肠道微生物菌群在肿瘤不同疗法中的研究进展#br#

肠道微生物菌群由共生细菌和生活在宿主肠道上皮的其他微生物组成,影响多种生理功能,如维持肠道上皮内稳态及调节新陈代谢、炎症和免疫力等。肠道微生物菌群也参与肿瘤的发生发展和转移。肠道微生物菌群能够影响机体对肿瘤治疗的效果及毒副作用的敏感性。在肿瘤治疗中,肠道微生物菌群与手术、化疗、放疗和免疫治疗等有着密切关系,有可能成为精准医疗和个性化医疗的前沿方向之一。本文就肠道微生物菌群在肿瘤不同疗法中的研究进展作一简要综述。     

肠道菌群在肿瘤免疫治疗中的作用研究进展

肠道微生物与肿瘤发生、发展关系密切。机体暴露于大量肠道菌群及其代谢产物中,构成机体的生态环境,肠道微生物通过多种途径参与肿瘤的发生与发展。肠道菌群在肿瘤的治疗中发挥重要作用。目前,肿瘤免疫检测点抑制剂在多种恶性肿瘤中的治疗取得重要突破,肠道微生物组对肿瘤免疫治疗,尤其是免疫检测点抑制剂的疗效产生重要影响。本文就近年来肠道菌群对肿瘤免疫治疗中的作用及影响展开综述,为免疫检测点抑制剂在肿瘤治疗中的应用提供参考。      

肠道菌群与恶性肿瘤的研究进展

人类微生物群是由寄生在人体上皮屏障的细菌和其他微生物组成的，其中大部分位于肠道内，与宿主之间形成共生的关系。机体肠道微生物的组成虽然受到年龄、饮食、生活方式等因素的影响，但在正常生理情况下是相对稳定的。近年来，肠道菌群与恶性肿瘤的关系越来越受到重视。肠道菌群不但能够维持局部稳态，还能调节机体代谢、炎症和免疫等生理过程。有研究表明，微生物群，特别是肠道菌群能够显著调节机体对癌症治疗的反应性以及机体对毒副反应的敏感性。检查肠道菌群中各菌种之间的比例可作为筛查恶性肿瘤的新方法。本文将综述微生物群具有影响肿瘤的发生发展、抗肿瘤治疗疗效以及药物不良反应的证据，以及其中所涉及的微生物种类，从而为恶性肿瘤精准治疗提供证据。     

肠道菌群对肿瘤放疗的影响

肠道微生物群具有多种生理功能,在宿主健康和肠道内环境稳定中起着关键作用。肿瘤的放疗会导致肠道菌群紊乱、免疫失调,引起急慢性炎症。同时,肠道菌群及其代谢物会影响放疗的效果和不良反应发生。现已发现应用益生菌、抗生素、粪便移植、菌群代谢物等改变宿主肠道菌群的方法具有预防和治疗放射性肠炎、增加放射敏感性及增强放疗效果的作用。文章就肠道菌群对肿瘤放疗的影响进行综述。     

肠道菌群影响肿瘤对免疫检查点抑制剂的应答及其机制

人类肠道菌群种类超过1000种,是人体内最庞大的微生物群,被称为"被遗忘的器官"。肠道菌群易受多种因素影响。已有多项研究证明肠道菌群及其代谢产物参与宿主免疫构建和影响肿瘤微环境,与肿瘤对免疫检查点抑制剂(immune checkpoint inhibitor,ICI)的应答和ICI治疗相关不良反应的发生有关。随着人类微生物组计划的开展和测序分析技术的进步,肠道菌群的相关研究逐步深入,基因功能注释和代谢组学分析的成熟和推广丰富了肠道菌群与宿主免疫及免疫治疗间的探索维度,干预和塑造肠道菌群为提高肿瘤免疫治疗效果提供了新的思路。然而,微生物制品的食源性添加、粪菌移植等研究尚未获得足够证据,肠道菌群的免疫调控机制尚不完全清楚。本文就近年来肠道菌群影响肿瘤对ICI应答机制的研究进展作一综述。     

肠道菌群影响肿瘤免疫治疗的机制及临床应用研究进展

肿瘤免疫治疗是继手术、化疗、放疗后的第四种疗法，在部分上皮性肿瘤和血液性肿瘤的治疗中取得较大突破，但不良反应常见甚至比较严重，在部分实体肿瘤中的应答率也不够理想。随着基因组学和代谢组学技术的成熟，人们逐渐认识到肠道菌群在肿瘤发展与治疗中的作用。菌群可能通过调节宿主免疫系统和肿瘤微环境等方式影响肿瘤免疫，部分细菌通过激活免疫起到协助对抗肿瘤的作用，而有些细菌则介导免疫抑制帮助癌细胞逃避免疫系统的杀伤。越来越多的研究揭示肿瘤免疫治疗的效果和并发症与患者肠道菌群组成有关，对治疗敏感或易发生不良反应的患者肠道菌群组成有一定特征。这些特征可能作为生物标志物来预测免疫治疗的预后，也可能被开发为“免疫增效剂”（如Akk菌和双歧杆菌）来辅助免疫治疗。部分临床和临床前研究已证明包括菌群移植在内的微生物干预能一定程度上提高免疫治疗的敏感性或减轻不良反应。随着基因编辑技术和纳米技术的发展，有助于免疫治疗的工程细菌的设计开发成为了新的研究热点。基于肠道菌群和免疫治疗的关系，正确挖掘微生物信息、开发合理可行的微生物干预手段，有希望在很大程度上优化肿瘤免疫疗法，为肿瘤治疗带来新的突破。     

肠道菌群对肿瘤治疗的影响

肠道菌群是寄居在人体肠道内的正常微生物群落,维持着宿主肠道微生态的稳态,肠道微生态失调促进肿瘤的发生,但特异的肠道共生菌及其代谢产物可能抑制肿瘤的发生。肠道菌群对宿主固有免疫和适应性免疫系统的成熟与调节具有重要作用,其可增强烷化剂、Toll 样受体（Toll-like receptor,TLR ）激动剂、免疫检验点抑制剂、过继性细胞免疫治疗等的抗肿瘤作用。肠道菌群主要通过调节肿瘤浸润髓源细胞的分化和功能影响抗肿瘤免疫反应,重新编程肿瘤浸润髓源细胞可能是一种理想的肿瘤治疗方法。肠道菌群为肿瘤治疗提供了新的策略,但其临床应用还面临着较多问题。本文就肠道菌群对肿瘤的发生和肿瘤治疗的有益影响进行综述。      

粪菌移植治疗肿瘤的研究进展

人体上皮表面存在微生物群，由共生细菌和其他微生物组成，产生的小分子和代谢物影响肿瘤的治疗反应。粪便微生物群移植（fecal microbiota transplant，FMT）是指将一个患者的粪便微生物移植到其他患者，成为肿瘤治疗的新策略。FMT通过重构肠道微生物群和提高抗肿瘤免疫反应而用于肿瘤临床治疗，其发展也经历了动物模型、人类向动物、患者间和编辑微生物群的粪菌移植等阶段。合成生物学编辑和合成新的菌群将为FMT提供新的材料。      

益生菌在肿瘤免疫治疗中的研究进展

肿瘤免疫治疗是利用免疫系统、恢复机体正常的抗肿瘤免疫反应,从而控制与清除肿瘤的一种治疗方法。肠道菌 群能够与宿主相互作用,共同维持机体的稳态与宿主健康,在人体生理活动过程中发挥着重要作用。肠道菌群影响肿瘤的发 生、发展,各类肿瘤患者肠道菌群的紊乱情况及潜在机制也逐渐被解析。同时在肿瘤免疫治疗过程中,患者肠道菌群也发挥了 重要作用,对免疫反应的调控也会直接影响肿瘤治疗效果。人为干预改变肠道菌群可作为提高肿瘤免疫治疗效果,实现肿瘤 精确和个性化治疗的新策略,单独或与常规免疫治疗联用,干预手段有抗生素、益生菌等。其中益生菌作为一类安全有效的微 生态制剂,在干预肠道菌群进行肿瘤免疫治疗方面具有较大的发展潜力,但仍需要更多临床数据支持及机制探讨。本文介绍 了肠道微生物组与肿瘤发生、发展的关系及其相关机制,并对益生菌在肿瘤免疫治疗中的研究进展进行探讨,为益生菌的应用 及益生菌干预肠道菌群影响宿主健康的机制研究提供理论支持。     

肿瘤组织中微生物群与肿瘤关系的研究进展

人体微生物群由人体内部和表面的微生物组成。宿主和微生物之间的相互作用影响了多个生理过程和致病因素。由于肠道菌群的丰富度和多样性,既往多数研究聚焦于肠道菌群并发现其对恶性肿瘤的发生发展和治疗反应具有重要作用,但对其他身体部位的微生物群在肿瘤中的作用了解较少。近十年来,由于16S rRNA基因测序技术的发展应用,越来越多的学者发现在许多类型的肿瘤中,瘤内菌具有肿瘤特异性,局部微生物群成为肿瘤微环境的重要组成部分。相关研究表明肿瘤相关的微生物群可能直接调控肿瘤的发生、进展及影响治疗效果。本文就肿瘤组织中微生物群及其对疾病发生发展和诊断治疗的影响进行综述。     

肠道菌群微生态与结直肠癌的研究进展

近年来中国结直肠癌的发病率逐年升高,已成为最常见的消化道恶性肿瘤之一。随着分子生物学及宏基因组学的深入研究,发现肠道菌群微生态及其代谢模式的改变可通过破坏正常组织细胞DNA、激活致癌信号传导途径,产生促肿瘤代谢物和抑制抗肿瘤免疫反应等多因素来影响结直肠癌的发生和发展。因此,研究者们尝试利用微生态制剂治疗和预防肿瘤。目前,以益生菌和排泄物移植技术为代表的微生态制剂可调节肠道菌群微生态,诱导结直肠癌细胞凋亡和细胞周期阻滞,分泌抗肿瘤细胞因子及调节免疫系统来抗肿瘤。微生态制剂为结直肠癌患者带来了希望,但目前肠道菌群微生态在结直肠癌中的具体作用机制仍不明确,仍需进一步的大样本研究深入探讨。本文就肠道菌群微生态与结直肠癌的研究进展进行综述,以期为结直肠癌的诊治探索新的方法。      

Intestinal microflora and cancer prevention

Based on the results of ecological studies of intestinal microflora, we have been studying from various perspectives, the relationship between health and intestinal microflora. Concerning intestinal microflora and cancer, we reported in Cancer Research (61: 2395-2398, 2001) that spontaneous colon cancers that developed in Tcr beta/p53-double knockout mice did not develop in germfree conditions. This study, catching the attention of researchers, was reviewed in the 'News Feature' column of Nature (415: 8-9, 2002), which introduces recent studies attracting significant attention. Cancers are diseases of genes. However, in this study, which Nature found to be an as intriguing transformation (development of colon cancer in this case), did not occur only by genetic changes, unless accompanied by environmental factors (intestinal flora in this case). The fact that intestinal microflora are involved in the development of colon cancer suggests, on the other hand, that cancers can be prevented by controlling intestinal microflora. Here, data will be presented to show the relationship between intestinal microflora and colon cancers, mainly from our studies, and the mechanism involved will be further discussed.     

Chemotherapy-induced mucositis: the role of gastrointestinal microflora and mucins in the luminal environment

Collectively, mucositis refers to the damage caused to the mucous membranes of the body following cytotoxic cancer therapy. Diarrhea is one such manifestation of mucositis and is a common side effect of chemotherapy that remains poorly understood. It affects the entire gastrointestinal tract. The exact number of patients affected by diarrhea as a result of treatment is uncertain, although it is believed that approximately 10% of patients with advanced cancer will be affected. Despite advances in the understanding of oral and small intestinal mucositis over recent years, large intestinal mucositis, including diarrhea, has not been well defined, and the underlying mechanisms of the condition have yet to be established. The majority of the literature concerning diarrhea is based on clinical observations, with little basic research. However, from the research conducted, it is likely that the intestinal microflora play a role in the development of chemotherapy-induced diarrhea. This review will examine in detail what is known about the mechanisms of chemotherapy-induced diarrhea and will explore the potentially important relationship among intestinal microflora, the luminal environment, and the subsequent development of chemotherapy-induced diarrhea.     

Biological activities of the intestinal microflora in mice treated with antibiotics or untreated and the effects of the microflora on absorption and metabolic activation of orally administered glutathione conjugates of K-region epoxides of 1-nitropyrene

To elucidate the effects of the intestinal microflora on absorptionand activation of glutathione conjugates of 4,5-epoxy-4,5-dihydro-1-nitropyrene(1-NP 4,5-oxide) and 9,10-epoxy-9,10-dihydro-1-nitropyrene (1-NP9,10-oxide), we investigated the biological activities of themicroflora in specific-pathogen-free (SPF) mice and SPF micetreated with various antibiotics and established the methodologyof antibiotic treatment to eliminate the intestinal microflora.Mice were given various kinds of antibiotics by intragastricgavage twice a day for five days. A mixture of antibiotics bacitracin(BC), neomycin (NM) and streptomycin (SM) was the most effectivein reducing the various activities of the intestinal microflora.The treatment decreased the bacterial counts and the activitiesof enzymes of the intestinal contents cysteine conjugate ß-lyase(ß-lyase), ß-glucuronidase and nitroreductasewhich were derived from the intestinal microflora, but did notaffect the activities of     

肠道菌群与结直肠癌关系研究进展*

人体肠道菌群代谢成分通过与受体结合、刺激炎症因子分泌，与其他变化一起，引起炎症反应，最终导致结直肠癌（colorectal cancer ，CRC ）的发生。而肠道内的益生菌则通过屏障作用、抑制DNA 损伤等机制保护肠道黏膜，抵御CRC 的发生，并可被用于预防及辅助治疗CRC 。胃肠道手术可以影响肠道菌群的代谢，影响微生态平衡。本文将针对肠道菌群与结直肠癌关系的最近进展进行综述。      

Probiotics, prebiotics and synbiotics: a role in chemoprevention for colorectal cancer?

Colorectal cancer (CRC) is the third most common form of cancer. Current treatments including chemotherapy, radiotherapy and surgery are all associated with a high risk of complications and are not always successful, highlighting the need to develop new treatment strategies. The ingestion of probiotics, prebiotics or combinations of both (synbiotics) represents a novel new therapeutic option. Probiotics and prebiotics act to alter the intestinal microflora by increasing concentrations of beneficial bacteria such as lactobacillus and bifidobacteria, and reducing the levels of pathogenic micro-organisms. This strategy has the potential to inhibit the development and progression of neoplasia via mechanisms including; decreased intestinal inflammation, enhanced immune function and anti-tumorigenic activity, binding to potential food carcinogens including toxins found in meat products, and a reduction in bacterial enzymes which hydrolyse precarcinogenic compounds, such as beta-glucuronidase. There is substantial experimental evidence to suggest that probiotics and prebiotics may be beneficial in the prevention and treatment of colon cancer, however to date there have been few conclusive human trials. Probiotics and prebiotics have the potential to impact significantly on the development, progression and treatment of colorectal cancer and may have a valuable role in cancer prevention.     

中药调节肠道菌群改善肿瘤恶液质作用的研究进展

肠道菌群与肿瘤相关性的研究目前仍是临床上一个值得期待的研究热点。肠道菌群失调与肿瘤恶液质的发生发展有着重大的联系。运用中药调节肠道菌群可以作为肿瘤放化疗后的辅助治疗，对机体的免疫调节起着很重要的作用，而肿瘤恶液质的发生与发展一定程度上会受到肠道菌群的影响，在肿瘤恶液质的防治中肠道菌群也起到了重要作用。从另一方面来讲，肿瘤恶液质的发生也会造成机体肠道菌群的失调，对于这种情况，用中药来对肠道菌群失调来进行调节，在一定程度上对肿瘤恶液质起到改善作用，通过中药调节肠道菌群对肿瘤恶液质的影响来探索中药、肠道菌群失调以及肿瘤恶液质三者之间的关系是本文所要阐述的，目的是促进祖国医学在肿瘤治疗方面发挥更大的效用，充分发挥中医的特色优势，尽早攻克肿瘤这个医学难题。     

Hypothesis: is antibiotic use associated with breast cancer?

The hypothesis that antibiotic use may increase cancer risk was first proposed several decades ago and some research suggests an increased risk of breast cancer among women with conditions likely to require long-term antibiotic use (e.g., acne, recurrent urinary-tract infections, UTI). However, this hypothesis has not been verified and the possible biological mechanisms are not entirely clear. A recent cohort study in Finland reported an increased risk of breast-cancer associated with antibiotic use for UTI. The effect of antibiotics on the ability of intestinal microflora to metabolise phytochemicals from edible plants into compounds that may protect against cancer was proposed as a potential mechanism. We extend this hypothesis by proposing that antibiotic use may be associated with breast-cancer risk through effects on immune and inflammatory factors, such as cytokines, T lymphocytes, prostaglandins, and matrix metalloproteinases, as well as disruption of phytochemical and oestrogen metabolism by intestinal microflora. We suggest that some mechanisms may increase breast-cancer risk, while others may decrease risk, depending on the antibiotic classification.