Colorectal carcinogenesis in germ-free and conventionally reared rats: different intestinal environments affect the systemic immunity

Intestinal microbiota are considered to play an important role both in colorectal tumor development and in the modulation of mucosal immunity. Studies on animals reared in germ-free (GF, without intestinal microbiota) versus conventional (CV, with regular microbiota colonization of the bowel) conditions can aid in clarifying the influence of bacteria on carcinogenesis and the anticancer immune response. The capability of the intestinal environment to modulate anticancer immunity not only at the mucosal but also at the systemic level is still an open question. In our study we found that, following the same protocol of colorectal cancer induction, GF rats developed less and smaller tumors than CV rats. The GF rats that did not develop cancer also presented a better anticancer immune response with an increase in NK, NKT, CTL, B cells and cytotoxicity in peripheral blood. We hypothesize that the lower antigenic challenge and the absence of the 'physiological inflammation', caused by the commensal microbiota in the gut of CV rats, may enhance the capability of the GF rats to develop more efficacious anticancer immune responses. The different levels of tolerance/regulatory mechanisms in GF versus the CV animals may modulate the anticancer response not only at the mucosal but also at the systemic immunity level.     

肠道菌群在肿瘤进程中的作用及其临床研究进展

肠道菌群在调控宿主的生长、发育、营养代谢以及免疫稳态方面具有重要的作用.近年来研究发现,肿瘤患者,特别是结直肠癌患者的肠道菌群多呈现失调的状态,而肠道菌群失调能够通过影响肠道代谢、肠道稳态以及肠道免疫等方面促进或者抑制肿瘤的发生发展.目前,通过干预肠道菌群来进行肿瘤治疗的临床实践已经显示出了良好的疗效和巨大的潜能.本文主要论述肠道菌群在肿瘤发生发展进程中的作用及其机制,以及目前利用肠道菌群治疗肿瘤的相关临床研究进展.     

肠道微生物群衍生的代谢产物调控结直肠癌的新进展

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,失衡的微生物群衍生的代谢产物也会影响结直肠癌的发生发展。本文综述了由特定肠道微生物群代谢产物触发结直肠癌进程的方式,总结了肠道微生物群代谢产物对结直肠癌贡献的最新进展,并考虑代谢产物的积累效应以及多种代谢产物相结合的方式来预测和预防结直肠癌。     

The role of microbiota in the development of colorectal cancer

Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation.     

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.     

Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome

Colorectal cancer is a multifactorial disease involving inherited DNA mutations, environmental factors, gut inflammation and intestinal microbiota. Certain germline mutations within the DNA mismatch repair system are associated with Lynch syndrome tumors including right-sided colorectal cancer with mucinous phenotype and presence of an inflammatory infiltrate. Such tumors are more often associated with bacterial biofilms, which may contribute to disease onset and progression. Inflammatory bowel diseases are also associated with colorectal cancer and intestinal dysbiosis. Herein we addressed the question, whether inflammation can aggravate colorectal cancer development under mismatch repair deficiency. MSH2^{loxP/loxP Vill-cre} mice were crossed into the IL-10^−/− background to study the importance of inflammation and mucosal bacteria as a driver of tumorigenesis in a Lynch syndrome mouse model. An increase in large bowel tumorigenesis was found in double knockout mice both under conventional housing and under specific pathogen-free conditions. This increase was mostly due to the development of proximal tumors, a hotspot for tumorigenesis in Lynch syndrome, and was associated with a higher degree of inflammation. Additionally, bacterial invasion into the mucus of tumor crypts was observed in the proximal tumors. Inflammation shifted fecal and mucosal microbiota composition and was associated with enrichment in Escherichia-Shigella as well as Akkermansia, Bacteroides and Parabacteroides genera in fecal samples. Tumor-bearing double knockout mice showed a similar enrichment for Escherichia-Shigella and Parabacteroides. Lactobacilli, Lachnospiraceae and Muribaculaceae family members were depleted upon inflammation. In summary, chronic inflammation aggravates colonic tumorigenesis under mismatch repair deficiency and is associated with a shift in microbiota composition.     

通过宏基因组学研究肠道微生物对结直肠癌患者影响的最新进展

人类肠道微生物已越来越受到医学界的广泛关注,人类肠道微生物不仅在人类健康方面,而且在人类疾病的发生和发展方面都有很大的作用。人们不断发现微生物与癌症之间的联系,特别是肠道微生物群和肠道肿瘤之间的联系。宏基因组学作为微生物研究的一种重要研究方法,在微生物与结直肠癌研究中发挥越来越重要的作用。近年来,通过宏基因组学研究肠道微生物菌群的变化为结直肠癌的发生和发展提供了新的见解,并且强调了癌症微生物群中宿主-微生物和微生物间相互作用的重要性。本综述回顾了通过宏基因组学研究肠道微生物与结直肠癌之间的关系,希望为癌症预防、诊断和治疗提供新的机会。     

Relationship between intestinal microbiota and colorectal cancer

The human gastrointestinal tract hosts a complex and vast microbial community with up to 10¹¹-10¹² microorganisms colonizing the colon. The gut microbiota has a serious effect on homeostasis and pathogenesis through a number of mechanisms. In recent years, the relationship between the intestinal microbiota and sporadic colorectal cancer has attracted much scientific interest. Mechanisms underlying colonic carcinogenesis include the conversion of procarcinogenic diet-related factors to carcinogens and the stimulation of procarcinogenic signaling pathways in luminal epithelial cells. Understanding each of these mechanisms will facilitate future studies, leading to the development of novel strategies for the diagnosis, treatment, and prevention of colorectal cancer. In this review, we discuss the relationship between colorectal cancer and the intestinal microbiota.     

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。     

肠道微生态与肿瘤免疫调节的相关研究

肠道微生态在消化、吸收、代谢、免疫以及抑制病原菌定植中起重要作用。肠道菌群既能调节机体的先天性免疫,又能通过细菌本身和其代谢产物刺激机体的获得性免疫应答。肠道菌群的失调可能导致机体免疫机制的异常,进而参与肿瘤的发生发展,特别是结直肠癌。     

Familial adenomatous polyposis and changes in the gut microbiota: New insights into colorectal cancer carcinogenesis

Patients with familial adenomatous polyposis (FAP), an autosomal dominant hereditary colorectal cancer syndrome, have a lifetime risk of developing cancer of nearly 100%. Recent studies have pointed out that the gut microbiota could play a crucial role in the development of colorectal adenomas and the consequent progression to colorectal cancer. Some gut bacteria, such as Fusobacterium nucleatum, Escherichia coli, Clostridium difficile, Peptostreptococcus, and enterotoxigenic Bacteroides fragilis, could be implicated in colorectal carcinogenesis through different mechanisms, including the maintenance of a chronic inflammatory state, production of bioactive tumorigenic metabolites, and DNA damage. Studies using the adenomatous polyposis coli^Min/+ mouse model, which resembles FAP in most respects, have shown that specific changes in the intestinal microbial community could influence a multistep progression, the intestinal “adenoma-carcinoma sequence”, which involves mucosal barrier injury, low-grade inflammation, activation of the Wnt pathway. Therefore, modulation of gut microbiota might represent a novel therapeutic target for patients with FAP. Administration of probiotics, prebiotics, antibiotics, and nonsteroidal anti-inflammatory drugs could potentially prevent the progression of the adenoma-carcinoma sequence in FAP. The aim of this review was to summarize the best available knowledge on the role of gut microbiota in colorectal carcinogenesis in patients with FAP.     

肠道微生态调控下的Th17/Treg细胞失衡及其在结直肠癌中的作用

辅助性T细胞17（T helper cell 17,Th17）与调节性T细胞（regulatory T cell, Treg）作为CD4+T细胞的重要亚群,既相互拮抗又存在可塑性,肠道微生态可影响两者的分化与平衡,介导结直肠癌的发生发展。本文拟结合国内外最新研究成果对肠道微生态调控下的Th17/Treg细胞失衡及其在结直肠癌发生发展中的作用进行简要综述。     

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story,yet mesmerizing

The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids–microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids–microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.     

肠道上皮细胞再生修复与恶性转化的研究现状

肠黏膜慢性炎症是肠道肿瘤发展的重要组成部分.近期,对肠道肿瘤患者的高通量测序研究发现了一个潜在的、以伤口愈合和先天免疫基因过表达为特征的结肠癌分子亚型,它提示了一种可能依赖于炎症细胞和细胞因子的肿瘤发展机制,增强了我们对细胞恶性转化的理解,以及突出了抗炎在肿瘤治疗中的作用.本文将对正常的肠黏膜更新、伤口愈合和恶变的机制做一综述.     

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。      

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...     

Prostate cancer chemoprevention by soy isoflavones: role of intestinal bacteria as the "second human genome"

It has been found that the composition of intestinal microbiota can indicate the risk of disease to each individual. The concepts of biodynamics as used by the Benziger Winery in California, which treats every part of an agricultural environment as a living, breathing entity, can be usefully used in the construction of a system for cancer prevention, which seeks to use the relationship of coexistence (symbiosis) shared between people and intestinal symbiosis, that is, microbiota. Changes in the incidence rate of cancer among Japanese emigrants to Hawaii demonstrate the effect of the changes in the living environment. This leads to the hypothesis that an intake of soy-derived food products and the metabolization of the isoflavones they contain by intestinal microbiota is one of the factors for the significant difference in the incidence rate of prostate cancer among Asian and European/North American populations. It is further hypothesized that isoflavones, particularly equol, are a key factor in the difference in incidence rate between Asia and the West. It is suggested that not having equol converting bacteria in the intestine (non-equol producers) can be a risk factor for prostate cancer and that one direction for future research will be to examine the possibility of improving the intestinal environment to enable equol production.     

具核梭杆菌与结直肠癌的关系及其临床意义

结直肠癌是常见的消化道肿瘤,是由多种因素共同影响的过程。肠道微生态的失衡可引起多种肠道疾病。随着分子生物学及宏基因组学的深入研究,发现肠道微生态与结直肠癌的发生、发展关系密切。许多研究发现具核梭杆菌参与了结直肠癌发生、发展的过程。本文通过总结现有的文献,就具核梭杆菌与结直肠癌的关系进行概括,为未来结直肠癌的治疗提供新方向。     

Hepatocyte growth factor ameliorates mucosal injuries leading to inhibition of colon cancer development in mice

Hepatocyte growth factor (HGF), which facilitates the repair of injured mucosa, has the potential to be a new therapeutic agent for inflammatory bowel disease (IBD). However, given that the incidence of colorectal cancer increases continuously with disease duration in patients with IBD, the fact that HGF is a potent mitogen for intestinal epithelial cells may further heighten the risk of bowel cancer in this patient population. In this study, we examined the effects of recombinant HGF on colorectal cancer development in mice with or without experimentally induced colitis. Although HGF stimulated proliferation of colonic epithelial cells in normal mucosa, the development of colorectal cancer induced by repeated injection of azoxymethane (AOM) was significantly inhibited by HGF treatment. In a mouse model of colitis-associated cancer, colorectal cancer frequently developed despite only a single injection of AOM prior to three cycles of dextran sulfate sodium administration. However, HGF treatment significantly facilitated the repair of injured mucosa, leading to inhibition of colorectal cancer development in a dose-dependent manner. Thus, HGF-induced repair of injured mucosa inhibits rather than accelerates the development of colorectal cancer, and these results also suggest the importance of blocking the cycles of mucosal injury and repair to prevent colitis-associated colorectal cancer.     

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.