Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8 + T cells

作者：Xing Kang, Changan Liu, Yanqiang Ding, Yun‐Bi Ni, Fenfen Ji, Harry Cheuk-Hay Lau, Lanping Jiang, Joseph J.�Y. Sung, Sunny H. Wong, Jun Yu · 发表于：Gut · 年份：2023 · DOI：10.1136/gutjnl-2023-330291 · 被引用次数：371 · 研究领域：Gut microbiota and health、Mycobacterium research and diagnosis、Cancer, Stress, Anesthesia, and Immune Response

Objective Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. Design R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in Apc Min/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. Results R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in Apc Min/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B + , interferon (IFN)-γ + and tumour necrosis factor (TNF)-α + CD8 + T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death...