Nature:胆汁酸代谢物化身“抗癌战士”,大大阻断癌症高危因素产生!

2020-04-20 佚名 转化医学网

癌症可谓是肠道微生物诸多相关研究中最浓墨重彩的一笔。大量研究表明,一些肠道微生物可以促进癌症的发生、帮助癌细胞转移、导致化疗耐药和影响免疫治疗的效果,可以说是全方位,多角度。近日,路德维希癌症在这一领

癌症可谓是肠道微生物诸多相关研究中最浓墨重彩的一笔。大量研究表明,一些肠道微生物可以促进癌症的发生、帮助癌细胞转移、导致化疗耐药和影响免疫治疗的效果,可以说是全方位,多角度。近日,路德维希癌症在这一领域又有了新的发现:胆汁酸的细菌代谢(有机酸异曲藻)可促进外周血调节性T细胞的产生,抑制自身免疫反应和炎症,从而阻碍大肠癌的发生发展。相关研究于15日在线发表在《Nature》杂志上。

胆汁酸是参与基本生理过程的胆固醇衍生分子,包括营养吸收、葡萄糖稳态和能量消耗调节。绝大部分初级胆汁酸经由肝肠循环为机体回收利用,但大约5%的胆汁酸将进入结肠,并由肠道微生物代谢为肠道胆汁酸代谢物。这些胆汁酸代谢产物可以作为重要的信号分子通过胆汁酸受体调节宿主的胆固醇代谢及能量平衡。

肠道固有层中的FOXP3+调节性T细胞 (FOXP3+ Tregs)对维持肠道稳态以及控制炎症反应至关重要。长期以来,鲁登斯基一直在探索共生细菌和Tregs之间的相互交流,这种细菌主要在胸腺中成熟,但也可以从其他组织,特别是肠道中的前体细胞诱导出来。研究表明,这些外围的tregs可以保护有益的肠道微生物免受免疫攻击,并有助于抑制慢性肠道炎症。

宿主和共生微生物群落之间有双向通信,微生物群落和宿主免疫系统之间极有可能通过共生细菌的代谢产物相互交流。

为了找到共生细菌代谢产物,他们筛选了细菌代谢产生的胆汁酸谱,以便在树突状细胞和树突状细胞的共培养中产生以上效果,从而帮助指导树突状细胞的产生。筛检发现,细菌胆汁代谢的两个产物:酸(ω-MCA)和二级胆汁酸3β-羟基脱氧胆酸(ISODCA)可以显着促进前体T细胞向外周的转化。ISODCA通过作用于树突状细胞(DCS)而增加Foxp3的诱导,以降低其免疫刺激性,值得注意的是,胆汁酸对树突状细胞的影响远大于对前体细胞的影响。而促炎TH17细胞的分化不受胆汁酸的存在(延长数据图1A)的影响,这表明其对调节性T细胞的生成有特定的影响。

研究发现,等密度区与树突状细胞中胆汁酸传感器发出的信号相反,这掩盖了树突状细胞表达的基因诱导保护性免疫反应,从而推动它们进入抗炎状态,在这一过程中,细菌胆汁酸代谢物促进了周围树突状细胞的产生(外周调节性T细胞)。

鲁登斯基和他的同事接下来在小鼠模型中进行了合成生物学实验,并设计了含有工程菌类菌株的最小微生物联盟,以证实他们的发现在生物学上的准确性。不出意外,小鼠实验进一步验证了细胞培养的结果。与那些拥有相同细菌的小鼠相比,在肠道中培养出Tregs的小鼠,它们的肠道中的外周调节性T细胞的数量要多得多,用另外两种类似工程的肠道细菌也得到了同样的结果。因此,内源性类固醇的微生物代谢对结肠的免疫平衡有重要影响,这为结肠癌的预防及治疗提供了新的策略。

参考文献:

Clarissa Campbell,et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature (2020).

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NATURE:单个肿瘤基因的多重突变和功能的关联 

至今为止,有较少的报告描述了在同一肿瘤基因中发生多个驱动突变(MMs)的癌症病例。然而,MMs的整体景观和相关性仍然难以捉摸。

北大肿瘤医院柯杨教授团队基于医保系统大数据构建“癌症发病监测”新模式

该研究创新性地利用南、北方两地区2012-2019年医保系统报销数据,专门针对“癌症新发病例识别”构建了一整套数据脱敏、清洗、质控、判定、分析、报告的流程标准。

Clinica Chimica Acta:通过对25种癌症类型的MSIcall进行靶向测序来确定微卫星的不稳定性状态

在实体肿瘤中微卫星不稳定性(MSI)发生是免疫检查点抑制剂显著反应的预测生物标志物。MSI状态的检测通常是通过PCR-电泳检测(MSI-PCR)和免疫组织化学(IHC)检测错配修复蛋白。

拓展阅读

【今天解读分享】癌症相关性抑郁非药物管理的最佳证据总结

本研究总结的癌症相关性抑郁非药物管理的最佳证据可为医护人员临床指导提供循证依据,建议医护人员根据临床情景应用证据,完善癌症相关性抑郁管理的护理措施。

Nature Methods:从模型到治疗:类器官在癌症研究中的革命性作用

通过光遗传学方法,可以空间和时间控制地激活致癌驱动突变,这些方法结合生物工程支架,为癌症早期阶段的模型提供了前景。

Pharmacol Res:中医药与癌症患者肠道菌群的相互作用:现状与未来展望

回顾了肠道菌群与肿瘤发展之间的关系,包括结直肠癌、肝癌、胃癌、乳腺癌和肺癌。进一步介绍了中药与肠道菌群相互作用的研究现状,重点介绍了其抗肿瘤功效。

Eur J Prev Cardiol:癌症患者心肌损伤与不良长期生存的关系

作为心肌损伤的标志物,hs-cTn与癌症患者较差的长期生存率独立相关,并与全因、心血管和癌症死亡率之间存在较强的关系。

Nat Rev Cancer:重磅综述癌症起源理论

2023年7月24日,英国剑桥大学的研究人员在《自然》子刊(Nature Reviews Cancer)上发表了题为:“癌症自招祸:癌症起源理论”的综述论文。

Cell:综合泛癌蛋白基因组学分析揭示跨越10种癌症类型的7种免疫亚型

该研究使用临床蛋白质组肿瘤分析联合会(CPTAC)的泛癌蛋白质基因组数据集全面表征了来自10种癌症的1056个肿瘤样本的免疫图谱。