粪便微生物移植与免疫检查点抑制剂联合治疗实体瘤的应用研究进展

免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）治疗作为免疫治疗的一项重大临床进步,已被证明可以提高多种类型癌症患者的总生存期。肠道菌群及其代谢产物在调节局部和全身免疫反应中发挥重要功能,因此研究肠道菌群对ICIs治疗的影响显得尤为重要。粪便微生物移植（fecal microbial transplantation,FMT）是从健康人捐献的粪便中分离出粪便菌群,以细菌液或胶囊的形式灌注或者口服移植到患者的肠道中,以取代患者体内不健康的肠道菌群。越来越多的证据证明,FMT在肿瘤治疗领域特别是提高肿瘤免疫治疗效果方面取得了许多进展。全文主要综述FMT与ICIs在治疗实体瘤中的研究进展,并对未来的研究方向进行了展望。     

肠道微生物群与血液肿瘤

近年来宏基因组学测序技术研究发现,肠道微生物群的组成和多样性的变化与血液肿瘤的发生发展有关,肠道微生物群影响造血系统的发育,同时也影响血液肿瘤的预后分层。肠道微生物易位在血流感染中起着重要作用,肠道菌群失调和血流感染影响血液肿瘤的治疗效果,使用益生菌和粪菌移植可恢复肠道菌群的多样性。     

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。     

肠道微生物群稳态与肝细胞癌关系的研究进展

肠道微生物群与宿主形成共生关系，在许多方面对人身体健康是有益。肠道和肝脏的解剖、功能联系密切，肠-肝轴在维持肠道微生物群和肝脏功能的稳态、免疫调节以及营养支持等方面具有重要作用。肠道微生物群稳态的改变会影响胆汁酸代谢，肠屏障的破坏会影响LPS-TLR4的平衡，这些变化在肝细胞癌（HCC）发生发展中发挥重要作用。根据目前的研究进展，利用益生菌、粪便微生物群移植和抗生素治疗等可能是未来有效的HCC预防和治疗策略。     

微生物群在放疗诱导损伤中的作用研究进展

人类的微生物群由细菌、病毒、真菌等微生物组成,它们分布于口腔、鼻腔、肠道、阴道、皮肤等部位,并且对宿主的代谢、免疫、激素和稳态功能有着至关重要影响。它既保护宿主和维持体内平衡,又能够引起炎症和肿瘤发生。微生物群已被发现可以调节某些肿瘤化疗和免疫治疗疗效及不良反应,但尚无肿瘤放疗背景下的大型研究。本文对微生物群与患者放疗反应和损伤变化的联系进行总结,以期为患者制订最佳治疗方案,为放疗及其诱导损伤的预防及治疗提供依据。     

肠道微生物群在肿瘤中的作用和机制研究进展

肠道微生物群参与人类疾病的调控。随着宏基因组学和代谢组学技术的发展,肠道微生物群在癌症中的作用受到了研究者们的重视。相比于健康人群,不同癌症患者肠道微生物群的种类和丰度及其代谢产物存在差别,这提示我们可以借助肠道微生物群检测为癌症无创诊断提供更加敏感且易于被接受的新方法,以期实现癌症的早期诊断。不同的肠道微生物群和其代谢产物可能对肿瘤起着促进或抑制的作用,并且这一过程可能受到饮食、吸烟等其他因素的影响。相比于健康人群,癌症患者的肠道微生物群发生了变化,而这些变化还可以影响癌症患者对化疗或免疫治疗的反应。靶向肠道微生物群为癌症的诊断和治疗提供了新的思路和方法。本文综述了肠道微生物群在癌症中的作用和机制研究进展。     

肿瘤患者脂肪酸营养与肠道微环境的关系

我国恶性肿瘤的发病率和死亡率呈逐年上升趋势。恶性肿瘤，尤其是胃肠道肿瘤的发生和发展与肠道微环境失 调即肠道微生物紊乱密切相关；脂肪酸尤其是必需脂肪酸是人体生长发育及维持生命过程的重要营养物质，肠道微生物介 导胃肠道消化和吸收脂肪酸。脂代谢失调和肠道微生物作用密切关联，引发胃肠道炎症，导致肠道通透性增加，毒素进入 体内，最终产生免疫反应。肠道微生物群通过病原微生物和肿瘤抗原之间的交叉反应，形成T细胞储备和（或）微生物产品， 刺激模式识别受体，从而影响免疫反应的类型和强度。通过对免疫的影响， 微生物群有助于对远处肿瘤的免疫控制或逃逸。 微生物源性代谢产物也可以通过直接细胞自主致癌机制来促进局部肿瘤的发展。恶性肿瘤的防治过程中，应重视脂肪酸营 养和肠道微环境的重要作用。脂肪酸也可以根据患者的需要通过肠外通路提供。晚期恶性肿瘤患者往往伴有营养不良或异 质性。补充ω-3 多不饱和脂肪酸可以改善患者的体质，有助于肿瘤的治疗。通过补充益生菌或移植肠道微生物群，可以矫 正肠道微生物群紊乱，在肿瘤的防治中发挥重要作用。     

肠道微生物群与免疫治疗疗效的关系

摘 要：肠道微生物群是一个极其复杂的群体,因其重要的作用被认为是人体器官或人类的“第二基因组”。肠道微生物群不仅与肠道免疫的关系密切,而且影响了全身免疫系统。近年的研究显示,肠道微生物群可以影响免疫治疗疗效。由于可能导致肠道微生物群失调,因此在接受免疫检查点抑制剂（ICIs）治疗前后应尽量避免使用抗生素;此外,对部分患者进行粪便移植有望提高免疫治疗疗效。基于上述原因,管理肠道微生物群也成为了免疫治疗管理的一个重要内容,肠道微生物群有望成为一个潜在的预测免疫治疗疗效的生物标志物。     

肿瘤内微生物群（组）相关研究进展

肿瘤内微生物群（组）已被证实广泛存在于各类肿瘤内,对肿瘤微环境的形成、调控肿瘤生长均发挥着重要作用,并直接影响药物干预肿瘤的疗效。随着新一代基因测序技术的广泛应用,针对肿瘤内微生物功能和分类的研究日益增温。诸多研究表明不同肿瘤内微生物种属分布不同,且不同种微生物所发挥的促/抑瘤机制不同。针对肿瘤内微生物的编辑技术亦取得了许多成果,有望成为检测与治疗肿瘤的新手段。本文旨在对近年来肿瘤内微生物群（组）相关研究进展加以综述,并展望其应用前景。     

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。     

Fecal microbiota transplantation in cancer management: Current status and perspectives

The human gut is home to a large and diverse microbial community, comprising about 1,000 bacterial species. The gut microbiota exists in a symbiotic relationship with its host, playing a decisive role in the host's nutrition, immunity and metabolism. Accumulating studies have revealed the associations between gut dysbiosis or some special bacteria and various cancers. Emerging data suggest that gut microbiota can modulate the effectiveness of cancer therapies, especially immunotherapy. Manipulating the microbial populations with therapeutic intent has become a hot topic of cancer research, and the most dramatic manipulation of gut microbiota refers to fecal microbiota transplantation (FMT) from healthy individuals to patients. FMT has demonstrated remarkable clinical efficacy against Clostridium difficile infection (CDI) and it is highly recommended for the treatment of recurrent or refractory CDI. Lately, interest is growing in the therapeutic potential of FMT for other diseases, including cancers. We briefly reviewed the current researches about gut microbiota and its link to cancer, and then summarized the recent preclinical and clinical evidence to indicate the potential of FMT in cancer management as well as cancer-treatment associated complications. We also presented the rationale of FMT for cancer management such as reconstruction of intestinal microbiota, amelioration of bile acid metabolism, and modulation of immunotherapy efficacy. This article would help to better understand this new therapeutic approach for cancer patients by targeting gut microbiota.     

The gut microbiome: what the oncologist ought to know

The gut microbiome (GM) has been implicated in a vast number of human pathologies and has become a focus of oncology research over the past 5 years. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation and protection against pathogens. Strong evidence is emerging to support the effects of the GM on the development of some malignancies but also on responses to cancer therapies, most notably, immune checkpoint inhibition. Tools for manipulating the GM including dietary modification, probiotics and faecal microbiota transfer (FMT) are in development. Current understandings of the many complex interrelationships between the GM, cancer, the immune system, nutrition and medication are ultimately based on a combination of short‐term clinical trials and observational studies, paired with an ever-evolving understanding of cancer biology. The next generation of personalised cancer therapies focusses on molecular and phenotypic heterogeneity, tumour evolution and immune status; it is distinctly possible that the GM will become an increasingly central focus amongst them. The aim of this review is to provide clinicians with an overview of microbiome science and our current understanding of the role the GM plays in cancer.Subject terms: Cancer microenvironment, Microbiome     

Race,the microbiome and colorectal cancer

In the past decade, more cancer researchers have begun to understand the significance of cancer prevention, which has prompted a shift in the increasing body of scientific literature. An area of fascination and great potential is the human microbiome. Recent studies suggest that the gut microbiota has significant roles in an individual’s ability to avoid cancer, with considerable focus on the gut microbiome and colorectal cancer. That in mind, racial disparities with regard to colorectal cancer treatment and prevention are generally understudied despite higher incidence and mortality rates among Non-Hispanic Blacks compared to other racial and ethnic groups in the United States. A comprehension of ethnic differences with relation to colorectal cancer, dietary habits and the microbiome is a meritorious area of investigation. This review highlights literature that identifies and bridges the gap in understanding the role of the human microbiome in racial disparities across colorectal cancer. Herein, we explore the differences in the gut microbiota, common short chain fatty acids produced in abundance by microbes, and their association with racial differences in cancer acquisition.     

Differential susceptibility to colorectal cancer due to naturally occurring gut microbiota

Recent studies investigating the human microbiome have identified particular bacterial species that correlate with the presence of colorectal cancer. To evaluate the role of qualitatively different but naturally occurring gut microbiota and the relationship with colorectal cancer development, genetically identical embryos from the Polyposis in Rat Colon (Pirc) rat model of colorectal cancer were transferred into recipients of three different genetic backgrounds (F344/NHsd, LEW/SsNHsd, and Crl:SD). Tumor development in the pups was tracked longitudinally via colonoscopy, and end-stage tumor burden was determined. To confirm vertical transmission and identify associations between the gut microbiota and disease phenotype, the fecal microbiota was characterized in recipient dams 24 hours pre-partum, and in Pirc rat offspring prior to and during disease progression. Our data show that the gut microbiota varies between rat strains, with LEW/SsNHsd having a greater relative abundance of the bacteria Prevotella copri. The mature gut microbiota of pups resembled the profile of their dams, indicating that the dam is the primary determinant of the developing microbiota. Both male and female F344-Pirc rats harboring the Lewis microbiota had decreased tumor burden relative to genetically identical rats harboring F344 or SD microbiota. Significant negative correlations were detected between tumor burden and the relative abundance of specific taxa from samples taken at weaning and shortly thereafter, prior to observable adenoma development. Notably, this naturally occurring variation in the gut microbiota is associated with a significant difference in severity of colorectal cancer, and the abundance of certain taxa is associated with decreased tumor burden.     

粪便菌群移植在癌症治疗中的研究进展

大量研究证明,肠道菌群失衡与人类癌症之间有密切的关系。肠道菌群不仅在维持肠道屏障和代谢营养方面发挥作用,更重要的是,这些微生物有助于调节局部和全身免疫功能,进而参与机体癌症的发病机制。粪便菌群移植(FMT)是一种调节肠道菌群的方法,它的有效机制主要基于有益微生物的增强、微生物组多样性的增加以及正常菌群的恢复。最近有研究表明,以病原体数量明显增加和有益细菌水平相对降低为特征的微生物改变与胃肠道和胃肠道外癌症的发展有关,提示调节肠道菌群是治疗人类癌症具有前景的手段之一。本文围绕FMT在治疗消化系统癌症、非消化系统癌症和癌症相关并发症上的作用展开论述,总结FMT在癌症治疗方面的最新进展。     

Analysis of the fecal metagenome in long-term survivors of pancreas cancer

Background

The 5-year overall survival of pancreas adenocarcinoma (PCa) remains less than 10%. Clinical and tumor genomic characteristics have not differentiated PCa long-term survivors (LTSs) from unselected patients. Preclinical studies using fecal transplant experiments from LTSs of PCa have revealed delayed tumor growth through unknown mechanisms involving the fecal microbiota. However, features of the fecal microbiome in patients with long-term survival are not well described.

Methods

In this cross-sectional study, comprehensive shotgun metagenomics was performed on stool from PCa patients with long-term survival (n = 16). LTS was defined as >4 years from pancreatectomy and all therapy without recurrence. LTSs were compared to control patients with PCa who completed pancreatectomy and chemotherapy (n = 8). Stool was sequenced using an Illumina NextSeq500. Statistical analyses were performed in R with MicrobiomeSeq and Phyloseq for comparison of LTSs and controls.

Results

All patients underwent pancreatectomy and chemotherapy before sample donation. The median time from pancreatectomy of 6 years (4–14 years) for LTSs without evidence of disease compared to a median disease-free survival of 1.8 years from pancreatectomy in the control group. No differences were observed in overall microbial diversity for LTSs and controls using Shannon/Simpson indexes. Significant enrichment of species relative abundance was observed in LTSs for the Ruminococacceae family specifically Faecalibacterium prausnitzii species as well as Akkermansia muciniphila species.

Conclusions

Stool from patients cured from PCa has more relative abundance of Faecalibacterium prausnitzii and Akkermansia muciniphila. Additional studies are needed to explore potential mechanisms by which the fecal microbiota may influence survival in PCa.

Plain Language Summary

• Although pancreatic cancer treatments have improved, the number of long-term survivors has remained stagnant with a 5-year overall survival estimate of 9%.
• Emerging evidence suggests that microbes within the gastrointestinal tract can influence cancer response through activation of the immune system.
• In this study, we profiled the stool microbiome in long-term survivors of pancreas cancer and controls.
• Several enriched species previously associated with enhanced tumor immune response were observed including Faecalibacterium prausnitzii and Akkermansia muciniphila.
• These findings warrant additional study assessing mechanisms by which the fecal microbiota may enhance pancreatic cancer immune response.

     

Gut microbiome in non-alcoholic fatty liver disease associated hepatocellular carcinoma: Current knowledge and potential for therapeutics

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver via the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis via effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.     

The role of the microbiome in cancer development and therapy

Answer questions and earn CME/CNE The human body harbors enormous numbers of microbiota that influence cancer susceptibility, in part through their prodigious metabolic capacity and their profound influence on immune cell function. Microbial pathogens drive tumorigenesis in 15% to 20% of cancer cases. Even larger numbers of malignancies are associated with an altered composition of commensal microbiota (dysbiosis) based on microbiome studies using metagenomic sequencing. Although association studies cannot distinguish whether changes in microbiota are causes or effects of cancer, a causative role is supported by rigorously controlled preclinical studies using gnotobiotic mouse models colonized with one or more specific bacteria. These studies demonstrate that microbiota can alter cancer susceptibility and progression by diverse mechanisms, such as modulating inflammation, inducing DNA damage, and producing metabolites involved in oncogenesis or tumor suppression. Evidence is emerging that microbiota can be manipulated for improving cancer treatment. By incorporating probiotics as adjuvants for checkpoint immunotherapy or by designing small molecules that target microbial enzymes, microbiota can be harnessed to improve cancer care. CA Cancer J Clin 2017;67:326–344. © 2017 American Cancer Society.     

The Role of the Gut Microbiome in Colorectal Cancer: Where Are We? Where Are We Going?

Microbiome (microbiota) is a community of all microorganisms inhabiting a specific site of the body, including pathogens, which distinguishes it from the physiological microflora. Intestinal dysbiosis plays a key role in the development of colorectal cancer. In the process of carcinogenesis, inflammation, immune response, and toxic metabolites play a significant role. Specific species of bacteria might affect the risk of colorectal cancer and growth of tumor already present. Assessment of changes in the intestinal microbiome during the development and progression of colorectal cancer might create a simple diagnostic tool, a useful biomarker, or might influence treatment strategies in colorectal cancer patients. Analysis of the gut microbiome provides the potential to develop noninvasive diagnostic tests that would be useful as new protective markers of colorectal cancer, prognostic markers in already present colorectal cancer, and predictive markers of response to treatment, especially immunotherapy.     

Periodontitis as a Risk Factor for Breast Cancer – What We Know Till Date?

A healthy microbiome is important for human health because it exhibits a variety of functions in the human body wherein the microbiome dysbiosis can lead to a variety of diseases, including cancer. Recent advances in technology and cost reduction of sequencing have made it possible and much easier for researchers to investigate the role of the microbiome in carcinogenesis. Furthermore, modulation of microflora may serve as an effective adjunct to conventional anticancer therapy that is very important to improve the patient’s quality of life. Additionally, microbiome biomarkers can also be used as a diagnostic tool for cancer. So far the association between oral microbial consortia and their interactions with the host in maintaining the human health and the pathogenesis of multiple cancers has gained much popularity in the scientific research community. While the interactions of oral microflora are better established in cancer- like gastric cancer, it is far less understood in others like breast cancer. Therefore, this review briefly outlines the current information on the role of oral microbiota in breast cancer with emphasis on the mechanisms of oral microflora induced carcinogenesis and discusses the emerging role of periodontitis as a risk factor for breast cancer. Clinical relevance; Periodontitis is a very common disease that is characterized by chronic polymicrobial infection and inflammation of gingiva. It might be associated as a risk factor for breast cancer. If this association is validated in large cohort studies, it would serve as a non-invasive biomarker for breast cancer.Key Words: Breast, cancer, microbiome, microflora, oral