An Insight on Gut Flora, Colorectal Cancer Mechanism, and Treatment Strategies

Kumar, Rajendra; Kaur, Ashmeen; Rajput, Divyanshu

doi:https://doi.org/10.1155/2023/7429949

Advanced Gut & Microbiome Research

On this page

Abstract Introduction Conclusions Conflicts of Interest References Copyright Related Articles

Review Article | Open Access

Volume 2023 | Article ID 7429949 | https://doi.org/10.1155/2023/7429949

An Insight on Gut Flora, Colorectal Cancer Mechanism, and Treatment Strategies

Rajendra Kumar,¹Ashmeen Kaur,¹and Divyanshu Rajput¹

Academic Editor: Jian Wu

Received30 Mar 2023

Revised07 Oct 2023

Accepted01 Dec 2023

Published20 Dec 2023

Abstract

The microbiota in the stomach functions like an actual organ. To maintain gut homeostasis, the digestive tract’s symbiotic relationships with the local microorganisms are crucial. This symbiotic connection may be upset, and illnesses like inflammatory bowel disorders and cancer can be promoted. Infections, dietary changes, and lifestyle modifications are a few examples of environmental factors that might alter the microbiome. It is becoming increasingly clear that the microbiota plays a part in the development of colorectal cancer. The complex interplay of tumour cells, nonneoplastic cells, and a large variety of microbes results in colorectal cancer. About 10% of new cancer cases globally are colorectal cancer instances (CRC). The gut microflora, which is situated adjacent to the colorectal epithelium, is made up of a sizable population of bacteria that interact with host cells to control a variety of physiological functions, including energy production, metabolism, and immune response. Sequencing research has revealed microbial compositional and ecological changes in CRC patients, while functional research in animal models has identified several bacteria, including Fusobacterium nucleatum, specific strains of Escherichia coli, and Bacteroides fragilis, as key players in the development of colorectal cancer. In this review, we focus on dysbiosis and the potentially carcinogenic characteristics of bacteria to evaluate the possible connections between the bacterial microbiota and colorectal carcinogenesis. We also discuss pertinent mechanisms in microbiota-related carcinogenesis, the potential for using the microbiota as CRC biomarkers, and the possibility of manipulating the microbiota for CRC prevention or treatment.

1. Introduction

There is broad consensus on the significant impact of the gastrointestinal microflora on both humans’ and animals’ health [1]. Numerous bacterial species have developed and adjusted to survive and proliferate in the human gut. A person’s intestinal environment comprises between 300 and 500 distinct kinds of bacteria, and the number of microbial cells in the gut lumen is approximately 10 times more than the number of eukaryotic cells in the human body [2]. Natural selection has shaped the structure and makeup of the gut flora at both the microbial and host levels, fostering cooperation and maintaining the functionality of this intricate ecosystem [3]. We still do not fully understand the processes that determine the gut flora’s makeup and how it is built up. However, it is evident that facultative aerobes, such as streptococci and Escherichia coli, colonise humans when they are born. However, at the crucial time of weaning, there is a major change in the flora, with obligate anaerobes, notably Bacteroides species, becoming dominant [4]. Up to 10⁵ CFU/ml are present in the upper bowel’s (stomach, duodenum, and jejunum) scanty microbiota. 10⁵ organisms/g of stomach contents can be observed immediately after a meal, but the number reduces along with the drop in pH and falls below 103/g after an hour. In the ileum, the concentrations progressively rise to 10¹¹–10¹² CFU/g in the colon [5]. In order to do a traditional bacteriological examination of the intestinal flora, it is necessary to cultivate bacteria with great care on a variety of growth media and identify isolates using a variety of techniques. Anaerobic bacteria are 100–1000 times more numerous than aerobic bacteria, according to the findings of some studies. Aerobes (facultative anaerobes) including Escherichia, Enterobacter, enterococcus, klebsiella, lactobacillus, and proteus are among the subdominant genera. The most common genera in humans include Bacteroides, Bifidobacterium, eubacterium, clostridium, Peptococcus, Peptostreptococcus, and ruminococcus [2] as shown in Figure 1. Metchnikoff made the initial theory on the significance of lactobacilli for human health and lifespan at the beginning of this century. He claimed that the majority of gut microorganisms were harmful rather than helpful and that yoghurt bacteria could only replace them to provide the desired results. The pharmacokinetics of various probiotics in humans have been the subject of several research, and our understanding of these effects, particularly the intricate mechanism behind them, is continuously expanding [1]. Therefore, consuming live microorganisms in the form of concentrated preparations like powders, pills, or capsules, or through meals like yoghurt and other fermented foods, can have a probiotic effect on the gut microbiota. They may contain a single species of microorganism or multiple [6]. Due to its intricacy, the ecosystem’s inaccessibility in some areas, and the temporal and geographical variety, methods for identifying the gut flora are restricted [7]. New identification technologies have allowed us a fresh look at the gut microbiota. Genome analysis is being used to enhance standard microbiological techniques like as culture and microscopy. Techniques for detecting and semiquantifying both culturable and nonculturable gut bacteria are now accessible, sparking increasing interest in the study of the intestinal flora [7]. There are no single bacteria in the faecal flora that has been linked to the aetiology of inflammatory bowel illness. Several investigations employing various approaches, however, have frequently demonstrated that the stool microbiota differs between people having inflammatory bowel disease and healthy controls. In terms of mucosal adherent flora, several investigations have consistently demonstrated that as compared to controls, individuals with inflammatory bowel illness have a larger concentration of bacteria in the mucosa. This appears to be true both in the mucus layer and at the epithelial surface, where bacteria are significantly less prevalent physiologically. The bacterial makeup of the mucus layer has been demonstrated to stay stable throughout the colon in both Crohn’s disease patients and healthy persons [8]. The distribution of gut flora is confounded by changes not just along the gastrointestinal tract, but also inside the intestinal lumen. The metabolism of pharmaceuticals and other xenobiotics by gut flora has led to the conclusion that metabolic alterations in the gut flora are considerably more widespread than in any other area of the body. The toxicological relevance of gut flora metabolism was initially emphasised. Hydrolysis, dihydroxylation, decarboxylation, dealkylation, dehalogenation, deamination, heterocyclic ring fission, reduction, aromatization, and oxidation have all been recognised as metabolic processes done by gut flora. The majority of drug metabolic alterations by gut flora are studied in terms of enzymatic changes, although chemical reactions including the formation of H₂S and methanethiol in the gut contents should also be considered [9]. Probiotics may have an important role in the treatment of inflammatory bowel disease, according to mounting data from both human and animal research. Ingestion of a significant number of live bacteria necessitates a guarantee of safety. If bacteria obtained from natural flora are employed, their natural existence attests to their safety [7].

2. Colorectal Cancer

Nearly 2 million new instances of colorectal cancer are diagnosed each year, making it the second most prevalent cause of cancer-related deaths globally [10]. CRC reduced somewhat among individuals aged years, in contrast to a rise in incidence of around 20% among adults aged 50 years, with a 10% increase in death [11]. Numerous epidemiological studies have shown that consuming an excessive amount of animal protein and fat, particularly red meat, and processed meat, may induce colorectal carcinogenesis [12]. Climate conditions, socioeconomic circumstances, education, and stress are examples of general external influences. Infections, radiation, alcohol, smoking, nutrition, physical activity, antibiotics, and pharmaceuticals are examples of external environmental influences. Internal environmental factors include metabolic parameters, the gut microbiota, oxidative stress, inflammation, and hormones [13]. The gut microbiota is one of the most significant internal environmental influences. Under some conditions, exposure to an external environmental element, such as stress or antibiotics, or an internal one, such as inflammation, causes dysbiosis in the gut microbiota (shown in Figure 2) and, as a result, CRC. Certain bacteria, for example, mediate the effects of a certain diet on CRC risk by producing butyrate, folate, and biotin, all of which play important roles in the control of epithelial proliferation. The microbiota associated with CRC also contributes to carcinogenic epigenetic signatures [14]. The bidirectional contact of tumour cells with their milieu has been observed in chick and zebrafish models, where the embryonic microenvironment restored the cancer phenotype of transplanted tumour cells [15]. In 1975, researchers found that germ-free rats had fewer chemically induced colorectal tumours than conventional rats, which led to the first finding associating gut microbiota with CRC [16]. These findings have been replicated in CRC-prone mice [17].

3. Diet and the Gut Microbiota’s Composition

Transit time, pH, oxygen exposure, nutrition availability, host secretions (including bile and digestive enzymes), mucosal surfaces, and immune system interactions are all variables that affect microbial colonisation in the various regions of the digestive tract [18]. In healthy people, the large intestine possesses the densest and most metabolically active microbial community, which is dominated by anaerobic bacteria from two phyla (Firmicutes and Bacteroidetes), as well as Actinobacteria, Proteobacteria, and Verrucomicrobia [19]. Many of the taxa that respond to changes in carbohydrate consumption appear to be nutritionally adapted Firmicutes and Actinobacteria [20]. Ruminococcaceae increase in response to resistant starch-enriched diets, but Lachnospiraceae increase in response to wheat bran-enriched diets [21]. Although the association between dietary fibre intake and the risk of cancer has been disputed, recent meta-analysis studies demonstrate that a high intake of dietary fibre, especially from cereals and whole grains, is linked to a lower risk of CRC [22], and patients with advanced colorectal adenomas—which are CRC precursor lesions—have lower dietary fibre intakes than healthy controls [23]. On the other hand, a higher risk of CRC has been associated with diets heavy in red and processed meat, fat, and alcohol [24].

4. Inflammation and Gut Flora

Gut microbiota has a substantial impact on immune responses, and chronic inflammation is well-known to increase the risk of colorectal cancer. T cells, B cells, tissue-associated macrophages, and other innate immune cells engage in direct interactions with one another and other cells in the tumour microenvironment or send signals via cytokines and chemokines to regulate tumour development [25]. T cells are the immune cells that are most common in the cancer microenvironment, followed by TAMs. T lymphocytes may both encourage and inhibit the development of tumours. Increased numbers of CD4+ T helper 1 (TH1) and CD8+ cytotoxic T cells are linked to the direct lysis of cancer cells and the generation of cytotoxic cytokines, which slow the development of colorectal cancer [26]. Notably, the absence of gut microbiota or microbial products prevents inflammation from causing CRC [27]. Through a variety of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) that regulate the inflammatory response to molecular patterns associated with microorganisms (MAMPs), including lipopolysaccharide (LPS), flagellin, and nucleic acids, the microbiota can recognise the host [28]. In the colonic environment, PRRs are essential for preserving mucosal homeostasis and limiting inflammation. Changes in TLR4 signalling, which is the main LPS receptor, have been specifically associated to the development of CRC [29].

5. Gut Microbiota in Colorectal Adenoma

The majority of CRC are known to have colorectal adenomas as their precursor [30]. The high-risk advanced adenoma is a significant focus for CRC screening since the majority of CRC starts with the malignant transformation of benign polyps. New methods to identify, control, or stop the evolution of these CRC precursors may emerge as a result of better understanding the biology of colorectal adenomas [31, 32]. In a 2019 investigation, 616 people who had colonoscopies provided stool samples, and it was shown that microbiota changes were present in cases of multiple colorectal adenomas and intramucosal carcinomas [33]. Stage-specific investigations revealed that some bacterial species, such F. nucleatum and Solobacterium moorei, showed a gradual rise in abundance from early to late stages of carcinogenesis, while other species, like Atopobium parvulum and Actinomyces odontolyticus, were raised in abundance only at an early stage of carcinogenesis (in patients with multiple adenomas or intramucosal carcinoma). In a research that examined the mycobiome of people with colorectal adenomas of various sizes and stages, the variation in abundance of numerous fungal taxa, such as Basidiomycota, was also noticeable [34]. Due to existing stool-based occult blood tests’ inability to detect early adenomatous lesions, these variations in abundance make them potentially useful as indicators for these lesions.

6. Mechanisms in Colorectal Carcinogenesis

The development of colorectal cancer is a complex process that is impacted by both hereditary and environmental variables and has a variety of etiological processes. Inflammation, immunological control, dietary component metabolism, and the formation of genotoxin are a few of these processes that have been well examined and are strongly related to the gut microbiota [35]. Here, we focus on a few microbiota-associated elements in CRC carcinogenesis that may be modified and applied in the clinic.

6.1. Inflammation and Immune Regulation

The gastrointestinal tract serves as a crucial point of contact for interactions between the host immune system and the gut bacteria [36]. Chronic inflammation is a hallmark [37, 38] and a recognised risk factor for CRC, as demonstrated by the higher risk of the cancer in people with inflammatory bowel disease compared to the general population [39]. Patients with Crohn’s disease have a risk of 8.3% [40], whereas those with ulcerative colitis had a risk of 18.4% over the course of 30 years [41]. However, the reported levels of risk varied depending on the study population (for instance, high-risk cases versus population cohorts), hospital setting (for instance, tertiary versus general hospitals), and clinical practise (for instance, rate of proctocolectomy) [42]. The gut microbiota can have an impact on the inflammatory process in the gastrointestinal tract by intimately interacting with the host immune system. Since microorganisms in the gut can cause chemotactic factors (such as CXCL9 and CXCL10 for cytotoxic T lymphocytes and type 1 T helper (TH1) cells, and CCL17 and CCL20 for IL-17-producing TH cells) to recruit T cells into tumours [43], oral administration of stool from CRC patients to germ-free and carcinogen-fed mice increased histological inflammation and the expression of inflammatory gene markers [44]. Regarding specific bacterial species, it has been documented that F. nucleatum can activate the nuclear factor-B pathway and cause myeloid cell infiltration in tumours [45], creating an inflammatory environment that is favourable for the progression of colorectal neoplasia in ApcMin mice (a popular mouse model of CRC) [46]. Through its virulence component B. fragilis toxin, enterotoxigenic B. fragilis, a strain that is more prevalent in CRC patients [47], may cause an inflammatory cascade involving IL-17, signal transducer and activator of transcription 3, and nuclear factor-B signalling in colonic epithelial cells [48]. These signalling pathways then cause CXC chemokines to attract polymorphonuclear immature myeloid cells in ApcMin mice, resulting in the development of an inflammatory milieu, particularly at the distal colon [49]. Other bacteria, such as the CRC-enriched genotoxic polyketide synthase (pks)+ E. coli [50–52], E. faecalis [53], and A. finegoldii [54], also contribute to the development of cancer by causing inflammation. The human immune system and the gut bacteria are connected through pattern recognition receptors (PRRs). Through a downstream cascade of signalling molecules, PRRs that recognise microbial antigens trigger the intestinal immune system. Toll-like receptors (TLRs) [55], nucleotide-binding oligomerization-like receptors [56], RIG-I-like receptors [57], and missing in melanoma 2-like receptors [58] are a few of these PRRs that have been linked to colitis-associated carcinogenesis in animal models. Particularly, F. nucleatum, a CRC-enriched bacteria, may stimulate TLR4 signalling to increase tumour growth in mice [59, 60], whereas Peptostreptococcus anaerobius, another bacterium, can activate TLR2 and/or TLR4 to promote carcinogenesis in mice [61].

6.2. CRC Induced by Heme Iron from Red Meat

Red and processed meat consumption, poor dietary fibre, and other lifestyle variables such as alcohol, cigarettes, and inactivity are all causally related to CRC [62, 63]. According to epidemiological research, eating meat increases the risk of developing CRC [64, 65]. The International Agency for Research on Cancer rated red meat as probably carcinogenic in humans in 2015 and processed meat consumption as carcinogenic. In comparison to white meat, like chicken, red meat—such as beef and lamb—has a higher myoglobin content and contains more heme iron [66, 67]. Interestingly, eating heme considerably raises the risk for CRC, according to a meta-analysis of epidemiological research [68].

Heme is a collective term for several proteins, including the oxygen-transporting haemoglobin and myoglobin [69]. Haemoglobin is made up of two and two-chain subunits that can bind up to four oxygen molecules in the lung and carry them to the tissue through the bloodstream. The monomeric myoglobin in tissue with a single chain receives oxygen thanks to the Bohr effect [70]. It is well-known that (heme-) iron catalyses the Fenton’s reaction, which produces ROS [71]. Ferrous iron (Fe2+) is oxidised to ferric iron (Fe3+) in this redox reaction, while H2O2 is reduced to a hydroxyl anion and a hydroxyl radical. The latter directly interacts with macromolecules at its place of origin and has a relatively short half-life. By abstracting hydrogen atoms from the C-H bonds of the 2-deoxyribose sugar moiety and adding to the double bonds of DNA bases, the hydroxyl radical damages DNA and causes oxidative DNA lesions like 8-oxoguanine (8-OxoG) and thymine glycol, single-strand breaks, and abasic sites [72]. Specific DNA glycosylases, such as 8-oxoguanine glycosylase-1 (OGG1), which removes the damaged base as the initial stage of base excision repair (BER), can detect oxidative base damage [73]. Surprisingly, there are surprisingly few studies available that address the oxidative DNA damage caused by heme or haemoglobin in cultured cells. According to an FPG-modified alkaline comet assay, haemoglobin at high dosages was found to marginally exacerbate oxidative DNA damage [74]. Dietary heme disrupts the intestinal barrier and results in a microbial dysbiosis, which exposes the epithelium to enterobacteria and, consequently, bacterial lipopolysaccharides (LPS). Although one study found no indication of innate immune reaction and inflammation pathways induced by Toll-like receptor 4 (TLR4) in heme-fed mice, it is plausible that bacteria reaching the epithelium will provoke an immune response and maybe worsen intestinal inflammation [75]. Inflammatory mechanisms are known to promote colorectal carcinogenesis [76, 77]. Supporting evidence comes from two recent investigations that found eating heme makes chemically induced colitis in animals worse [78, 79]. Aside from these indirect effects, heme directly promotes or inhibits the activity of several populations of blood cells. The primary cell type that absorbs heme from ageing erythrocytes and provides heme iron for erythropoiesis is macrophages. Heme’s toxicity towards healthy tissue is reduced by internalisation into macrophages, and pathogens are prevented from accessing heme iron, which is necessary for their proliferation [80].

6.3. Intestinal Tumorigenesis, Heme Iron, and Red Meat

Consuming red meat and heme iron increases the likelihood of developing CRC, according to epidemiological studies. The colon cancer incidence was higher in the group with haemoglobin when the alkylating chemical methylnitrosurea was given intrarectally to rats over a period of two weeks, followed by a high-fat diet with or without 3% haemoglobin for 36 weeks [81]. A later study established a direct connection between dietary heme iron and colon cancer for the first time [82]. Azoxymethane (AOM), a colonotropic tumour inducer, was administered to rats in this study before heme iron or haemoglobin was administered for 100 days. When isolated colon tissue was stained with methylene blue, it revealed an increase in the size and number of dysplastic aberrant crypt foci (ACF), which are thought to be the precursor lesions of colon cancer [83]. Additionally, dietary supplementation with high calcium or antioxidants decreased the number as well as the size of ACF, and heme iron was found to be a more potent inducer of ACF than haemoglobin [82]. To confirm these conclusions, meals containing beef or black pudding considerably induced the development of ACF and mucin-depleted foci (MDF) in AOM-initiated rats, but eating chicken only slightly increased the ACF and MDF number [84]. Importantly, animals lacking the tumour initiator AOM did not develop intestinal neoplasia or ACFs when fed a diet containing 2.5% haemoglobin (1.5 mol heme iron/g food) [85], indicating a significant role for heme iron in the production of tumours. An experiment feeding rats processed meat made from gammon further supported this. Following a ham-based diet (0.25 mol heme iron/g diet) for 100 days, the mice received an injection of the alkylating chemical dimethylhydrazine as a tumour initiator, which accelerated the production of ACF and MDF [86].

7. Use Microflora as a Biomarker

A biomarker is a biological sign of a disease’s presence or severity. A reliable and noninvasive screening test might significantly lessen the burden of CRC on global health, given the strong evidence that identifying average-risk persons for screening can lower CRC incidence and mortality [87]. The possibility for employing these indicators for treatment prediction and prognostication has also increased because of the connections between bacterial markers and treatment efficacies or clinical outcomes that have been documented in a number of studies. Potential biomarkers can be found in abundance by studying the gut microbiome. We go over possible applications for CRC screening and prognostication of microbiota-related indicators in this section.

8. Screening Biomarkers

8.1. CRC Detection by Faecal Markers

In particular, early CRC, which may be treated with outstanding clinical results, requires accurate biomarkers for screening. In contrast to 14% in distant metastatic cancers, localised CRC, for instance, has a 5-year survival rate of 90% [88]. The current faecal immunochemical test (FIT) only has a 79% sensitivity rate to detect CRC [89] and a 25–27% rate to detect advanced colorectal adenomas [90]. Despite having a higher sensitivity than FIT (92.3%), the multitarget stool DNA test is nonetheless constrained by a worse sensitivity for detecting advanced adenoma (42.4%) [91]. Therefore, it would be ideal to have a test that is sensitive enough to detect advanced adenomas as well as CRC and is also accurate, inexpensive, and noninvasive. An abundant source for creating faecal microbial markers for illness detection is the growing quantity of metagenomic datasets in the CRC. Many studies have used the prevalence of different bacterial species to distinguish between CRC patients and healthy people, including two case-control studies that achieved areas under the receiver operating characteristic (ROC) curves (AUC) of 0.84 to 0.85 using 22 and 34 microbial markers, respectively [92, 93]. A group of 20 microbial genes were linked to disease presence in a prior metagenomic investigation that compared CRC () and healthy persons () in Hong Kong [94]. Butyryl-CoA dehydrogenase from F. nucleatum and RNA polymerase subunit (rpoB) from P. micra, two useful biomarkers that can be quantified by PCR, might be used to reduce this group of gene markers and reach an AUC of 0.84. In one study using a Bayesian methodology, a logistic regression model combining data on the abundance of six different bacterial species in faeces could distinguish between patients with CRC and healthy people with an AUC of 0.80. This AUC increased to 0.92 when age, race, and BMI were factored into the model [95]. Additionally, given the newly discovered metagenomic landscapes of the virome and mycobiome in CRC, microbial signatures derived from these communities may be used as screening biomarkers for CRC [96, 97]. When measured either by itself [98, 99] or in combination with other bacteria [93, 100], particularly Clostridium symbiosum [101], C. hathewayi, and bacteria that produce colibactin (clbA+) [102], F. nucleatum stood out as a major marker among a number of bacterial contenders. In comparison to utilising FIT alone, the faecal abundance of F. nucleatum can enhance the effectiveness of FIT and provide higher sensitivity and specificity for the detection of CRC [92, 103]. For example, it has been demonstrated that increasing the FIT with faecal F. nucleatum abundance causes the AUC to rise from 0.86 to 0.95. While the best panel will likely have the variety of markers balanced between accuracy, logistic feasibility, and simplicity of the analysis, this method demonstrates the benefits of a multitarget test in which separate components can complement one another to decrease the cases of missed malignancy. Only 16 species could accomplish cross-validation for the bulk of the datasets in a large-scale meta-analysis research that tested a random forest classifier and was published in 2019 [104]. This discovery supports the development of a precise stool-based diagnostic test that uses markers that focus on a small subset of bacteria species or genes. Lastly, meta-analyses using metagenomes from varied geographic regions reveal that polymicrobial classifiers are resilient against regional and technological variations and are relevant globally [104–106].

8.2. Faecal Indicators for Adenoma Detection

It has been determined that the progression of CRC from a healthy mucosa to a precursor lesion and then a malignant tumour occurs over time. The main lesion that precedes CRC is an adenoma, which can be surgically removed to stop the progression of cancer after being discovered [107]. To prevent and lower CRC, it is therefore important to find adenomatous polyps, especially advanced neoplasms. Colorectal adenomas are difficult to detect using the current noninvasive stool-based screening methods, such as FIT and the multitarget stool test. After integrating abundance data from five bacterial species with clinical characteristics, faecal microbial indicators could discriminate patients with colorectal adenoma from healthy controls with an AUC of 0.90, resulting in a 4.5-fold increase in posttest chance of identifying an adenoma [95]. These findings imply that microbial composition data might be used to diagnose colorectal adenomas [27, 92, 95]. Nonetheless, in identifying individuals with adenomas from healthy controls, a meta-analysis study of faeces metagenomes revealed a lower AUC value (highest AUC 0.58) [104]. According to several studies [87, 99, 108–110], F. nucleatum was shown to be a particular individual bacterium that was more prevalent in colorectal adenomas; however, the magnitude of the abundance differences was lower than that between patients with CRC and healthy persons. With the help of other microbial markers [93, 95] or in combination with FIT [98], it has been demonstrated that the quantification of F. nucleatum in faecal samples can distinguish patients with colorectal adenomas from healthy individuals as controls. However, differences between adenoma cases and controls were less pronounced [111, 112].

9. Cancer Biomarkers for Prognosis

In addition to their potential as diagnostic tools for CRC, connections between bacterial biomarkers and the clinical outcomes of CRC have increased the likelihood of their use as prognostic indicators. Tumoural F. nucleatum levels in tissue, as determined by quantitative PCR, were found to be negatively correlated with CRC survival in many molecular epidemiology investigations [87, 113, 114]. The hazard ratio for CRC-specific death in F. nucleatum-low and F. nucleatum-high patients, respectively, was 1.25 and 1.58, respectively, as compared to F. nucleatum-negative individuals [113]. This discovery emphasises the potential for measuring F. nucleatum in tumour tissue as a prognostic marker and, more crucially, offers encouragement that the bacterium’s elimination may enhance prognosis and disease survival. Nevertheless, some research indicates that F. nucleatum may be related to the CRC genetic subtype (high lesions with the CpG island methylator phenotype) and tumour site (proximal malignancies) [92, 115, 116]. These variables may confuse the prognostication; hence, additional validation studies are essential before using these biomarkers in a clinical setting.

10. Modifying the Microbiome to Prevent CRCs

A tempting approach to lessening the burden of CRC is prevention. Numerous risk factors for CRC have been found by extensive epidemiological research, including eating patterns, obesity, and other lifestyle variables that may be easily modifiable [117]. According to two studies conducted in the United States, changing one’s lifestyle might prevent more than half of CRC incidents [118, 119]. Additionally, a number of probiotic microorganisms have been researched in relation to CRC prevention. Here, we examine how these elements could affect the gut microbiome to lessen the risk of CRC.

10.1. Manage Obesity

Obesity has been identified as a risk factor for CRC. Accumulation of fat and the risk of CRC have a strong dose-response positive association, with individuals with a BMI over 27 kg/m2 having a nonlinearly greater risk [117]. The modulation of microorganism-derived proinflammatory molecules and metabolites by the gut microbiota has emerged as a key player in the relationship between obesity and CRC among several mechanisms involving insulin or insulin-like growth factor 1 signalling, adipokines, sex hormone, and systemic inflammation. Obesity is linked to decreased microbial diversity [120] and a change in the makeup of the gut microbiota [121, 122]. In animals, diet-induced obesity can, in a way reliant on the gut microbiota, result in extensive histone methylation and acetylation along with a transcriptome pattern that, downstream, resembles the development of cancer [123, 124]. The gut flora can alter significantly when weight is controlled in obese people because of these interactions [125, 126]. Few clinical research have examined the impact of preventing weight gain or generating weight reduction on cancer risk generally, despite the fact that obesity and CRC have favourable relationships. Although the connection is not clear for women, observational studies point to a decreased risk of CRC in males with lesser weight increase over adulthood [127]. Although this study lacked the capacity to examine the risk of a specific cancer type, it was noted that people who were obese and had maintained weight reduction following bariatric surgery had reduced risks of obesity-related malignancies than matched obese controls who did not undergo surgery [128]. Observational data with conflicting findings were published, with the risk of CRC following bariatric surgery either rising [129] or remaining unchanged [130]. On the other hand, compared to 66,427 matched nonsurgical persons, 22,198 people who underwent bariatric surgery had a decreased incidence of obesity-related malignancies, including colon (but not rectal) cancer [131]. An article written in 2018 highlighted the varying impact of bariatric surgery on the risk of CRC [132].

10.2. Diet/Nutritional Interventions

The gut microbiota is largely determined by diet [133, 134]. Populations with diverse diets have significantly variable gut microbial assemblages, which are therefore associated with varying CRC risks. Researchers found that African Americans had a larger abundance of Bacteroides than the rural African group in one research comparing their diets, and that this difference was connected with higher intakes of animal protein, fat, and fibre in African Americans [135]. There has been a lot of interest in using dietary treatments to affect CRC incidence and development through the gut microbiota since dietary changes have the potential to significantly alter our microbiome [136]. One research found that converting African Americans to a high-fibre, low-fat diet for two weeks might alter the gut microbiota and lessen indicators of inflammation and cell growth in colon tissue [137]. On the other hand, moving rural Africans to a high-fat, low-fibre diet had striking reciprocal effects on mucosal cancer risk indicators. Dietary fibre, which may be obtained from natural food sources or added as a prebiotic preparation, has been identified by studies on individual dietary components as a significant influence regulating gut microbial composition and diversity [138, 139]. Prebiotics are described as a substrate that host bacteria use only when they want to provide a health advantage [140]. Through microbial fermentation, dietary fibre interventions such as fructans and galactooligosaccharides changed the gut microbiota’s composition to raise the number of Bifidobacterium and Lactobacillus spp., and they elevated the content of butyrate in human faeces [141]. Importantly, a gnotobiotic mouse research has shown that dietary fibre suppresses tumour growth in the setting of colorectal neoplasia in a way that is reliant on both the microbiota and butyrate [142]. Clinical trials examining the effects of fibre supplementation in people with a history of colorectal adenomas, however, found little evidence that it might stop recurrent adenomas [143, 144]. The discrepancy in these results may be due to the diverse effects of SCFAs at the cellular level [145]. Strong epidemiological research indicate that consumption of processed and red meat is linked to a higher risk of CRC [146, 147]. Red and processed meat diet rises linearly with the risk of CRC up to a threshold of 140 g per day, according to a comprehensive assessment of data from 13 prospective studies [148]. As a result, processed meat has been labelled as a carcinogen (class 1) by the International Agency for Research on Cancer, whereas red meat has been categorised as a possible carcinogen (class 2A) [149], and consumers are advised to limit their intake of processed meat. A follow-up of vegetarians for 7.3 years demonstrated a 20% decreased incidence of CRC compared to nonvegetarians, lending validity to this advice [150]. The makeup of the gut microbiota can be significantly influenced by dietary fat consumption, as demonstrated in animal models [151, 152]. The enterohepatic circulation of bile acids, including deoxycholic acid, which accelerated the development of intestinal tumours in an ApcMin mice model, can be increased by dietary fat, which can also stimulate the hepatic production of bile acids to assist fat emulsification [153, 154]. However, association studies in people have shown contradictory findings on the link between dietary fat intake and CRC [155, 156]. The incidence of colorectal neoplasia has not been shown to be reduced by low-fat diets, either on their own [157, 158] or in combination with a high-fibre component [159, 160].

10.3. Probiotic Administration

Probiotics are living microorganisms that, when consumed in sufficient quantities, might provide health benefits [161]. The notion of probiotics has been around for over a century, and these microbes have been researched for their anticancer properties, with many putative immunological pathways hypothesised [162]. In preclinical studies for CRC, several bacteria, including Bifidobacterium and Lactobacillus spp., demonstrated anticancer properties through various mechanisms [163], including inhibiting cell proliferation [164, 165], inducing cancer cell apoptosis [166, 167], modulating host immunity [168, 169], inactivating carcinogenic toxins [170, 171], and producing anticarcinogenic compounds [172]. Probiotics’ effectiveness for CRC in people has not been well studied in clinical studies. When Lactobacillus casei was given orally to patients who had undergone resection, it decreased the frequency of moderate- or high-grade dysplastic tumours but not the overall number of tumours [173]. Additionally, a synbiotic intervention using the prebiotic inulin along with the probiotics Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 caused changes in the faecal microbiota (increased Lactobacillus and Bifidobacterium, decreased Clostridium perfringens), reduced cell proliferation, and improved epithelial barrier function in patients with a history of colonic polyps [174] Nevertheless, despite changes in the faecal microbiota with a higher percentage of patients having Lachnospiraceae spp., a subsequent symbiotic intervention involving resistant starch and B. lactis in 20 human volunteers failed to replicate the changes in cell proliferation or other physiological markers [175]. However, there is only preliminary direct evidence that using probiotics can prevent CRC, despite in vitro and in vivo experimental results to the contrary. Probiotics’ therapeutic usefulness for CRC prevention will be defined by more clinical research.

11. Utilising Gut Bacteria in CRC Treatment

There is growing evidence that the gut microbiota modulates the effectiveness and toxicity of chemotherapy and immunotherapy in addition to its functions in carcinogenesis and tumour growth [176]. This makes it possible to manipulate the gut microbiota for better cancer therapy and patient outcomes while also using it as a biomarker to identify treatment response or bad effects. Possibilities for clinical use of microbiota in CRC have been depicted in Figure 3.

11.1. Immunotherapy’s Therapeutic Repercussions

Numerous tumours respond well to immunotherapy, which has grown to be a cornerstone of cancer care. Immune checkpoint drugs block inhibitory signals that prevent T cells from becoming activated, allowing tumour-reactive T cells to generate a potent antitumour response [177]. Immune checkpoint inhibitors that target the programmed cell death 1- (PD-1-) programmed cell death 1 ligand 1 (PD-L1) axis [178, 179] and the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) axis [180] can be affected by the gut microbiota, which is necessary for an efficient immune response in immunotherapy [181]. Akkermansia muciniphila [181], B. fragilis [180], Bifidobacterium spp. [179], Eubacterium limosum [182], Faecalibacterium spp. [183], and Alistipes shahii [184] are only a few of the bacteria that have been favourably connected with the success of immunotherapeutic treatment. Importantly, oral administration of A. shahii restored the immunotherapeutic defence against colon tumours in mice receiving antibiotic treatment [184]. Despite discrepancies in the main research, elevation of A. muciniphila and Ruminococcus champanellensis was seen in immunotherapy responders in a study that pooled shotgun metagenome data from three investigations on anti-PD-1 antibody response [185]. This discovery has opened up the idea of using these core microorganisms as biomarkers that can predict how well an immunotherapy would work. While a lack of genes in the pathways for polyamine transport and vitamin B production was linked to greater susceptibility to colitis, larger presence of the Bacteroidetes phylum was tied with resistant to immune checkpoint inhibitor-associated colitis [186]. Faecal microbiota transplantation (FMT) has also been shown to be a successful treatment for refractory immunotherapy-associated colitis in two reports of human cases, with gut microbial changes correlating with full resolution of colitis up to 53 days after one dose and up to 78 days after 2 doses of faecal microbiota transplantation, respectively [187]. Anti-PD-1 [188] and anti-CTLA-4 checkpoint inhibitors may offer a long-lasting response for metastatic CRC with high levels of microsatellite instability or a deficiency in DNA mismatch repair [189, 190], even though immunotherapy may not be as effective as a treatment for all CRC subtypes [183, 191] as it is for other cancers. This subgroup of CRC has characteristics that make it amenable to PD-1 inhibition, including high mutational load, cancer neoepitopes, lymphocytes that have infiltrated the tumour, and activation of immunological checkpoints [192, 193]. Given the growing usage of these medications in some CRC patients, the gut microflora may be able to improve the effectiveness of treatment and decrease the side effects of immunotherapy [188].

11.2. Chemotherapy’s Therapeutic Repercussions

An increasing body of research indicates that the gut microflora may mediate the anticancer effects of some chemotherapy drugs, such as 5-fluorouracil [194], cyclophosphamide [195], gemcitabine [196], and oxaliplatin [184], through a variety of mechanisms, including microbial translocation, immunomodulation, metabolism, and decreased ecological diversity [197]. Myeloid-derived tumour-infiltrating cells in mice treated with antibiotics or raised in germ-free environments did not respond well to treatment, leading to inadequate generation of reactive oxygen species and cytotoxicity following chemotherapy [184]. As demonstrated by experimental evidence, F. nucleatum may activate autophagy to impart resistance to oxaliplatin and 5-fluorouracil [198], the gut microbiota’s function in chemotherapy resistance has also been examined. A new approach to prognosticating outcomes and treating CRC patients could involve measuring and focusing on F. nucleatum. Irinotecan (CPT-11), a prodrug of SN-38 and a topoisomerase inhibitor often used to treat CRC, is also metabolised differently and has more side effects because of the gut bacteria. Pharmacologically, host liver enzymes convert SN-38 into a conjugate that is inactive (SN-38G). The glucuronidase enzymes produced by gut bacteria hydrolyze SN-38G back to SN-38 when it enters the stomach by biliary excretion, leading to intestinal ulceration and chronic diarrhea [199]. A method of changing microbial activity to lessen the negative effects of chemotherapy treatments is shown by the administration of a specific inhibitor, which might prevent the reactivation of SN-38 in the gut and its associated toxicity in mice [200, 201].

12. Other Treatment Strategies Using the Microbiome

Tumours may be prevented or reduced as a result of cancer treatment using microbial agents or their products [162]. Using antibiotics to prevent microorganisms linked to cancer (e.g., metronidazole may decrease tumour size in Fusobacterium-positive xenografts in mice) [202], commensals (e.g., Bifidobacteria spp. [178], A. muciniphila [181], and Bacteroides spp. [180] may enhance antitumour T cell responses [162]), and small (e.g., targeting bacterial ClbP enzyme to reduce colibactin [203]) are some strategies for combating cancer-associated bacteria. Despite not having been studied in CRC patients, FMT is currently being evaluated in combination with chemotherapy or cancer immunotherapy to see how it affects the disease [204, 205]. The chemical method also provides a possible treatment option since the host-microbial interactions in CRC are partially influenced by microbial metabolites [206]. These include dietary substances known as prebiotics [207] or postbiotics [145, 208] that are metabolites produced by the microbiota. Using bacteriocins, bacteriophages, or genetically modified probiotics to alter the gut microbiota are some further innovative strategies. Bioengineering the gut microbiota is another.

13. Conclusions

It is complicated how the host and the gut-resident bacteria interact. Since birth, each person has carried a unique gut microbiota signature, and as they age, alter their food, and are exposed to a variety of environments throughout their lives, their intestinal microbiota changes and evolves. This equilibrium is indeed extremely fragile and undergoes several alterations throughout the course of a lifetime. During gut dysbiosis, certain bacterial subpopulations can grow, which in turn can cause the environment to become inflammatory and cancer-promoting. On the other hand, many probiotics originating from the gut have the ability to protect the host and restore the circumstances of a good gut microbiome in patients who are dysbiotic, including those who are suffering from cancer. The relevance of the gut microbiota in CRC has been the subject of exponential knowledge growth over the last few years. As meta-analyses have combined data from many populations to show the CRC microbiome landscape on a global basis, association studies have grown in frequency and sample size. Additionally, these investigations have advanced functional studies to investigate the part that certain microorganisms play in the development of cancer. Together, these findings have presented a once-in-a-lifetime chance to advance microbiome research toward therapeutic applications. The discoveries about the microbiota will probably usher in a new era of oncology in the coming years as additional advances are made in the fields of CRC genomics, metabolomics, and immunology.

Conflicts of Interest

The authors have declared that no competing interests exist.

References

W. H. Holzapfel, P. Haberer, J. Snel, U. Schillinger, and J. H. Huisin't Veld, “Overview of gut flora and probiotics,” International Journal of Food Microbiology, vol. 41, no. 2, pp. 85–101, 1998.
View at: Publisher Site | Google Scholar
F. Guarner and J. R. Malagelada, “Gut flora in health and disease,” Lancet, vol. 361, no. 9356, pp. 512–519, 2003.
View at: Publisher Site | Google Scholar
A. M. O'Hara and F. Shanahan, “The gut flora as a forgotten organ,” EMBO Reports, vol. 7, no. 7, pp. 688–693, 2006.
View at: Publisher Site | Google Scholar
C. L. Sears, “A dynamic partnership: celebrating our gut flora,” Anaerobe, vol. 11, no. 5, pp. 247–251, 2005.
View at: Publisher Site | Google Scholar
S. Salminen, E. Isolauri, and T. Onnela, “Gut flora in normal and disordered states,” Chemotherapy, vol. 41, no. 1, pp. 5–15, 2004.
View at: Publisher Site | Google Scholar
L. Fooks and G. Gibson, “Probiotics as modulators of the gut flora,” British Journal of Nutrition, vol. 88, no. S1, pp. S39–S49, 2002.
View at: Publisher Site | Google Scholar
A. L. Hart, A. J. Stagg, M. Frame et al., “The role of the gut flora in health and disease, and its modification as therapy,” Alimentary Pharmacology & Therapeutics, vol. 16, no. 8, pp. 1383–1393, 2002.
View at: Publisher Site | Google Scholar
P. Marteau, P. Lepage, I. Mangin et al., “Gut flora and inflammatory bowel disease,” Alimentary Pharmacology & Therapeutics, vol. 20, Supplement s4, pp. 18–23, 2004.
View at: Publisher Site | Google Scholar
M. Mikov, “The metabolism of drugs by the gut flora,” European Journal of Drug Metabolism and Pharmacokinetics, vol. 19, no. 3, pp. 201–207, 1994.
View at: Publisher Site | Google Scholar
F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA: a Cancer Journal for Clinicians, vol. 68, no. 6, pp. 394–424, 2018.
View at: Publisher Site | Google Scholar
R. L. Siegel, K. D. Miller, S. A. Fedewa et al., “Colorectal cancer statistics, 2017,” CA: a Cancer Journal for Clinicians, vol. 67, no. 3, pp. 177–193, 2017.
View at: Publisher Site | Google Scholar
J. Yang and J. Yu, “The association of diet, gut microbiota and colorectal cancer: what we eat may imply what we get,” Protein & Cell, vol. 9, no. 5, pp. 474–487, 2018.
View at: Publisher Site | Google Scholar
L. J. Hofseth, J. R. Hebert, A. Chanda et al., “Early-onset colorectal cancer: initial clues and current views,” Nature Reviews Gastroenterology & Hepatology, vol. 17, no. 6, pp. 352–364, 2020.
View at: Publisher Site | Google Scholar
S. H. Wong and J. Yu, “Gut microbiota in colorectal cancer: mechanisms of action and clinical applications,” Nature Reviews Gastroenterology & Hepatology, vol. 16, no. 11, pp. 690–704, 2019.
View at: Publisher Site | Google Scholar
M. J. Hendrix, E. A. Seftor, R. E. Seftor, J. Kasemeier-Kulesa, P. M. Kulesa, and L. M. Postovit, “Reprogramming metastatic tumour cells with embryonic microenvironments,” Nature Reviews Cancer, vol. 7, no. 4, pp. 246–255, 2007.
View at: Publisher Site | Google Scholar
J. H. Weisburger, B. S. Reddy, T. Narisawa, and E. L. Wynder, “Germ-free status and colon tumor induction by N-methyl-N'-nitro-N-nitrosoguanidine,” Proceedings of the Society for Experimental Biology and Medicine, vol. 148, no. 4, pp. 1119–1121, 1975.
View at: Publisher Site | Google Scholar
L. Vannucci, R. Stepankova, H. Kozakova, A. Fiserova, P. Rossmann, and H. Tlaskalova-Hogenova, “Colorectal carcinogenesis in germ-free and conventionally reared rats: different intestinal environments affect the systemic immunity,” International Journal of Oncology, vol. 32, no. 3, pp. 609–617, 2008.
View at: Publisher Site | Google Scholar
H. J. Flint, K. P. Scott, P. Louis, and S. H. Duncan, “The role of the gut microbiota in nutrition and health,” Nature Reviews Gastroenterology & Hepatology, vol. 9, no. 10, pp. 577–589, 2012.
View at: Publisher Site | Google Scholar
P. B. Eckburg, E. M. Bik, C. N. Bernstein et al., “Diversity of the human intestinal microbial flora,” Science, vol. 308, no. 5728, pp. 1635–1638, 2005.
View at: Publisher Site | Google Scholar
H. J. Flint, K. P. Scott, S. H. Duncan, P. Louis, and E. Forano, “Microbial degradation of complex carbohydrates in the gut,” Gut Microbes, vol. 3, no. 4, pp. 289–306, 2012.
View at: Publisher Site | Google Scholar
A. W. Walker, J. Ince, S. H. Duncan et al., “Dominant and diet-responsive groups of bacteria within the human colonic microbiota,” The ISME Journal, vol. 5, no. 2, pp. 220–230, 2011.
View at: Publisher Site | Google Scholar
D. Aune, D. S. Chan, R. Lau et al., “Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies,” BMJ, vol. 343, p. d6617, 2011.
View at: Publisher Site | Google Scholar
H. M. Chen, Y. N. Yu, J. L. Wang et al., “Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma,” The American of Clinical Nutrition, vol. 97, no. 5, pp. 1044–1052, 2013.
View at: Publisher Site | Google Scholar
N. Food, Physical Activity, and the Prevention of Cancer: A Global Perspective, World Cancer Research Fund and American Institute for Cancer Research, Washington DC, 2007.
S. I. Grivennikov, F. R. Greten, and M. Karin, “Immunity, inflammation, and cancer,” Cell, vol. 140, no. 6, pp. 883–899, 2010.
View at: Publisher Site | Google Scholar
R. D. Schreiber, L. J. Old, and M. J. Smyth, “Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion,” Science, vol. 331, no. 6024, pp. 1565–1570, 2011.
View at: Publisher Site | Google Scholar
J. C. Arthur, E. Perez-Chanona, M. Mühlbauer et al., “Intestinal inflammation targets cancer-inducing activity of the microbiota,” Science, vol. 338, no. 6103, pp. 120–123, 2012.
View at: Publisher Site | Google Scholar
R. F. Schwabe and C. Jobin, “The microbiome and cancer,” Nature Reviews Cancer, vol. 13, no. 11, pp. 800–812, 2013.
View at: Publisher Site | Google Scholar
M. D. Neal, C. P. Sodhi, H. Jia et al., “Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the p53 up-regulated modulator of apoptosis,” Journal of Biological Chemistry, vol. 287, no. 44, pp. 37296–37308, 2012.
View at: Publisher Site | Google Scholar
W. B. Strum, “Colorectal adenomas,” New England Journal of Medicine, vol. 374, no. 11, pp. 1065–1075, 2016.
View at: Publisher Site | Google Scholar
Q. Feng, S. Liang, H. Jia et al., “Gut microbiome development along the colorectal adenoma–carcinoma sequence,” Nature Communications, vol. 6, no. 1, pp. 1–13, 2015.
View at: Publisher Site | Google Scholar
G. Zeller, J. Tap, A. Y. Voigt et al., “Potential of fecal microbiota for early-stage detection of colorectal cancer,” Molecular Systems Biology, vol. 10, no. 11, p. 766, 2014.
View at: Publisher Site | Google Scholar
S. Yachida, S. Mizutani, H. Shiroma et al., “Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer,” Nature Medicine, vol. 25, no. 6, pp. 968–976, 2019.
View at: Publisher Site | Google Scholar
C. Luan, L. Xie, X. Yang et al., “Dysbiosis of fungal microbiota in the intestinal mucosa of patients with colorectal adenomas,” Scientific Reports, vol. 5, no. 1, pp. 1–9, 2015.
View at: Publisher Site | Google Scholar
H. Tilg, T. E. Adolph, R. R. Gerner, and A. R. Moschen, “The intestinal microbiota in colorectal cancer,” Cancer Cell, vol. 33, no. 6, pp. 954–964, 2018.
View at: Publisher Site | Google Scholar
J. L. Round and S. K. Mazmanian, “The gut microbiota shapes intestinal immune responses during health and disease,” Nature Reviews Immunology, vol. 9, no. 5, pp. 313–323, 2009.
View at: Publisher Site | Google Scholar
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
View at: Publisher Site | Google Scholar
A. Lasry, A. Zinger, and Y. Ben-Neriah, “Inflammatory networks underlying colorectal cancer,” Nature Immunology, vol. 17, no. 3, pp. 230–240, 2016.
View at: Publisher Site | Google Scholar
L. Beaugerie and S. H. Itzkowitz, “Cancers complicating inflammatory bowel disease,” New England Journal of Medicine, vol. 372, no. 15, pp. 1441–1452, 2015.
View at: Publisher Site | Google Scholar
C. Canavan, K. R. Abrams, and J. Mayberry, “Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease,” Alimentary Pharmacology & Therapeutics, vol. 23, no. 8, pp. 1097–1104, 2006.
View at: Publisher Site | Google Scholar
J. A. Eaden, K. R. Abrams, and J. F. Mayberry, “The risk of colorectal cancer in ulcerative colitis: a meta-analysis,” Gut, vol. 48, no. 4, pp. 526–535, 2001.
View at: Publisher Site | Google Scholar
S. Sebastian, H. V. Hernández, P. Myrelid et al., “Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I),” Journal of Crohn's and Colitis, vol. 8, no. 1, pp. 5–18, 2014.
View at: Publisher Site | Google Scholar
S. H. Wong, L. Zhao, X. Zhang et al., “Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice,” Gastroenterology, vol. 153, no. 6, pp. 1621–1633.e6, 2017.
View at: Publisher Site | Google Scholar
E. Cremonesi, V. Governa, J. F. G. Garzon et al., “Gut microbiota modulate T cell trafficking into human colorectal cancer,” Gut, vol. 67, no. 11, pp. 1984–1994, 2018.
View at: Publisher Site | Google Scholar
A. D. Kostic, E. Chun, L. Robertson et al., “Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment,” Cell Host & Microbe, vol. 14, no. 2, pp. 207–215, 2013.
View at: Publisher Site | Google Scholar
S. Tomkovich, Y. Yang, K. Winglee et al., “Locoregional effects of microbiota in a preclinical model of colon carcinogenesis,” Cancer Research, vol. 77, no. 10, pp. 2620–2632, 2017.
View at: Publisher Site | Google Scholar
A. Boleij, E. M. Hechenbleikner, A. C. Goodwin et al., “The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients,” Clinical Infectious Diseases, vol. 60, no. 2, pp. 208–215, 2015.
View at: Publisher Site | Google Scholar
S. Wu, K. J. Rhee, E. Albesiano et al., “A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses,” Nature Medicine, vol. 15, no. 9, pp. 1016–1022, 2009.
View at: Publisher Site | Google Scholar
L. Chung, E. T. Orberg, A. L. Geis et al., “Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells,” Cell Host & Microbe, vol. 23, no. 2, pp. 203–214.e5, 2018.
View at: Publisher Site | Google Scholar
T. Iyadorai, V. Mariappan, K. M. Vellasamy et al., “Prevalence and association of pks+ Escherichia coli with colorectal cancer in patients at the University Malaya Medical Centre, Malaysia,” PloS one, vol. 15, no. 1, article e0228217, 2020.
View at: Publisher Site | Google Scholar
J. C. Arthur, R. Z. Gharaibeh, M. Mühlbauer et al., “Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer,” Nature Communications, vol. 5, no. 1, pp. 1–11, 2014.
View at: Publisher Site | Google Scholar
M. Bonnet, E. Buc, P. Sauvanet et al., “Colonization of the human gut by E. coli and colorectal cancer risk,” Clinical Cancer Research, vol. 20, no. 4, pp. 859–867, 2014.
View at: Publisher Site | Google Scholar
X. Wang, Y. Yang, D. R. Moore, S. L. Nimmo, S. A. Lightfoot, and M. M. Huycke, “4-Hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis–infected macrophages,” Gastroenterology, vol. 142, no. 3, pp. 543–551.e7, 2012.
View at: Publisher Site | Google Scholar
A. R. Moschen, R. R. Gerner, J. Wang et al., “Lipocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations,” Cell Host & Microbe, vol. 19, no. 4, pp. 455–469, 2016.
View at: Publisher Site | Google Scholar
R. Kesselring, J. Glaesner, A. Hiergeist et al., “IRAK-M expression in tumor cells supports colorectal cancer progression through reduction of antimicrobial defense and stabilization of STAT3,” Cancer Cell, vol. 29, no. 5, pp. 684–696, 2016.
View at: Publisher Site | Google Scholar
A. Couturier-Maillard, T. Secher, A. Rehman et al., “NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer,” The Journal of Clinical Investigation, vol. 123, no. 2, pp. 700–711, 2013.
View at: Publisher Site | Google Scholar
H. Zhu, W. Y. Xu, Z. Hu et al., “RNA virus receptor Rig-I monitors gut microbiota and inhibits colitis-associated colorectal cancer,” Journal of Experimental & Clinical Cancer Research, vol. 36, no. 1, pp. 1–11, 2017.
View at: Publisher Site | Google Scholar
S. M. Man, Q. Zhu, L. Zhu et al., “Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer,” Cell, vol. 162, no. 1, pp. 45–58, 2015.
View at: Publisher Site | Google Scholar
Y. Yang, W. Weng, J. Peng et al., “Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor− κB, and up-regulating expression of microRNA-21,” Gastroenterology, vol. 152, no. 4, pp. 851–866.e24, 2017.
View at: Publisher Site | Google Scholar
Y. Wu, J. Wu, T. Chen et al., “Fusobacterium nucleatum potentiates intestinal tumorigenesis in mice via a toll-like receptor 4/p21-activated kinase 1 cascade,” Digestive Diseases and Sciences, vol. 63, no. 5, pp. 1210–1218, 2018.
View at: Publisher Site | Google Scholar
H. Tsoi, E. S. Chu, X. Zhang et al., “Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice,” Gastroenterology, vol. 152, no. 6, pp. 1419–1433.e5, 2017.
View at: Publisher Site | Google Scholar
N. N. Keum and E. Giovannucci, “Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies,” Nature Reviews Gastroenterology & Hepatology, vol. 16, no. 12, pp. 713–732, 2019.
View at: Publisher Site | Google Scholar
N. Murphy, V. Moreno, D. J. Hughes et al., “Lifestyle and dietary environmental factors in colorectal cancer susceptibility,” Molecular Aspects of Medicine, vol. 69, pp. 2–9, 2019.
View at: Publisher Site | Google Scholar
A. Chao, M. J. Thun, C. J. Connell et al., “Meat consumption and risk of colorectal cancer,” JAMA, vol. 293, no. 2, pp. 172–182, 2005.
View at: Publisher Site | Google Scholar
T. Norat, S. Bingham, P. Ferrari et al., “Meat, fish, and colorectal cancer risk: the European prospective investigation into cancer and nutrition,” Journal of the National Cancer Institute, vol. 97, no. 12, pp. 906–916, 2005.
View at: Publisher Site | Google Scholar
G. Lombardi-Boccia, B. Martinez-Dominguez, and A. Aguzzi, “Total heme and non-heme iron in raw and cooked meats,” Journal of Food Science, vol. 67, no. 5, pp. 1738–1741, 2002.
View at: Publisher Site | Google Scholar
B. Lauby-Secretan, N. Vilahur, F. Bianchini, N. Guha, and K. Straif, “The IARC perspective on colorectal cancer screening,” New England Journal of Medicine, vol. 378, no. 18, pp. 1734–1740, 2018.
View at: Publisher Site | Google Scholar
L. Qiao and Y. Feng, “Intakes of heme iron and zinc and colorectal cancer incidence: a meta-analysis of prospective studies,” Cancer Causes & Control, vol. 24, no. 6, pp. 1175–1183, 2013.
View at: Publisher Site | Google Scholar
C. J. Reedy and B. R. Gibney, “Heme protein assemblies,” Chemical Reviews, vol. 104, no. 2, pp. 617–650, 2004.
View at: Publisher Site | Google Scholar
K. O. Okonjo, “Bohr effect of hemoglobins: accounting for differences in magnitude,” Journal of Theoretical Biology, vol. 380, pp. 436–443, 2015.
View at: Publisher Site | Google Scholar
S. J. Stohs and D. Bagchi, “Oxidative mechanisms in the toxicity of metal ions,” Free Radical Biology and Medicine, vol. 18, no. 2, pp. 321–336, 1995.
View at: Publisher Site | Google Scholar
M. S. Cooke, M. D. Evans, M. Dizdaroglu, and J. Lunec, “Oxidative DNA damage: mechanisms, mutation, and disease,” The FASEB Journal, vol. 17, no. 10, pp. 1195–1214, 2003.
View at: Publisher Site | Google Scholar
M. T. Russo, G. de Luca, P. Degan et al., “Accumulation of the oxidative base lesion 8-hydroxyguanine in DNA of tumor-prone mice defective in both the Myh and Ogg1 DNA glycosylases,” Cancer Research, vol. 64, no. 13, pp. 4411–4414, 2004.
View at: Publisher Site | Google Scholar
J. P. F. Angeli, C. C. M. Garcia, F. Sena et al., “Lipid hydroperoxide-induced and hemoglobin-enhanced oxidative damage to colon cancer cells,” Free Radical Biology and Medicine, vol. 51, no. 2, pp. 503–515, 2011.
View at: Publisher Site | Google Scholar
N. IJssennagger, M. Derrien, G. M. van Doorn et al., “Dietary heme alters microbiota and mucosa of mouse colon without functional changes in host-microbe cross-talk,” PLoS One, vol. 7, no. 12, article e49868, 2012.
View at: Publisher Site | Google Scholar
M. Schmitt and F. R. Greten, “The inflammatory pathogenesis of colorectal cancer,” Nature Reviews Immunology, vol. 21, no. 10, pp. 653–667, 2021.
View at: Publisher Site | Google Scholar
B. Dörsam, N. Seiwert, S. Foersch et al., “PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression,” Proceedings of the National Academy of Sciences, vol. 115, no. 17, pp. E4061–E4070, 2018.
View at: Publisher Site | Google Scholar
M. A. A. Schepens, C. Vink, A. J. Schonewille, G. Dijkstra, R. van der Meer, and I. M. J. Bovee-Oudenhoven, “Dietary heme adversely affects experimental colitis in rats, despite heat-shock protein induction,” Nutrition, vol. 27, no. 5, pp. 590–597, 2011.
View at: Publisher Site | Google Scholar
M. Constante, G. Fragoso, A. Calvé, M. Samba-Mondonga, and M. M. Santos, “Dietary heme induces gut dysbiosis, aggravates colitis, and potentiates the development of adenomas in mice,” Frontiers in Microbiology, vol. 8, p. 1809, 2017.
View at: Publisher Site | Google Scholar
A.,. M. Zahidul, S. Devalaraja, and M. Haldar, “The heme connection: linking erythrocytes and macrophage biology,” Frontiers in Immunology, vol. 8, p. 33, 2017.
View at: Publisher Site | Google Scholar
T. Sawa, T. Akaike, K. Kida, Y. Fukushima, K. Takagi, and H. Maeda, “Lipid peroxyl radicals from oxidized oils and heme-iron: implication of a high-fat diet in colon carcinogenesis,” Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 7, no. 11, pp. 1007–1012, 1998.
View at: Google Scholar
F. Pierre, S. Taché, C. R. Petit, R. van der Meer, and D. E. Corpet, “Meat and cancer: haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats,” Carcinogenesis, vol. 24, no. 10, pp. 1683–1690, 2003.
View at: Publisher Site | Google Scholar
J. E. Paulsen, E. M. Løberg, H. B. Ølstørn, H. Knutsen, I.-L. Steffensen, and J. Alexander, “Flat dysplastic aberrant crypt foci are related to tumorigenesis in the colon of azoxymethane-treated rat,” Cancer Research, vol. 65, no. 1, pp. 121–129, 2005.
View at: Publisher Site | Google Scholar
F. Pierre, S. Taché, D. E. Corpet, A. Freeman, and R. van der Meer, “Beef meat and blood sausage promote the formation of azoxymethane-induced mucin-depleted foci and aberrant crypt foci in rat colons,” The Journal of Nutrition, vol. 134, no. 10, pp. 2711–2716, 2004.
View at: Publisher Site | Google Scholar
F. Pierre, R. Santarelli, S. Taché, F. Guéraud, and D. E. Corpet, “Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium,” British Journal of Nutrition, vol. 99, no. 5, pp. 1000–1006, 2008.
View at: Publisher Site | Google Scholar
F. H. F. Pierre, R. L. Santarelli, O. Allam et al., “Freeze-dried ham promotes azoxymethane-induced mucin-depleted foci and aberrant crypt foci in rat colon,” Nutrition and Cancer, vol. 62, no. 5, pp. 567–573, 2010.
View at: Publisher Site | Google Scholar
L. Bailly, R. Fabre, C. Pradier, and A. Iannelli, “Colorectal Cancer Risk Following Bariatric Surgery in a Nationwide Study of French Individuals With Obesity,” JAMA Surgery, vol. 155, no. 5, pp. 395–402, 2020.
View at: Publisher Site | Google Scholar
R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2019,” CA: a Cancer Journal for Clinicians, vol. 69, no. 1, pp. 7–34, 2019.
View at: Publisher Site | Google Scholar
J. K. Lee, E. G. Liles, S. Bent, T. R. Levin, and D. A. Corley, “Accuracy of fecal immunochemical tests for colorectal cancer,” Annals of Internal Medicine, vol. 160, no. 3, pp. 171–181, 2014.
View at: Publisher Site | Google Scholar
S. Hundt, U. Haug, and H. Brenner, “Comparative evaluation of immunochemical fecal occult blood tests for colorectal adenoma detection,” Annals of Internal Medicine, vol. 150, no. 3, pp. 162–169, 2009.
View at: Publisher Site | Google Scholar
T. F. Imperiale, D. F. Ransohoff, S. H. Itzkowitz et al., “Multitarget stool DNA testing for colorectal-cancer screening,” New England Journal of Medicine, vol. 370, no. 14, pp. 1287–1297, 2014.
View at: Publisher Site | Google Scholar
M. Ito, S. Kanno, K. Nosho et al., “Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway,” International Journal of Cancer, vol. 137, no. 6, pp. 1258–1268, 2015.
View at: Publisher Site | Google Scholar
N. T. Baxter, M. T. Ruffin, M. A. Rogers, and P. D. Schloss, “Microbiota-based model improves the sensitivity of fecal immunochemical test for detecting colonic lesions,” Genome Medicine, vol. 8, no. 1, pp. 1–10, 2016.
View at: Publisher Site | Google Scholar
J. Yu, Q. Feng, S. H. Wong et al., “Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer,” Gut, vol. 66, no. 1, pp. 70–78, 2017.
View at: Publisher Site | Google Scholar
J. P. Zackular, M. A. Rogers, M. T. Ruffin IV, and P. D. Schloss, “The human gut microbiome as a screening tool for colorectal cancer,” Cancer Prevention Research, vol. 7, no. 11, pp. 1112–1121, 2014.
View at: Publisher Site | Google Scholar
G. Nakatsu, H. Zhou, W. K. K. Wu et al., “Alterations in enteric virome are associated with colorectal cancer and survival outcomes,” Gastroenterology, vol. 155, no. 2, pp. 529–541.e5, 2018.
View at: Publisher Site | Google Scholar
O. O. Coker, G. Nakatsu, R. Z. Dai et al., “Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer,” Gut, vol. 68, no. 4, pp. 654–662, 2019.
View at: Publisher Site | Google Scholar
S. H. Wong, T. N. Kwong, T. C. Chow et al., “Quantitation of faecal fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia,” Gut, vol. 66, no. 8, pp. 1441–1448, 2017.
View at: Publisher Site | Google Scholar
Y. Suehiro, Y. Zhang, S. Hashimoto et al., “Highly sensitive faecal DNA testing of TWIST1 methylation in combination with faecal immunochemical test for haemoglobin is a promising marker for detection of colorectal neoplasia,” Annals of Clinical Biochemistry, vol. 55, no. 1, pp. 59–68, 2018.
View at: Publisher Site | Google Scholar
S. Guo, L. Li, B. Xu et al., “A simple and novel fecal biomarker for colorectal cancer: ratio of Fusobacterium nucleatum to probiotics populations, based on their antagonistic effect,” Clinical Chemistry, vol. 64, no. 9, pp. 1327–1337, 2018.
View at: Publisher Site | Google Scholar
Y. H. Xie, Q. Y. Gao, G. X. Cai et al., “Fecal Clostridium symbiosum for noninvasive detection of early and advanced colorectal cancer: test and validation studies,” eBioMedicine, vol. 25, pp. 32–40, 2017.
View at: Publisher Site | Google Scholar
V. Eklöf, A. Löfgren-Burström, C. Zingmark et al., “Cancer-associated fecal microbial markers in colorectal cancer detection,” International Journal of Cancer, vol. 141, no. 12, pp. 2528–2536, 2017.
View at: Publisher Site | Google Scholar
Q. Liang, J. Chiu, Y. Chen et al., “Fecal bacteria act as novel biomarkers for noninvasive diagnosis of colorectal cancer,” Clinical Cancer Research, vol. 23, no. 8, pp. 2061–2070, 2017.
View at: Publisher Site | Google Scholar
A. M. Thomas, P. Manghi, F. Asnicar et al., “Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation,” Nature Medicine, vol. 25, no. 4, pp. 667–678, 2019.
View at: Publisher Site | Google Scholar
J. Wirbel, P. T. Pyl, E. Kartal et al., “Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer,” Nature Medicine, vol. 25, no. 4, pp. 679–689, 2019.
View at: Publisher Site | Google Scholar
Z. Dai, O. O. Coker, G. Nakatsu et al., “Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers,” Microbiome, vol. 6, no. 1, pp. 1–12, 2018.
View at: Publisher Site | Google Scholar
E. R. Fearon and B. Vogelstein, “A genetic model for colorectal tumorigenesis,” Cell, vol. 61, no. 5, pp. 759–767, 1990.
View at: Publisher Site | Google Scholar
I. Allali, S. Delgado, P. I. Marron et al., “Gut microbiome compositional and functional differences between tumor and non-tumor adjacent tissues from cohorts from the US and Spain,” Gut Microbes, vol. 6, no. 3, pp. 161–172, 2015.
View at: Publisher Site | Google Scholar
A. N. McCoy, F. Araujo-Perez, A. Azcarate-Peril, J. J. Yeh, R. S. Sandler, and T. O. Keku, “Fusobacterium is associated with colorectal adenomas,” PLoS One, vol. 8, no. 1, article e53653, 2013.
View at: Publisher Site | Google Scholar
S. Rezasoltani, H. A. Aghdaei, H. Dabiri, A. A. Sepahi, M. H. Modarressi, and E. N. Mojarad, “The association between fecal microbiota and different types of colorectal polyp as precursors of colorectal cancer,” Microbial Pathogenesis, vol. 124, pp. 244–249, 2018.
View at: Publisher Site | Google Scholar
L. Flanagan, J. Schmid, M. Ebert et al., “Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome,” European Journal of Clinical Microbiology & Infectious Diseases, vol. 33, no. 8, pp. 1381–1390, 2014.
View at: Publisher Site | Google Scholar
J. Yu, Y. Chen, X. Fu et al., “Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway,” International Journal of Cancer, vol. 139, no. 6, pp. 1318–1326, 2016.
View at: Publisher Site | Google Scholar
K. Mima, R. Nishihara, Z. R. Qian et al., “Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis,” Gut, vol. 65, no. 12, pp. 1973–1980, 2016.
View at: Publisher Site | Google Scholar
Z. Wei, S. Cao, S. Liu et al., “Could gut microbiota serve as prognostic biomarker associated with colorectal cancer patients' survival? A pilot study on relevant mechanism,” Oncotarget, vol. 7, no. 29, pp. 46158–46172, 2016.
View at: Publisher Site | Google Scholar
T. Tahara, E. Yamamoto, H. Suzuki et al., “Fusobacterium in colonic flora and molecular features of colorectal carcinoma,” Cancer Research, vol. 74, no. 5, pp. 1311–1318, 2014.
View at: Publisher Site | Google Scholar
K. Mima, Y. Cao, A. T. Chan et al., “Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location,” Clinical and Translational Gastroenterology, vol. 7, no. 11, article e200, 2016.
View at: Publisher Site | Google Scholar
J. Kerr, C. Anderson, and S. M. Lippman, “Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence,” The Lancet Oncology, vol. 18, no. 8, pp. e457–e471, 2017.
View at: Publisher Site | Google Scholar
M. Song and E. Giovannucci, “Preventable incidence and mortality of carcinoma associated with lifestyle factors among white adults in the United States,” JAMA Oncology, vol. 2, no. 9, pp. 1154–1161, 2016.
View at: Publisher Site | Google Scholar
F. Islami, A. Goding Sauer, K. D. Miller et al., “Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States,” CA: a Cancer Journal for Clinicians, vol. 68, no. 1, pp. 31–54, 2018.
View at: Publisher Site | Google Scholar
E. Le Chatelier, T. Nielsen, J. Qin et al., “Richness of human gut microbiome correlates with metabolic markers,” Nature, vol. 500, no. 7464, pp. 541–546, 2013.
View at: Publisher Site | Google Scholar
R. E. Ley, F. Bäckhed, P. Turnbaugh, C. A. Lozupone, R. D. Knight, and J. I. Gordon, “Obesity alters gut microbial ecology,” Proceedings of the National Academy of Sciences, vol. 102, no. 31, pp. 11070–11075, 2005.
View at: Publisher Site | Google Scholar
R. E. Ley, P. J. Turnbaugh, S. Klein, and J. I. Gordon, “Human gut microbes associated with obesity,” Nature, vol. 444, no. 7122, pp. 1022-1023, 2006.
View at: Publisher Site | Google Scholar
R. Li, S. A. Grimm, K. Chrysovergis et al., “Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression,” Cell Metabolism, vol. 19, no. 4, pp. 702–711, 2014.
View at: Publisher Site | Google Scholar
Y. Qin, J. D. Roberts, S. A. Grimm et al., “An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression,” Genome Biology, vol. 19, no. 1, pp. 1–14, 2018.
View at: Publisher Site | Google Scholar
R. Liu, J. Hong, X. Xu et al., “Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention,” Nature Medicine, vol. 23, no. 7, pp. 859–868, 2017.
View at: Publisher Site | Google Scholar
F. B. Seganfredo, C. A. Blume, M. Moehlecke et al., “Weight-loss interventions and gut microbiota changes in overweight and obese patients: a systematic review,” Obesity Reviews, vol. 18, no. 8, pp. 832–851, 2017.
View at: Publisher Site | Google Scholar
N. Keum, D. C. Greenwood, D. H. Lee et al., “Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies,” Journal of the National Cancer Institute, vol. 107, no. 2, article djv088, 2015.
View at: Publisher Site | Google Scholar
L. Sjöström, A. Gummesson, C. D. Sjöström et al., “Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects study): a prospective, controlled intervention trial,” The Lancet Oncology, vol. 10, no. 7, pp. 653–662, 2009.
View at: Publisher Site | Google Scholar
M. Derogar, M. A. Hull, P. Kant, M. Östlund, Y. Lu, and J. Lagergren, “Increased risk of colorectal cancer after obesity surgery,” Annals of Surgery, vol. 258, no. 6, pp. 983–988, 2013.
View at: Publisher Site | Google Scholar
A. Aravani, A. Downing, J. D. Thomas, J. Lagergren, E. J. Morris, and M. A. Hull, “Obesity surgery and risk of colorectal and other obesity-related cancers: an English population-based cohort study,” Cancer Epidemiology, vol. 53, pp. 99–104, 2018.
View at: Publisher Site | Google Scholar
D. P. Schauer, H. S. Feigelson, C. Koebnick et al., “Bariatric surgery and the risk of cancer in a large multisite cohort,” Annals of Surgery, vol. 269, no. 1, pp. 95–101, 2019.
View at: Publisher Site | Google Scholar
M. A. Hull, S. R. Markar, and E. J. Morris, “Cancer risk after bariatric surgery–is colorectal cancer a special case?” Nature Reviews Gastroenterology & Hepatology, vol. 15, no. 11, pp. 653-654, 2018.
View at: Publisher Site | Google Scholar
R. N. Carmody, G. K. Gerber, J. M. Luevano Jr. et al., “Diet dominates host genotype in shaping the murine gut microbiota,” Cell Host & Microbe, vol. 17, no. 1, pp. 72–84, 2015.
View at: Publisher Site | Google Scholar
D. Rothschild, O. Weissbrod, E. Barkan et al., “Environment dominates over host genetics in shaping human gut microbiota,” Nature, vol. 555, no. 7695, pp. 210–215, 2018.
View at: Publisher Site | Google Scholar
J. Ou, F. Carbonero, E. G. Zoetendal et al., “Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans,” The American Journal of Clinical Nutrition, vol. 98, no. 1, pp. 111–120, 2013.
View at: Publisher Site | Google Scholar
L. A. David, C. F. Maurice, R. N. Carmody et al., “Diet rapidly and reproducibly alters the human gut microbiome,” Nature, vol. 505, no. 7484, pp. 559–563, 2014.
View at: Publisher Site | Google Scholar
S. J. O’Keefe, J. V. Li, L. Lahti et al., “Fat, fibre and cancer risk in African Americans and rural Africans,” Nature Communications, vol. 6, no. 1, pp. 1–14, 2015.
View at: Publisher Site | Google Scholar
C. De Filippo, D. Cavalieri, M. Di Paola et al., “Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa,” Proceedings of the National Academy of Sciences, vol. 107, no. 33, pp. 14691–14696, 2010.
View at: Publisher Site | Google Scholar
K. Makki, E. C. Deehan, J. Walter, and F. Bäckhed, “The impact of dietary fiber on gut microbiota in host health and disease,” Cell Host & Microbe, vol. 23, no. 6, pp. 705–715, 2018.
View at: Publisher Site | Google Scholar
G. R. Gibson, R. Hutkins, M. E. Sanders et al., “Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics,” Nature Reviews Gastroenterology & Hepatology, vol. 14, no. 8, pp. 491–502, 2017.
View at: Publisher Site | Google Scholar
D. So, K. Whelan, M. Rossi et al., “Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis,” The American Journal of Clinical Nutrition, vol. 107, no. 6, pp. 965–983, 2018.
View at: Publisher Site | Google Scholar
D. R. Donohoe, D. Holley, L. B. Collins et al., “A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner,” Cancer Discovery, vol. 4, no. 12, pp. 1387–1397, 2014.
View at: Publisher Site | Google Scholar
D. S. Alberts, M. E. Martínez, D. J. Roe et al., “Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas,” New England Journal of Medicine, vol. 342, no. 16, pp. 1156–1162, 2000.
View at: Publisher Site | Google Scholar
E. Lanza, B. Yu, G. Murphy et al., “The polyp prevention trial–continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization,” Cancer Epidemiology Biomarkers & Prevention, vol. 16, no. 9, pp. 1745–1752, 2007.
View at: Publisher Site | Google Scholar
S. J. Bultman and C. Jobin, “Microbial-derived butyrate: an oncometabolite or tumor-suppressive metabolite?” Cell Host & Microbe, vol. 16, no. 2, pp. 143–145, 2014.
View at: Publisher Site | Google Scholar
D. D. Alexander, D. L. Weed, C. A. Cushing, and K. A. Lowe, “Meta-analysis of prospective studies of red meat consumption and colorectal cancer,” European Journal of Cancer Prevention, vol. 20, no. 4, pp. 293–307, 2011.
View at: Publisher Site | Google Scholar
S. J. O'keefe, “Diet, microorganisms and their metabolites, and colon cancer,” Nature Reviews Gastroenterology & Hepatology, vol. 13, no. 12, pp. 691–706, 2016.
View at: Publisher Site | Google Scholar
D. S. Chan, R. Lau, D. Aune et al., “Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies,” PLoS One, vol. 6, no. 6, article e20456, 2011.
View at: Publisher Site | Google Scholar
V. Bouvard, D. Loomis, K. Z. Guyton et al., “Carcinogenicity of consumption of red and processed meat,” The Lancet Oncology, vol. 16, no. 16, pp. 1599-1600, 2015.
View at: Publisher Site | Google Scholar
M. J. Orlich, P. N. Singh, J. Sabaté et al., “Vegetarian dietary patterns and the risk of colorectal cancers,” JAMA Internal Medicine, vol. 175, no. 5, pp. 767–776, 2015.
View at: Publisher Site | Google Scholar
M. A. Hildebrandt, C. Hoffmann, S. A. Sherrill–Mix et al., “High-fat diet determines the composition of the murine gut microbiome independently of obesity,” Gastroenterology, vol. 137, no. 5, pp. 1716–1724.e2, 2009.
View at: Publisher Site | Google Scholar
C. Zhang, M. Zhang, X. Pang, Y. Zhao, L. Wang, and L. Zhao, “Structural resilience of the gut microbiota in adult mice under high-fat dietary perturbations,” The ISME Journal, vol. 6, no. 10, pp. 1848–1857, 2012.
View at: Publisher Site | Google Scholar
H. Bernstein, C. Bernstein, C. M. Payne, and K. Dvorak, “Bile acids as endogenous etiologic agents in gastrointestinal cancer,” World Journal of Gastroenterology: WJG, vol. 15, no. 27, pp. 3329–3340, 2009.
View at: Publisher Site | Google Scholar
H. Cao, S. Luo, M. Xu et al., “The secondary bile acid, deoxycholate accelerates intestinal adenoma–adenocarcinoma sequence in Apc min/+ mice through enhancing Wnt signaling,” Familial Cancer, vol. 13, no. 4, pp. 563–571, 2014.
View at: Publisher Site | Google Scholar
B. S. Drasar and D. Irving, “Environmental factors and cancer of the colon and breast,” British Journal of Cancer, vol. 27, no. 2, pp. 167–172, 1973.
View at: Publisher Site | Google Scholar
L. Liu, W. Zhuang, R. Q. Wang et al., “Is dietary fat associated with the risk of colorectal cancer? A meta-analysis of 13 prospective cohort studies,” European Journal of Nutrition, vol. 50, no. 3, pp. 173–184, 2011.
View at: Publisher Site | Google Scholar
R. MacLennan, F. Macrae, C. Bain et al., “Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas,” JNCI Journal of the National Cancer Institute, vol. 87, no. 23, pp. 1760–1766, 1995.
View at: Publisher Site | Google Scholar
C. A. Thomson, L. Van Horn, B. J. Caan et al., “Cancer incidence and mortality during the intervention and postintervention periods of the Women's Health Initiative Dietary Modification Trial,” Cancer Epidemiology, Biomarkers & Prevention, vol. 23, no. 12, pp. 2924–2935, 2014.
View at: Publisher Site | Google Scholar
A. Schatzkin, E. Lanza, D. Corle et al., “Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas,” New England Journal of Medicine, vol. 342, no. 16, pp. 1149–1155, 2000.
View at: Publisher Site | Google Scholar
K. Almendingen, B. Hofstad, and M. H. Vatn, “Dietary Habits and Growth and Recurrence of Colorectal Adenomas: Results From a Three-Year Endoscopic Follow-Up Study,” Nutrition and Cancer, vol. 49, no. 2, pp. 131–138, 2004.
View at: Publisher Site | Google Scholar
C. Hill, F. Guarner, G. Reid et al., “Expert consensus document: the International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic,” Nature Reviews Gastroenterology & Hepatology, vol. 11, no. 8, pp. 506–514, 2014.
View at: Publisher Site | Google Scholar
L. Zitvogel, R. Daillère, M. P. Roberti, B. Routy, and G. Kroemer, “Anticancer effects of the microbiome and its products,” Nature Reviews Microbiology, vol. 15, no. 8, pp. 465–478, 2017.
View at: Publisher Site | Google Scholar
S. A. Dos Reis, L. L. da Conceição, N. P. Siqueira, D. D. Rosa, L. L. da Silva, and G. P. Maria do Carmo, “Review of the mechanisms of probiotic actions in the prevention of colorectal cancer,” Nutrition Research, vol. 37, pp. 1–19, 2017.
View at: Publisher Site | Google Scholar
M. Thirabunyanon, P. Boonprasom, and P. Niamsup, “Probiotic potential of lactic acid bacteria isolated from fermented dairy milks on antiproliferation of colon cancer cells,” Biotechnology Letters, vol. 31, no. 4, pp. 571–576, 2009.
View at: Publisher Site | Google Scholar
C. C. Chen, W. C. Lin, M. S. Kong et al., “Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue,” British Journal of Nutrition, vol. 107, no. 11, pp. 1623–1634, 2012.
View at: Publisher Site | Google Scholar
Y. Wan, Y. Xin, C. Zhang et al., “Fermentation supernatants of Lactobacillus delbrueckii inhibit growth of human colon cancer cells and induce apoptosis through a caspase 3-dependent pathway,” Oncology Letters, vol. 7, no. 5, pp. 1738–1742, 2014.
View at: Publisher Site | Google Scholar
H. Konishi, M. Fujiya, H. Tanaka et al., “Probiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis,” Nature Communications, vol. 7, no. 1, pp. 1–12, 2016.
View at: Publisher Site | Google Scholar
B. Corthésy, H. R. Gaskins, and A. Mercenier, “Cross-talk between probiotic bacteria and the host immune system1,” The Journal of Nutrition, vol. 137, no. 3, pp. 781S–790S, 2007.
View at: Publisher Site | Google Scholar
V. Delcenserie, D. Martel, M. Lamoureux, J. Amiot, Y. Boutin, and D. Roy, “Immunomodulatory effects of probiotics in the intestinal tract,” Current Issues in Molecular Biology, vol. 10, no. 1-2, pp. 37–54, 2008.
View at: Google Scholar
A. J. Burns and I. R. Rowland, “Antigenotoxicity of probiotics and prebiotics on faecal water-induced DNA damage in human colon adenocarcinoma cells,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol. 551, no. 1-2, pp. 233–243, 2004.
View at: Publisher Site | Google Scholar
A. Nowak and Z. Libudzisz, “Ability of probiotic Lactobacillus casei DN 114001 to bind or/and metabolise heterocyclic aromatic amines in vitro,” European Journal of Nutrition, vol. 48, no. 7, pp. 419–427, 2009.
View at: Publisher Site | Google Scholar
J. Zhu, C. Zhu, S. Ge et al., “Lactobacillus salivarius Ren prevent the early colorectal carcinogenesis in 1, 2-dimethylhydrazine-induced rat model,” Journal of Applied Microbiology, vol. 117, no. 1, pp. 208–216, 2014.
View at: Publisher Site | Google Scholar
H. Ishikawa, I. Akedo, T. Otani et al., “Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumors,” International Journal of Cancer, vol. 116, no. 5, pp. 762–767, 2005.
View at: Publisher Site | Google Scholar
J. Rafter, M. Bennett, G. Caderni et al., “Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients,” The American Journal of Clinical Nutrition, vol. 85, no. 2, pp. 488–496, 2007.
View at: Publisher Site | Google Scholar
D. L. Worthley, R. K. Le Leu, V. L. Whitehall et al., “A human, double-blind, placebo-controlled, crossover trial of prebiotic, probiotic, and synbiotic supplementation: effects on luminal, inflammatory, epigenetic, and epithelial biomarkers of colorectal cancer,” The American Journal of Clinical Nutrition, vol. 90, no. 3, pp. 578–586, 2009.
View at: Publisher Site | Google Scholar
L. Zitvogel, Y. Ma, D. Raoult, G. Kroemer, and T. F. Gajewski, “The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies,” Science, vol. 359, no. 6382, pp. 1366–1370, 2018.
View at: Publisher Site | Google Scholar
S. C. Wei, C. R. Duffy, and J. P. Allison, “Fundamental mechanisms of immune checkpoint blockade therapy,” Cancer Discovery, vol. 8, no. 9, pp. 1069–1086, 2018.
View at: Publisher Site | Google Scholar
A. Sivan, L. Corrales, N. Hubert et al., “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy,” Science, vol. 350, no. 6264, pp. 1084–1089, 2015.
View at: Publisher Site | Google Scholar
V. Matson, J. Fessler, R. Bao et al., “The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients,” Science, vol. 359, no. 6371, pp. 104–108, 2018.
View at: Publisher Site | Google Scholar
M. Vétizou, J. M. Pitt, R. Daillère et al., “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota,” Science, vol. 350, no. 6264, pp. 1079–1084, 2015.
View at: Publisher Site | Google Scholar
B. Routy, E. Le Chatelier, L. Derosa et al., “Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors,” Science, vol. 359, no. 6371, pp. 91–97, 2018.
View at: Publisher Site | Google Scholar
J. U. Peled, S. M. Devlin, A. Staffas et al., “Intestinal microbiota and relapse after hematopoietic-cell transplantation,” Journal of Clinical Oncology, vol. 35, no. 15, pp. 1650–1659, 2017.
View at: Publisher Site | Google Scholar
N. Chaput, P. Lepage, C. Coutzac et al., “Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab,” Annals of Oncology, vol. 28, no. 6, pp. 1368–1379, 2017.
View at: Publisher Site | Google Scholar
N. Iida, A. Dzutsev, C. A. Stewart et al., “Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment,” Science, vol. 342, no. 6161, pp. 967–970, 2013.
View at: Publisher Site | Google Scholar
R. Z. Gharaibeh and C. Jobin, “Microbiota and cancer immunotherapy: in search of microbial signals,” Gut, vol. 68, no. 3, pp. 385–388, 2019.
View at: Publisher Site | Google Scholar
K. Dubin, M. K. Callahan, B. Ren et al., “Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis,” Nature Communications, vol. 7, no. 1, pp. 1–8, 2016.
View at: Publisher Site | Google Scholar
Y. Wang, D. H. Wiesnoski, B. A. Helmink et al., “Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis,” Nature Medicine, vol. 24, no. 12, pp. 1804–1808, 2018.
View at: Publisher Site | Google Scholar
S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and immune correlates of anti–PD-1 antibody in cancer,” New England Journal of Medicine, vol. 366, no. 26, pp. 2443–2454, 2012.
View at: Publisher Site | Google Scholar
M. J. Overman, R. McDermott, J. L. Leach et al., “Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study,” The Lancet Oncology, vol. 18, no. 9, pp. 1182–1191, 2017.
View at: Publisher Site | Google Scholar
M. J. Overman, S. Lonardi, K. Y. M. Wong et al., “Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer,” Journal of Clinical Oncology, vol. 36, no. 8, pp. 773–779, 2018.
View at: Publisher Site | Google Scholar
J. R. Brahmer, C. G. Drake, I. Wollner et al., “Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates,” Journal of Clinical Oncology, vol. 28, no. 19, pp. 3167–3175, 2010.
View at: Publisher Site | Google Scholar
U. J. N. Le DT, H. Wang, B. R. Bartlett et al., “PD-1 blockade in tumors with mismatch-repair deficiency,” New England Journal of Medicine, vol. 372, no. 26, pp. 2509–2520, 2015.
View at: Publisher Site | Google Scholar
D. J. N. Le DT, K. N. Smith, H. Wang et al., “Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade,” Science, vol. 357, no. 6349, pp. 409–413, 2017.
View at: Publisher Site | Google Scholar
A. P. García-González, A. D. Ritter, S. Shrestha, E. C. Andersen, L. S. Yilmaz, and A. J. Walhout, “Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics,” Cell, vol. 169, no. 3, pp. 431–441.e8, 2017.
View at: Publisher Site | Google Scholar
S. Viaud, F. Saccheri, G. Mignot et al., “The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide,” Science, vol. 342, no. 6161, pp. 971–976, 2013.
View at: Publisher Site | Google Scholar
J. V. Voorde, S. Sabuncuoğlu, S. Noppen et al., “Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine,” Journal of Biological Chemistry, vol. 289, no. 19, pp. 13054–13065, 2014.
View at: Publisher Site | Google Scholar
J. L. Alexander, I. D. Wilson, J. Teare, J. R. Marchesi, J. K. Nicholson, and J. M. Kinross, “Gut microbiota modulation of chemotherapy efficacy and toxicity,” Nature Reviews Gastroenterology & Hepatology, vol. 14, no. 6, pp. 356–365, 2017.
View at: Publisher Site | Google Scholar
T. Yu, F. Guo, Y. Yu et al., “Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy,” Cell, vol. 170, no. 3, pp. 548–563.e16, 2017.
View at: Publisher Site | Google Scholar
B. D. Wallace, H. Wang, K. T. Lane et al., “Alleviating cancer drug toxicity by inhibiting a bacterial enzyme,” Science, vol. 330, no. 6005, pp. 831–835, 2010.
View at: Publisher Site | Google Scholar
B. D. Wallace, A. B. Roberts, R. M. Pollet et al., “Structure and inhibition of microbiome β-glucuronidases essential to the alleviation of cancer drug toxicity,” Chemistry & Biology, vol. 22, no. 9, pp. 1238–1249, 2015.
View at: Publisher Site | Google Scholar
C. Y. Yeung, W. T. Chan, C. B. Jiang et al., “Amelioration of chemotherapy-induced intestinal mucositis by orally administered probiotics in a mouse model,” PLoS One, vol. 10, no. 9, article e0138746, 2015.
View at: Publisher Site | Google Scholar
S. Bullman, C. S. Pedamallu, E. Sicinska et al., “Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer,” Science, vol. 358, no. 6369, pp. 1443–1448, 2017.
View at: Publisher Site | Google Scholar
A. Cougnoux, J. Delmas, L. Gibold et al., “Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria,” Gut, vol. 65, no. 2, pp. 278–285, 2016.
View at: Publisher Site | Google Scholar
G. R. D’Haens and C. Jobin, “Fecal microbial transplantation for diseases beyond recurrent Clostridium difficile infection,” Gastroenterology, vol. 157, no. 3, pp. 624–636, 2019.
View at: Publisher Site | Google Scholar
J. L. McQuade, C. R. Daniel, B. A. Helmink, and J. A. Wargo, “Modulating the microbiome to improve therapeutic response in cancer,” The Lancet Oncology, vol. 20, no. 2, pp. e77–e91, 2019.
View at: Publisher Site | Google Scholar
J. Suez and E. Elinav, “The path towards microbiome-based metabolite treatment,” Nature Microbiology, vol. 2, no. 6, pp. 1–5, 2017.
View at: Publisher Site | Google Scholar
Y. Hu, R. K. Le Leu, C. T. Christophersen et al., “Manipulation of the gut microbiota using resistant starch is associated with protection against colitis-associated colorectal cancer in rats,” Carcinogenesis, vol. 37, no. 4, pp. 366–375, 2016.
View at: Publisher Site | Google Scholar
G. E. Kaiko, S. H. Ryu, O. I. Koues et al., “The colonic crypt protects stem cells from microbiota-derived metabolites,” Cell, vol. 165, no. 7, pp. 1708–1720, 2016.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2023 Rajendra Kumar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

430

Downloads

211

Citations