleviate colitis. Here, we aimed to investigate the clinical potential and mechanism of berberine for immunotherapy in colorectal cancer. <h3>Methods</h3> We used murine models of colorectal cancer to evaluate whether oral administration of berberine improves the efficacy of ICIs therapies and immunotherapy-induced Colitis. We performed whole genome shotgun metagenome sequencing, targeted metabolomics of stools, and RNA sequencing of CD8+ T cells. In a series of in vitro and in vivo experiments, we further defined the immunological and molecular mechanisms of berberine-mediated antitumor immunity. <h3>Results</h3> We demonstrate that berberine can improve the efficacy of immunotherapy in colorectal cancer <i>in vivo</i> (IDDF2024-ABS-0459 Figure 1 (A)). Concomitantly, berberine mitigated the exacerbated colitis induced by ICIs (IDDF2024-ABS-0459 Figure 1 (B)). Through metagenomic sequencing and targeted metabolomics analysis, oral administration of berberine can reshape gut microbial diversity and modulate the microbial composition (IDDF2024-ABS-0459 Figure 1 (C,D)), and then increase the content of microbial metabolite indole-3-lactic acid in patients and mice (IDDF2024-ABS-0459 Figure 1 (E)). Mechanistically, indole-3-lactic acid enhances the function of CD8+ T cells to contribute to anti-tumor immunity and ameliorate ICIs-induced colitis (IDDF2024-ABS-0459 Figure 1 (F,G)). <h3>Conclusion</h3> Berberine manipulates gut microbiota and metabolites toward a more favorable profile, improves immunotherapy efficacy, and alleviates colitis induced by ICIs in colorectal cancer.