Single probiotic supplement suppresses colitis-associated colorectal tumorigenesis by modulating inflammatory development and microbial homeostasis

Background and Aim Chronic inflammation is a major contributor to the initiation and progression of cancers. Lactobacillus helveticus NS8, which was originally separated from fermented koumiss, exhibited anti-inflammatory functions in our prior studies. In this study, NS8 was investigated for its potential to prevent colitis-associated colorectal cancer (CAC). Methods The protective effects of NS8 against CAC was explored by employing the azoxymethane plus dextran sodium sulfate-induced carcinogenesis mouse model. The prevalences of T cells expressing specific inflammatory cytokines were measured by flow cytometry at the early stage of CAC. Inflammatory modulation by NS8 was also tested in the Caco2-Raw264.7 cell co-culture system. The alternations in the intestinal microbiota following the health-inflammation-cancer sequence were analyzed by 16S rDNA sequencing. Results Oral intake of NS8 lactobacilli clearly reduced tumor number and the degree of hyperplasia. The increased proliferation of enterocytes at the early stage of CAC was significantly suppressed by NS8, while the level of apoptosis was elevated. The anticancer effects of NS8 were associated with its anti-colitis outcomes before tumor formation. NS8 significantly suppressed the activation of NF-kappa B and upregulated the anti-inflammatory cytokine IL-10. Further analysis revealed the marked downregulation of IL-17-producing T cells by NS8. Furthermore, NS8 modulated intestinal dysbiosis by promoting beneficial commensal microbes while suppressing cancer-associated microbes. Notably, Bacteroides acidifaciens was the most sensitive commensal bacteria to NS8 intervention. Conclusion These results provide insight into the protective effects of L. helveticus NS8 against colorectal cancer.

背景与目的 慢性炎症是癌症发生和进展的主要诱因。瑞士乳杆菌NS8最初从发酵的马奶酒中分离出来，在我们先前的研究中显示出抗炎功能。在本研究中，对NS8预防结肠炎相关结直肠癌（CAC）的潜力进行了研究。 方法 通过使用偶氮甲烷加葡聚糖硫酸钠诱导的致癌小鼠模型，探索NS8对CAC的保护作用。在CAC早期，通过流式细胞术检测表达特定炎症细胞因子的T细胞的患病率。还在Caco2 - Raw264.7细胞共培养系统中测试了NS8的炎症调节作用。通过16S rDNA测序分析健康 - 炎症 - 癌症进程中肠道微生物群的变化。 结果 口服NS8乳酸菌明显减少了肿瘤数量和增生程度。NS8显著抑制了CAC早期肠上皮细胞增殖的增加，同时提高了细胞凋亡水平。NS8的抗癌作用与其在肿瘤形成前的抗结肠炎效果相关。NS8显著抑制了NF - κB的激活，并上调了抗炎细胞因子IL - 10。进一步分析显示，NS8显著下调了产生IL - 17的T细胞。此外，NS8通过促进有益共生微生物同时抑制癌症相关微生物来调节肠道菌群失调。值得注意的是，嗜酸拟杆菌是对NS8干预最敏感的共生菌。 结论 这些结果为瑞士乳杆菌NS8对结直肠癌的保护作用提供了见解。