Department of Chemical Engineering, Tsinghua University, 100084 Beijing, China.
Key Lab of Industrial Biocatalysis, Ministry of Education, Tsinghua University, 100084 Beijing, China.
J Immunol Res. 2022 Jul 19;2022:9202491. doi: 10.1155/2022/9202491. eCollection 2022.
Colitis is a frequently occurred side effect of immune checkpoint inhibitors (ICIs), which are increasingly used in cancer treatment, whereas antibiotics are widely used to treat colitis, their effectiveness in ICI-associated colitis remains controversial. In this study, we firstly assessed the effectiveness of several commonly used antibiotics and antibiotic cocktails in alleviating of dextran sulfate sodium- (DSS-) induced colitis. We observed that two narrow-spectrum antibiotics, neomycin and metronidazole, were more effective in alleviating colitis, as evidenced by the remission of loss of the body weight, enlargement of the spleen, shortening of the colon, secretion of proinflammatory cytokines, and histological score of the colon tissue. Moreover, these two antibiotics resulted in better relief of colitis symptoms in the MC38 tumor-bearing male mice receiving the anti-PD-L1 mAb (PD-L1) treatment, compared to the females. In the meantime, an enhanced response to PD-L1 efficiency against mice colon cancer was observed in the male mouse group upon the application of these two antibiotics. In contrast, both neomycin and metronidazole showed destructive effects on the antitumor efficiency of PD-L1 in female mice, despite relief from colitis. We found that antibiotic treatment attenuated the increased infiltration of granulocytes and myeloid cells in colon tissue induced by DSS in female mice, while reducing the proportion of Th17 cells in male mice. These differences were further associated with the sex-biased differences in the gut microbiota. These findings indicated that sex-dependent alterations in the gut microbiota should be considered when applying antibiotics for the treatment of ICI-associated colitis.
结肠炎是免疫检查点抑制剂（ICIs）治疗癌症时经常出现的副作用，而抗生素广泛用于治疗结肠炎，但它们在 ICI 相关结肠炎中的疗效仍存在争议。在这项研究中，我们首先评估了几种常用抗生素和抗生素鸡尾酒在缓解葡聚糖硫酸钠（DSS）诱导的结肠炎中的效果。我们观察到两种窄谱抗生素新霉素和甲硝唑在缓解结肠炎方面更有效，表现在体重减轻、脾脏肿大、结肠缩短、促炎细胞因子分泌和结肠组织学评分的缓解。此外，与女性相比，这两种抗生素在接受抗 PD-L1 mAb（PD-L1）治疗的 MC38 荷瘤雄性小鼠中，能更好地缓解结肠炎症状。同时，在应用这两种抗生素后，观察到雄性小鼠组对 PD-L1 对抗小鼠结肠癌的效率有增强的反应。相比之下，尽管能缓解结肠炎，但新霉素和甲硝唑对女性小鼠 PD-L1 的抗肿瘤效率都有破坏作用。我们发现抗生素治疗可减轻 DSS 诱导的雌性小鼠结肠组织中粒细胞和髓样细胞浸润的增加，同时降低雄性小鼠 Th17 细胞的比例。这些差异与肠道微生物群的性别差异有关。这些发现表明，在应用抗生素治疗 ICI 相关结肠炎时，应考虑肠道微生物群的性别依赖性改变。
