肠道菌群与结直肠癌发生及中医药调节作用的研究现状

人类肠道菌群是一个复杂的微生态体系,具有抗炎、抗菌、免疫、神经、营养、代谢等多方面作用。结直肠癌（colorectal cancer,CRC）是人体常见的消化道恶性肿瘤,研究表明,肠道菌群失调与CRC的发生发展密不可分,而中医药作为我国医疗体系中一个特色治疗技术,在通过调节肠道菌群达到抗肿瘤作用方面发挥着显著作用。本文就肠道菌群与CRC的发生关系以及中医药调节作用加以综述,为中医药调节肠道菌群并防治CRC提供依据。     

肠道菌群失衡和结直肠癌关系的研究进展

结直肠癌是最常见的恶性肿瘤之一,发病率逐年上升.研究表明肠道菌群失衡在结直肠癌的发生中可能发挥重要作用,肠道菌群可能通过肠道黏膜屏障受损、慢性炎症反应、细菌酶和毒性代谢产物作用等多种机制促进肿瘤的发生.近年来通过无菌动物实验、基因敲除动物实验以及新一代的高通量测序使人们对肠道菌群和大肠癌间关系的认识不断深化,继而从不同角度提出肠道菌群失衡导致结直肠癌发病的作用模式,本文将结合相关作用模式从肠道菌群先后影响结直肠癌不同发病阶段的角度阐述结直肠癌发生、发展过程中的相关机制,为进一步认识结直肠癌的发病机制和结直肠癌的早期诊疗提供新的思路.     

高脂饮食、肠道菌群代谢与结直肠癌

结直肠癌是全球常见恶性肿瘤之一,在西方国家尤其常见。饮食是结直肠癌的重要影响因素之一。近年来,随着 我国社会经济的不断发展,结直肠癌发病率出现了逐年上升以及年轻化的现象,推测可能与西方高脂饮食流行、肥胖、运动缺 乏等因素相关。高脂饮食与结直肠癌的发生发展紧密相关。高脂饮食可引起肠道菌群结构改变,具体表现为肠道微生态多样 性的下降,以及拟杆菌属菌丰度降低和厚壁菌门细菌的富集,同时还可对肠道菌群代谢产生重要影响,产生大量次级胆汁酸、 脂肪酸和硫化物衍生物等。其中,过量的次级胆汁酸具有促进结直肠肿瘤发生发展的作用。次级胆汁酸可引起肠道上皮细胞 DNA损伤,加剧炎症反应,同时还可促进肠道类干性样细胞‐Lgr5（+）细胞的增殖,从而促进结直肠癌的发生发展。本文将围绕 高脂饮食对结直肠癌发生发展的影响、膳食脂肪对肠道菌群的影响、膳食脂肪对肠道菌群代谢的影响,以及结直肠癌的饮食预 防进行介绍和讨论。     

膳食模式、肠道菌群与结直肠癌

结直肠癌是一种发病率和致死率均极高的肿瘤疾病,其发生和发展由基因、环境、生活方式等多方面因素共同决 定,并往往伴随着肠道微环境的改变。膳食成分是调节肠道微环境的重要因素。现阶段,越来越多的研究关注了饮食模式、膳 食成分和结直肠癌间的关系。本文首先讨论了不同膳食模式对结直肠癌发生风险的影响,证明了西方饮食可能促进结直肠癌 的发生,而地中海饮食、能量限制饮食、素食饮食和生酮饮食对结直肠癌具有一定的预防和干预作用。进一步分析了各类膳食 成分如何通过直接作用或通过调节肠道菌群间接影响了结直肠癌的发生发展。其中,多酚类物质、胡萝卜素、膳食纤维等,可 以维持肠道稳态,改善肠道内炎症及氧化应激等,从而降低结直肠癌的发病风险。而特定膳食成分的缺失或过剩则可以改变 肠道微生物组成,诱导肿瘤相关微生物丰度的升高,造成有毒代谢产物的积累,进而促进肠道炎症和肿瘤的发生。最后,本文 提出了一套针对结直肠癌患者的个性化饮食干预策略思路。利用宏基因组、宏转录组、代谢组等多组学手段,结合人工智能分 析结直肠患者菌群组成及功能上的异常,进一步设计个性化的膳食模式,以实现患者肠道菌群的精准调节,并对结直肠癌患者 进行膳食干预。     

炎症相关结直肠癌致病因素分析

全球每年有超100万例结直肠癌（colorectal cancer,CRC）新诊断病例。CRC是世界第三大常见恶性肿瘤及第四大常见癌症死亡原因。炎症相关结直肠癌（colitis associated cancer,CAC）是CRC的主要临床类型之一,患有长期炎症性肠病（inflammatory bowel disease,IBD）患者发生CAC的风险显著增加,这可能与慢性炎症的累积密切相关。本文就遗传性基因突变,慢性炎症与免疫,肠道菌群丰度及产物变化三种致病因素分析,了解三种因素相互作用关系对CAC发病机制的影响,对理解炎症环境下肿瘤发生具有重要意义。     

中药防治肠道菌群相关性结直肠癌的研究进展

结直肠癌发病率和死亡率居我国全部恶性肿瘤的第 3 和第 5 位,严重威胁居民健康。结直肠癌病因复杂,其中 肠道微生态是影响癌变过程的关键环节。肠道菌群是维持人体胃肠道及机体健康的重要因素,肠道微生物病原体在结直肠 癌发病机制包括微生物代谢、宿主免疫和炎症途径的调节、氧化应激与抗氧化防御调节、细菌基因毒素等环节。传统中药 给药方式主要为口服,中药进入胃肠道后不可避免与肠道微生物发生相互作用。中药主要通过调节肠道菌群结构,从而调 节宿主免疫功能,以及氧化应激与抗氧化防御调节等途径实现防治结直肠癌的作用。实验研究证实,中药对肠道微生态系 统的平衡具有很好的保护作用,对菌群失调具有改善作用;中药可以提高宿主抗癌免疫反应以及通过调节肿瘤微环境下的 骨髓来源的细胞功能发挥抗肿瘤疗效;促进有氧培养菌的耐酸能力并抑制了厌氧培养菌的耐酸能力,从而增强了整体肠道 菌群的抗氧化性。另外,中药亦能改善微生物的代谢、减轻代谢性炎症,以及抑制产生大肠杆菌的体外和体内基因毒性, 中草药的药效成分经肠道微生物转化后发挥抗炎、镇痛和抗肿瘤等药理作用。综上,肠道菌群在部分结直肠癌的发生发展 中具有重要作用,调节肠道菌群是中医药防治结直肠癌的重要靶标。     

胆囊疾病与结直肠腺瘤及结直肠癌关系的研究进展

在中国,结直肠癌（CRC）的发病率较高,疾病负担较为严重。胆囊疾病（包括胆囊结石、胆囊息肉、胆囊切除术后状态）在临床中较为常见,近几年来,大量研究认为胆囊疾病与CRC及结直肠腺瘤（CRA）有关,但也存在争议。胆囊结石及胆囊息肉与结直肠肿瘤之间的关系可能与它们存在共同的危险因素有关,例如肥胖、脂代谢异常、高龄等,有学者提出胆囊疾病可能通过影响胆汁酸代谢、微生物菌群改变及炎症反应等促进结直肠肿瘤的发生发展。本文就胆囊疾病与CRA和CRC关系的研究进展及可能存在的机制进行综述。     

肠道菌群与结直肠癌关系及其研究技术进展

结直肠癌是常见的肿瘤之一,在中国肿瘤发病率中排名第三。肠道菌群对肿瘤增殖、存活、转移与肿瘤发生都产生 重要影响,特别是肿瘤微环境中的代谢物可以刺激炎症细胞诱导慢性炎症反应。肠道菌群会影响机体和调节结直肠甚至整个 消化系统的生理功能,这与结直肠癌有着密切的关系。目前测序技术和细菌‐宿主机制相互作用是研究肠道菌群和结直肠癌 的主要方法,测序技术可以快速大量的对粪便样本进行菌群的种类、基因和功能上的分析,细菌‐宿主相互作用技术可以从实 验角度研究细菌对疾病发生发展的机制,更精准地确定肠道菌群和结直肠癌的关系。但DNA提取差异、引物偏差、测序深度, 以及细菌菌株差异、未知细菌的影响等都制约着研究的进展。随着研究技术的发展,培养组学以及肠道类器官技术为肠道菌 群和结直肠癌关系研究带来了新的技术和方法,一定程度上弥补了测序技术和实验技术的不足。本文就针对肠道菌群和结直 肠癌关系的研究技术展开综述,讨论了其研究进展及发展方向。     

肠道微生物在结直肠癌发生发展及诊疗中作用的新进展

肠道生态系统的改变会影响人类的健康，甚至引发结直肠癌。大量证据表明，在结直肠癌患者的肠道中普遍存在一种病理性微生物群失衡状态。本综述从免疫与炎症反应、肠道微生物代谢产物和基因损伤三个方面总结了肠道微生物引发结直肠癌的机制，介绍了肠道微生物群相关的结直肠癌诊断标志物，分析了肠道微生物在结直肠癌放化疗及免疫治疗中的新进展,希望为结直肠癌的防治及诊疗提供新的机会。     

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。      

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.     

The role ofantioxidants andpro-oxidants in colon cancer Stone WL,Krishnan K,Campbell SE,Palau VE简

This review focuses on the roles antioxidants and pro-oxidants in colorectal cancer (CRC). Considerable evidence suggests that environmental factors play key roles in the incidence of sporadic CRC. If pro-oxidant factors play an etiological role in CRC it is reasonable to expect causal interconnections between the well-characterized risk factors for CRC, oxidative stress and genotoxicity. Cigarette smoking, a high dietary consumption of n-6 polyunsaturated fatty acids and alcohol intake are all associated with increased CRC risk. These risk factors are all pro-oxidant stressors and their connections to oxidative stress, the intestinal microbiome, intestinal microfold cells, cyclooxygenase-2 and CRC are detailed in this review. While a strong case can be made for pro-oxidant stressors in causing CRC, the role of food antioxidants in preventing CRC is less certain. It is clear that not every micronutrient with antioxidant activity can prevent CRC. It is plausible, however, that the optimal food antioxidants for preventing CRC have not yet been critically evaluated. Increasing evidence suggests that RRR-gamma-tocopherol (the primary dietary form of vitamin E) or other “non-alpha-tocopherol” forms of vitamin E (e.g., tocotrienols) might be effective. Aspirin is an antioxidant and its consumption is linked to a decreased risk of CRC.     

Genetic heterogeneity of colorectal cancer and the microbiome

In 2020, the International Agency for Research on Cancer and the World Health Organization’s GLOBOCAN database ranked colorectal cancer(CRC) as the third most common cancer in the world. Most cases of CRC(> 95%) are sporadic and develop from colorectal polyps that can progress to intramucosal carcinoma and CRC. Increasing evidence is accumulating that the gut microbiota can play a key role in the initiation and progression of CRC, as well as in the treatment of CRC, acting as an important met...     

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

Colorectal cancer (CRC), a complex multi-step process involving progressive disruption of homeostatic mechanisms controlling intestinal epithelial proliferation/inflammation, differentiation, and programmed cell death, is the third most common malignant neoplasm worldwide. A number of promising targets such as inducible nitric acid (iNOS), cyclooxygenase (COX)-2, NF-E2-related factor 2 (Nrf2), Wnt/β-catenin, Notch and apoptotic signaling have been identified by researchers as useful targets to prevent or therapeutically inhibit colon cancer development. In this review article, we aimed to explore the current targets available to eliminate colon cancer with an update of dietary and non-nutritional compounds that could be of potential use for interaction with regulatory molecules to prevent CRC.     

Immunomodulatory properties of CNF1 toxin from E. coli: implications for colorectal carcinogenesis

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. The risk of developing CRC is influenced by both environmental and genetic factors. Recently, chronic inflammation and gut microbiota modifications have been associated with increased CRC risk. Escherichia coli belongs to the commensal intestinal flora and can become highly pathogenic following the acquisition of genes coding for virulence factors, such as the cytotoxic necrotizing factor type 1 (CNF1). Numerous reports highlight that, besides exerting direct effects on epithelial cells, CNF1 can also act on immune cells, modulating their responses and possibly contributing to disease development. In the present review, we summarized the key studies addressing the immunomodulatory functions of CNF1 and discussed the contribution that CNF1 can bring about to CRC through the creation of a pro-inflammatory microenvironment.     

Microbiota regulation in constipation and colorectal cancer

The relevance of constipation to the development and progression of colorectal cancer (CRC) is currently a controversial issue. Studies have shown that changes in the composition of the gut microbiota, a condition known as ecological imbalance, are correlated with an increasing number of common human diseases, including CRC and constipation. CRC is the second leading cause of cancer-related deaths worldwide, and constipation has been receiving widespread attention as a risk factor for CRC. Early colonoscopy screening of constipated patients, with regular follow-ups and timely intervention, can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC. As an important regulator of the intestinal microenvironment, the gut microbiota plays a critical role in the onset and progression of CRC. An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression, with alterations inducing changes in the expression of host genes, metabolic regulation, and local and systemic immunological responses. Furthermore, constipation greatly affects the composition of the gut microbiota, which in turn influences the susceptibility to intestinal diseases such as CRC. However, the crosstalk between the gut microbiota, constipation, and CRC is still unclear.     

Clusterin,a gene enriched in intestinal stem cells,is required for L1-mediated colon cancer metastasis

Hyperactive Wnt signaling is a common feature in human colorectal cancer (CRC) cells. A central question is the identification and role of Wnt/β-catenin target genes in CRC and their relationship to genes enriched in colonic stem cells, since Lgr5+ intestinal stem cells were suggested to be the cell of CRC origin. Previously, we identified the neural immunoglobulin-like adhesion receptor L1 as a Wnt/β-catenin target gene localized in cells at the invasive front of CRC tissue and showed that L1 expression in CRC cells confers enhanced motility and liver metastasis. Here, we identified the clusterin (CLU) gene that is also enriched in Lgr5+ intestinal stem cells, as a gene induced during L1-mediated CRC metastasis. The increase in CLU levels by L1 in CRC cells resulted from transactivation of CLU by STAT-1. CLU overexpression in CRC cells enhanced their motility and the reduction in CLU levels in L1 overexpressing cells suppressed the ability of L1 to confer increased tumorigenesis and liver metastasis. Genes induced during L1-mediated CRC cell metastasis and enriched in intestinal stem cells might be important for both CRC progression and colonic epithelium homeostasis.     

调节性T细胞在结直肠癌发生发展中的作用及相关治疗

调节性T细胞（regulatory T cell,Treg）是肿瘤微环境中重要的免疫抑制性细胞,在维持免疫稳态方面发挥重要的作用。Treg不仅可以通过分泌抑制性细胞因子阻碍有效的抗肿瘤免疫,还可以通过调节细胞因子进而调控结直肠癌（colorectal cancer,CRC）细胞生长,同时直接或间接地促进CRC血管新生,并与患者不良预后有关;但Treg也可能在炎症相关性肿瘤发生的早期,通过抑制炎症反应降低肠道肿瘤发生的风险。近年来,靶向Treg的免疫治疗也成为了研究热点,一些治疗策略已经在临床应用,还有一些正在进行临床前及临床试验。本文就Treg在CRC发生发展中的作用及靶向Treg的免疫治疗策略进行综述,探讨Treg作为治疗靶点的作用机制及临床应用前景。