目前,有多项临床试验正在开展,涵盖我们前面所介绍的各种方向,这可能会彻底改变未来的癌症治疗范式。
尽管如此,靶向肠道微生物治疗的应用仍然有很多限制和不足。
首先,确定微生物组成时的采样样本和分析方法的不统一,可能会造成研究结果的异质性。
其次,即使是健康人之间,肠道微生物组成也有很大差异,而且我们目前对许多肠道微生物的功能缺乏了解,无法定义“理想菌群”,因此,癌症患者如果想要进行益生菌治疗,需要慎之又慎。
再次,人类的肠道微生物组成更加复杂,动物研究的获益向临床研究获益的转化并不稳定,例如临床试验中,补充鼠李糖乳杆菌GG未能显著改善患者HSCT后的肠道微生物组成,而且相比对照组还发生了更高比例的移植物抗宿主病[26]。
另外,正如前面我们对抗生素的关注一样,饮食作为同样对肠道微生物组成影响较大的因素,也需要被额外关注。由于肿瘤同样需要饮食来源的营养成分,因此饮食辅助治疗也是研究方向之一,例如热量限制、生酮饮食,或是限制特定氨基酸含量的饮食等等,饮食在影响肿瘤的同时也会影响肠道微生物组成,这些影响是否有重叠或冲突?如何更有效地调节肠道微生物和抗肿瘤效果?这些都是重要的亟待解决的问题。
我们都知道,癌症的治疗无法依靠单一疗法获得成功,而是需要多方面的联合治疗。因此,还有许多的可能性值得去探索,例如,将手术、免疫治疗与饮食、益生菌/代谢产物治疗相结合,成为一种新的治疗范式,增强抗肿瘤效果,减少全身毒性,以改善癌症的全程管理。
已购买课程的朋友,
直接进入小程序收听加餐哦~
瞬息 , 交易担保 , 放心买 , 上新啦!《非小细胞肺癌精准治疗前沿10讲》免费加更3讲! 小程序
参考文献:
[1] Liu L, Shah K. The Potential of the Gut Microbiome to Reshape the Cancer Therapy Paradigm: A Review[J]. JAMA oncology, 2022.
[2] Murata-Kamiya N, Kurashima Y, Teishikata Y, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells[J]. Oncogene, 2007, 26(32): 4617-4626.
[3] Wilson M R, Jiang Y, Villalta P W, et al. The human gut bacterial genotoxin colibactin alkylates DNA[J]. Science, 2019, 363(6428): eaar7785.
[4] Drewes J L, Chen J, Markham N O, et al. Human colon cancer-derived Clostridioides difficile strains drive colonic tumorigenesis in mice[J]. Cancer discovery, 2022: candisc. 1273.2021-10-4 15: 58: 09.930.
[5] Goodwin A C, Shields C E D, Wu S, et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis[J]. Proceedings of the National Academy of Sciences, 2011, 108(37): 15354-15359.
[6] Bergounioux J, Elisee R, Prunier A L, et al. Calpain activation by the Shigella flexneri effector VirA regulates key steps in the formation and life of the bacterium's epithelial niche[J]. Cell Host & Microbe, 2012, 11(3): 240-252.
[7] Gur C, Ibrahim Y, Isaacson B, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack[J]. Immunity, 2015, 42(2): 344-355.
[8] Kostic A D, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment[J]. Cell host & microbe, 2013, 14(2): 207-215.
[9] Vétizou M, Pitt J M, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota[J]. Science, 2015, 350(6264): 1079-1084.
[10] Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy[J]. Science, 2015, 350(6264): 1084-1089.
[11] Si W, Liang H, Bugno J, et al. Lactobacillus rhamnosus GG induces cGAS/STING-dependent type I interferon and improves response to immune checkpoint blockade[J]. Gut, 2022, 71(3): 521-533.
[12] Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors[J]. Science, 2018, 359(6371): 91-97.
[13] Derosa L, Hellmann M D, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer[J]. Annals of Oncology, 2018, 29(6): 1437-1444.
[14] Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide[J]. science, 2013, 342(6161): 971-976.
[15] Daillère R, Vétizou M, Waldschmitt N, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects[J]. Immunity, 2016, 45(4): 931-943.
[16] Yu T C, Guo F, Yu Y, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy[J]. Cell, 2017, 170(3): 548-563. e16.
[17] Su W, Chen Y, Cao P, et al. Fusobacterium nucleatum promotes the development of ulcerative colitis by inducing the autophagic cell death of intestinal epithelial[J]. Frontiers in cellular and infection microbiology, 2020, 10: 594806.
[18] Liu Y, Baba Y, Ishimoto T, et al. Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma[J]. British journal of cancer, 2021, 124(5): 963-974.
[19] Wallace B D, Wang H, Lane K T, et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme[J]. Science, 2010, 330(6005): 831-835.
[20] Taur Y, Jenq R R, Perales M A, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation[J]. Blood, The Journal of the American Society of Hematology, 2014, 124(7): 1174-1182.
[21] Jenq R R, Taur Y, Devlin S M, et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease[J]. Biology of Blood and Marrow Transplantation, 2015, 21(8): 1373-1383.
[22] Peled J U, Devlin S M, Staffas A, et al. Intestinal microbiota and relapse after hematopoietic-cell transplantation[J]. Journal of Clinical Oncology, 2017, 35(15): 1650.
[23] Wang Q, Fu Y W, Wang Y Q, et al. Fecal microbiota transplantation for patients with refractory diarrhea after allogeneic hematopoietic stem cell transplantation[J]. Zhonghua xue ye xue za zhi= Zhonghua Xueyexue Zazhi, 2019, 40(10): 853-855.
[24] van Praagh J B, de Goffau M C, Bakker I S, et al. Mucus microbiome of anastomotic tissue during surgery has predictive value for colorectal anastomotic leakage[J]. Annals of Surgery, 2019, 269(5): 911-916.
[25] Valdez J C, Peral M C, Rachid M, et al. Interference of Lactobacillus plantarum with Pseudomonas aeruginosa in vitro and in infected burns: the potential use of probiotics in wound treatment[J]. Clinical microbiology and infection, 2005, 11(6): 472-479.
[26] Gorshein E, Wei C, Ambrosy S, et al. Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation[J]. Clinical Transplantation, 2017, 31(5): e12947.
本文作者丨应雨妍