· 76 · Journal of Nutritional Oncology, May 15, 2018, Volume 3, Number 2

Intestinal in the Carcinogenesis and Treatment of Colorectal Cancers

Shao Hua Ge, Yi Ba

Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin 300060, China

Abstract: The term “intestinal microbiota” mainly refers to the colonizing the gut. They are divided into different enterotypes, which have different distributions and functions. of the intestinal microbiota may cause a variety of , including colorectal cancers. Besides carcinogenesis, they are also related to the efficacy and side effects of antitumor therapies, as well as the prognosis of patients. There are two theoretical explanations for how microbiota is involved in carcinogenesis: the “alpha-bughypothesis” and the “driver-passenger” model. These theories explain the course of carcinogenesis related to intestinal microbiota. However, the relationship between the intestinal microbiota and colonic epithelial cells is excessively emphasized under both of these theories, and other factors related to carcinogenesis are neglected. Pathogenic microbiota may be associated with colorectal cancer through different mechanisms, and may act singly or in combination. With regard to treatment, some intestinal microbiota may exert chemopreventive effects and improve the dysbiosis besides anti-inflammatory drugs. Most importantly, the intestinal microbiota may affect the anticancer effects of chemotherapy and immunotherapy. For example, it has been shown that some probiotics can promote the antitumor effects of immune checkpoint inhibitors. Intestinal microbiota may also influence the effects of oxaliplatin and the incidence and grade of diarrhea associated with irinotecan. There are new clinical trials that have been initiated to further investigate the effects of intestinal microbiota on the efficacy and side effects of antitumor therapy. In addition, new targets for the prevention and treatment of colorectal cancers associated with intestinal microbiota are under investigation. Key Words: Intestinal microbiota; Colorectal cancer; Carcinogenesis; Antitumor treatment; Prognosis

Introduction nutrient metabolism and absorption, to stimulate the The term “intestinal microbiota” refers to the immune function, etc. [3-5]. There is enormous diversity bacteria, viruses, fungi, archaea and protozoa present in in the human intestinal microbiota, and most bacterial the intestine. Most studies on have species and their functions are still unknown under both focused on the bacteria in the small intestine, colon and physiological and pathological conditions. rectum. It has been reported that there are more than 1014 In order to obtain a better understanding of the bacteria in the gut of an adult, and the density in the intestinal microbiota, the different categories should be large intestine (~1012 cells per ml) is much higher than defined. The human intestinal microbiota is currently that in small intestine (~102 cells per ml). The stratified into different enterotypes, but this stratification composition of the bacteria is reasonably stable is sometimes controversial [6]. The recurrent throughout adult life, although there are short-term compositional patterns in the intestinal microbiota have variations and variations among individuals [1]. These previously been examined using sequencing bacteria play an important role in maintaining the technologies (Illumina, 454 and Sanger), as well as 16S dynamic balance of the intestinal environment and rRNA gene profiling. The enterotype is described as human health through interactions with intestinal “densely populated areas in a multidimensional space of epithelial pattern recognition receptors (PRRs) [2]. The community composition”. It has been proposed that intestinal microbiota is essential to maintain the there are at least three enterotypes [7]: enterotype 1 is intestinal barrier, to ensure the correct balance between represented by Bacteroides; enterotype 2 by Prevotella, pathogenic and nonpathogenic organisms, to regulate whose abundance is inversely correlated with Bacteroides; and enterotype 3 is comprised primarily by Firmicutes, most prominently Ruminococcus. These Corresponding Authors: Yi Ba, MD, PhD, Tianjin Medical University classifications are independent of geography and the Cancer Institute and Hospital, National Clinical Research Center for cultural background, age and gender of the individual. Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory This suggests that different compositions of bacteria of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin within these enterotypes may act differently in terms of 300060, China; Tel: +86 22 2334 0123; Email: [email protected] their functions and ecological properties [8]. Journal of Nutritional Oncology, May 15, 2018, Volume 3, Number 2 · 77 ·

Abnormities of intestinal microbiota may cause research on colorectal cancer. dysbiosis, which may be related to many diseases not only of the colorectum, but also other parts of the gut. In The Intestinal Microbiota Is Related to the the intestine, dysbiosis is associated with inflammatory Carcinogenesis of Colorectal Cancers bowel diseases, Crohn’s , ulcerative colitis and Due to the many functions of the intestinal colorectal cancers [5,9,10]. The microbiota can also have microbiota in the colorectum, dysbiosis may promote effects on other organs, including the liver, pancreas, carcinogenesis [20]. There is increasing evidence adipose tissue, cardiovascular system, lungs, and even showing that the intestinal microbiota is related to the the brain. As a result, the intestinal microbiota is carcinogenesis of colorectal cancer [21-25]. There are involved in metabolic syndrome, obesity, diabetes several hypotheses regarding the mechanisms by which mellitus, non-alcoholic fatty liver disease, and dysbiosis may lead to colorectal cancers. The most malnutrition, as well as other diseases affecting various important of these are the “alpha-bug hypothesis” and systems [11-13]. With regard to colorectal cancers, the “driver-passenger” model. The “alpha-bug hypothesis” intestinal microbiota is involved in many processes from was proposed by Sears CL et al. [26]. The hypothesis carcinogenesis to determining the prognosis. Some suggests that microbes and microbiome communities are bacteria, such as Lactobacilli and Bifidobacteria, may associated with colon carcinogenesis similar to the antagonize carcinogenesis [14-16]. On the contrary, relationship between Helicobacter pylori and gastric some can function as cancer-promoters, such as cancer, hepatitis virus B or C and liver cancer, or human Bacteroides fragilis, Spirochetes, Firmicutes, and papilloma virus (HPV) and cervical cancer. It considers Fusobacteria [17-19]. Therefore, the intestinal that the immune response to bacteria serves as the driver microbiota deserves more attention, especially in of colon epithelial cell transformation, and then the

Figure 1 How colorectal carcinogenesis may be related to intestinal microbiota A. The “alpha-bughypothesis” described by Sears CL and Pardoll DM [26]. It is considered that there are interactions among the intestinal microbiota, mucosal , and colonic epithelial cells. B. The “driver-passenger” model developed by Tjalsma H et al. [27]. Bacterial drivers may be pro•carcinogens and may cause a series of changes, in collaboration with bacterial passengers, to induce carcinogenesis. C. An ideal model for the carcinogenesis of colorectal cancer involving the intestinal microbiota, immune system and other factors, including dietary factors.

· 78 · Journal of Nutritional Oncology, May 15, 2018, Volume 3, Number 2 cancer originates through a series of exposures to prebiotics) [34-36], pharmacological factors (including pro-inflammatory cytokines. This hypothesis simplifies antibiotics) [37,38], lifestyle [39], and environmental the relationship between the intestinal microbiota and and other carcinogens. A prospective cohort study on colorectal cancer, and mainly concerns the interactions 137,217 nurses and health professionals showed that the among the intestinal microbiota, the host immune system risk of colorectal cancer was strongly influenced by diet, and colonic epithelial cells (Figure 1A). even in patients with other similar risk factors [35]. For The “driver-passenger” model was subsequently F.nucleatum-positive cancers, a “prudent” diet score was proposed by Tjalsma H et al. in 2012 [27]. This associated with a lower risk (P = 0.003 for the trend; hypothesis refers to the patterns of “driver-passenger” multivariable hazard ratio = 0.43; 95% CI, 0.25 - 0.72, gene mutations and combined this with the “alpha­bug” for the highest vs. the lowest score quartile). This hypothesis. The driver mutations in tumor suppressor explains why the risk of colorectal cancer differs even in genes or oncogenes can result in carcinogenesis, while individuals with similar intestinal microbiota. That is to the other numerous mutations in passenger genes may say, the diet affects the cancer risk, and may exert an not change the tumorigenesis process [28]. In this model, equally or more important influence on cancer the bacterial drivers are defined as pro•carcinogens that development as the factors in the “alpha-bug hypothesis”. may initiate colorectal cancers. The detailed mechanisms Therefore, an ideal model would include the various by which they serve as pro-carcinogens may involve the factors that might affect the risk, in addition to the production of DNA•damaging compounds by the intestinal microbiota and immune system (Figure 1C). bacteria [29]. The bacteria can also cause persistent The molecular mechanisms by which the intestinal inflammation, increase cell proliferation, initiate microbiota induce colorectal carcinogenesis involve pre•malignant lesions and finally become malignant. The various processes and factors, including the production bacterial passengers are defined as relatively poor of bacterial toxins [22] and cytokines [23], and the colonizers in the healthy intestinal tract, but which presence of immune abnormalities [40] and metabolic exhibit a competitive advantage in the tumor disturbances [41]. First, the local immune microenvironment. These passenger bacteria may microenvironment may be changed by pathogenic outcompete bacterial drivers in individuals with bacteria or dysbiosis [40,42]. A study by Nosho K et al. colorectal cancer (Figure 1B). Thus, the bacteria found showed that Fusobacterium nucleatum was enriched in in colorectal cancer tissues are mainly bacterial colorectal cancer, which resulted in immunosuppression passengers that thrive in the cancerous [40]. The changes in immunity involve the inhibition to microenvironment, and the initial driver bacteria may be T-cell proliferation, the induction of T-cell apoptosis, complete absent by the time a tumor is present. This is a macrophage-associated inflammatory responses and central concept of this model, where putative bacterial inhibition of the antigen-presenting capacities of drivers are outcompeted by opportunistic passengers. A dendritic cells. Second, some microbes can trigger the paper published in 2014 provides preliminary DNA damage response, resulting in a sustained experimental evidence supporting this “driver-passenger inflammatory response and carcinogenesis [43]. This model” in colorectal cancer [30]. This model explains response is induced by natural killer group 2 member D the interaction between the intestinal microbiota and ligands (NKG2D-Ls) [43] on the surface of stressed cells. carcinogenesis much more directly than the “alpha-bug Third, the reactive oxidation induced by intestinal hypothesis”. However, it neglects various other factors microbiota may participate in colorectal carcinogenesis that are involved in colorectal carcinogenesis. The [44]. Fourth, intestinal microbiota can activate or outcompetition concept also makes it difficult to identify inactivate potential carcinogens by β -glucosidase, the real driver bacteria for the carcinogenesis of β-glucosidase, azo reductase and nitro reductase [45]. colorectal cancer. Finally, abnormities in minerals or vitamins can be As alluded to above, there are deficiencies in both caused by intestinal microbiota. It has been reported that of these hypotheses. First, the findings in mice do not vitamin D deficiency and the high heme iron in the necessarily reflect the state in human beings. The first Western diet are related to the carcinogenesis of hypothesis was mainly based on experiments involving colorectal cancer [46,47]. enterotoxigenic Bacteroides fragilis (ETBF) in mice, which was published in 2009 [31]. However, the The Intestinal Microbiota May Lead to the composition and function of the intestinal microbiota in Chemoprevention of Colorectal Cancer the human gut is different from that in mice. Second, it Because of the high incidence of colorectal cancers, neglects the effects of other factors known to be related effective chemopreventive strategies are of great to the carcinogenesis of colorectal cancers, such as significance. As inflammatory bowel disease is related to heredity [32,33], diet (including probiotics and the carcinogenesis of colorectal cancers, approaches that Journal of Nutritional Oncology, May 15, 2018, Volume 3, Number 2 · 79 · lead to anti-inflammatory effects or that regulate the function and microbiota. Gastric, small bowel or colon intestinal microbiota to keep the immune system in resection can cause changes in the intestinal microbiota balance may be particularly promising. Chinese herbs in both of mice [58,59] and humans [60]. These findings and natural products, such as epigallocatechin gallate indicate that attention should be paid to the changes in [48], curcumin [49], and berberine [50] may be helpful the intestinal microbiota after colorectal and gastric in stabilizing the intestinal microbiota and functioned as surgeries. The corresponding functional changes should chemopreventive agents in in vitro research. It was also be followed and adjusted according to the most reported that the antibiotic cefoxitin may reduce colon recent researches. tumorigenesis driven by enterotoxigenic Bacteroides Chemotherapy is mainly used after surgery, or in fragilis [51]. However, caution should be exercised with patients with metastatic or unresectable colorectal regard to the application of antibiotics, because they may cancers. Oxaliplatin, irinotecan and fluorouracil are the be a double-edged sword that will also kill the beneficial most commonly used agents for colorectal cancers. The bacteria. Various dietary factors may also be regulators intestinal microbiota may influence the anticancer of the microbiota, such as rice bran [52], dietary fiber effects of oxaliplatin in colorectal cancers. For example, [53], probiotics [54], etc. It has been proven that oral it was shown that oxaliplatin-mediated tumor probiotics can ameliorate colitis-associated cancer in cytotoxicity may be reduced after administration to mice [54], improve the composition of the mucosal antibiotic-treated mice or germ-free mice due to microbial flora, and significantly reduce the abundance down-regulated ROS production in myeloid cells [61]. of mucosa-associated pathogens in patients [55]. Another placebo-controlled trial showed that probiotics Bifidobacterium administration was related with lower Intestinal Microbiota May Interact with Antitumor incidence of fever and the use of intravenous antibiotics Treatments after chemotherapy. As a result, it resulted in fewer dose The main treatments used for colorectal cancers are reduction in chemotherapy [62]. It suggests that the surgery, chemotherapy, targeted therapy, intestinal microbiota may influence the antitumor immunotherapy, and in some circumstances, efficacy of chemotherapy in colorectal cancer. radiotherapy (e.g. for rectal cancer or for the local control of large tumors). Antitumor therapy may cause Intestinal Microbiota May Change the Side Effects of an imbalance in the intestinal microbiota, and dysbiosis Antitumor Therapies may also affect the response to anticancer therapies. Diarrhea is a common complication induced by Importantly, it was recently found that the intestinal chemotherapy or dysbiosis in colorectal cancer patients. microbiota is related to the response to treatment with Probiotics are promising agents which can modulate the immune checkpoint inhibitors [38,56,57]. intestinal ecosystem, relieving the diarrhea [63]. There is Immunotherapy with programmed cell death 1 (PD-1), a special type of diarrhea related to chemotherapy using programmed cell death 1 ligand 1 (PD-L1) and CTLA4 irinotecan, one of the most effective drugs in treatment is a new and promising treatment for various cancers of colorectal cancer [64,65]. Drug-related diarrhea may that is associated with T-cell mediated adaptive cause dehydration and weakness, although the detailed immunity. An analysis of 249 patients with advanced mechanism underlying this effect is unclear. The melanoma, non-small cell lung cancer (NSCLC) and intestinal microbiota may participate into the metabolism renal cell carcinoma (RCC) showed that the of the active metabolite of irinotecan, 7-ethyl-10- progression-free survival (PFS) and overall survival (OS) hydroxycamptothecin (SN38). Bacterial ß-glucuronidase were significantly shorter in antibiotic-treated patients can deconjugate inactive SN38G (SN38-glucuronide) to [38]. In univariate and multivariate Cox regression again generate the active SN38, which may then cause analyses, using antibiotics was a predictor for resistance severe diarrhea [66]. A study in mice showed that to PD-1 treatment. Oral supplementation with A. inhibitors of bacterial ß-glucuronidase may reduce the muciniphila after fecal microbiota transplantation may incidence of irinotecan-induced diarrhea [67]. restore the efficacy of PD-1 blockade. In addition, oral administration of Bacteroides thetaiotaomicron or The Intestinal Microbiota Is Related to the Prognosis Bacteroides fragilis to germ-free mice also enhanced the of Colorectal Cancers anticancer effects of CTLA-4 [14]. These findings The factors related to the prognosis of colorectal suggest that adjusting the gut microbiota may modulate cancer include the immune response, efficacy of the efficacy of cancer immunotherapy. treatments, side effects of treatment and inflammation Surgery is the primary curative treatment used for level, all of which are also related to intestinal colorectal cancers. However, surgery may change the microbiota. Therefore, some intestinal microbiota can anatomical structure of the colorectum, as well as its also serve as a prognostic biomarker. A study involving · 80 · Journal of Nutritional Oncology, May 15, 2018, Volume 3, Number 2

1,069 colorectal cancer patients showed that the Observational comparisons of intestinal microbiota characterizations, presence of F. nucleatum DNA in carcinoma tissue was immune enzyme activities, and muscle amino acid compositions of related to a shorter survival [68]. Compared with F. loach in paddy fields and ponds in Sichuan province. Appl Microbiol nucleatum-negative cases, the multivariable hazard Biotechnol 2017;101(11):4775-89. ratios for colorectal cancer-specific mortality in F. 4. Partida-Rodriguez O, Serrano-Vazquez A, Nieves-Ramirez ME, nucleatum-high and F. nucleatum-low patients were 1.58 Moran P, Rojas L, Portillo T, Gonzalez E, Hernandez E, Finlay BB, (1.04 to 2.39) and 1.25 (0.82 to 1.92), respectively. It Ximenez C. Human intestinal microbiota: Interaction between was also reported that F. nucleatum and B. fragilis are parasites and the host immune response. 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Received: March 1, 2018 Revised: April 7, 2018 Accepted: April 15, 2018