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SAGE Publications Sage UK: London, England

10.1177/20503121241274724
10.1177_20503121241274724
Review
Harmony unveiled: Intricate the interplay of dietary factor, gut microbiota, and colorectal cancer—A narrative review
https://orcid.org/0000-0002-4672-0551
Endale Hiwot Tezera 1
Tesfaye Winta 2
Hassen Fethiya Seid 1
Asrat Wastina Bitewlign 1
Temesgen Elizabeth Yihune 3
Shibabaw Yadelew Yimer 1
Asefa Tseganesh 4
1 Department of Medical Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
2 Department of Human Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
3 Amhara Regional State Health Bureau, Central Gondar Zone, Maksegnit Hospital, Gondar, Ethiopia
4 Department of Medical Nursing, School of Nursing, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
Hiwot Tezera Endale, Department of Medical Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar 196, Ethiopia. Email: hiwottezera1@gmail.com
31 8 2024
2024
12 2050312124127472412 2 2024
22 7 2024
© The Author(s) 2024
2024
SAGE Publications
https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Diet plays a critical role in shaping the gut microbiome, which in turn regulates molecular activities in the colonic mucosa. The state and composition of the gut microbiome are key factors in the development of colorectal cancer. An altered gut microbiome, linked to weakened immune responses and the production of carcinogenic substances, is a significant contributor to colorectal cancer pathogenesis. Dietary changes that involve low-fiber and phytomolecule intake, coupled with higher consumption of red meat, can raise the risk of colorectal cancer. Salutary filaments, which reach the colon undigested, are metabolized by the gut microbiome, producing short-chain fatty acids. Short-chain fatty acids possess beneficial anti-inflammatory and antiproliferative properties that promote colon health. A well-balanced microbiome, supported by beneficial fibers and phytochemicals, can regulate the activation of proto-oncogenes and oncogenic pathways, thereby reducing cell proliferation. Recent research suggests that an overabundance of specific microbes, such as Fusobacterium nucleatum, may contribute to adverse changes in the colonic mucosa. Positive lifestyle adjustments have been demonstrated to effectively inhibit the growth of harmful opportunistic organisms. Synbiotics, which combine probiotics and prebiotics, can protect the intestinal mucosa by enhancing immune responses and decreasing the production of harmful metabolites, oxidative stress, and cell proliferation. This narrative review provides a concise understanding of evolving evidence regarding how diet influences the gut microbiome, leading to the restoration of the colonic epithelium. It underscores the importance of a healthy, plant-based diet and associated supplements in preventing colorectal cancer by enhancing gut microbiome health.

Colorectal cancer
gut microbiome
dietary factors
microbial diversity
short-chain fatty acids
cover-dateJanuary-December 2024
typesetterts1
==== Body
pmcIntroduction

One of the most common forms of cancer and the third most cause of death globally is colorectal cancer (CRC). 1 Several epidemiological studies have shown that dietary fiber intake and a western diet are associated with the prevalence of CRC, underscoring the significance of the diet-cancer relationship.1–4 In this regard, the gut environment which includes the microbiome has gained attention and shown to be a significant risk factor for CRC. 5 The collective genes and genome of all microorganisms living in the gastrointestinal tract (GIT) is referred to as the gut microbiome. 6 The human GIT is home to over 100 trillion microbes, most of which are found in the colon. 7 Metagenomic research has revealed that 1952 uncultured bacterial species exist in the human gut, many of which have not yet been assigned a class, adding to the substantial diversity of the microbial ecosystem. 8 The relationship between the host and microbe can be pathogenic or symbiotic, and the microbial ecosystem is greatly influenced by a number of external factors, including diet, medication, and lifestyle. 9

The effects of symbiotic relationships between microbes and hosts on physiological processes and general health are numerous. The advantageous commensals perform a number of roles, including supplying vital micronutrients, controlling the immune system, altering enterocyte function, affecting metabolism, and halting the colonization of harmful microbes. Because the microbes in the gut ecosystem metabolize and flourish on the foods that humans eat, the human diet and its composition have a significant impact on the ecosystem. Short-chain fatty acids (SCFAs) are produced through the metabolism of dietary fibers, certain plant-based proteins, and microbiota accessible carbohydrates. SCFAs preserve microbial diversity, mucosal integrity, and anti-inflammatory qualities.10,11 Cancer is one of the many diseases linked to imbalances in the ratios of harmful toxins to essential nutrients. The main microbiome-induced mechanisms linked to cancer pathogenesis are altered microbial diversity, weakened immune response, and release of genotoxic or carcinogenic substances.12–15

The aim of this review is to provide new information regarding the dietary factors linked to the emergence of CRC. It examines the potential role of the gut microbiome, specifically focusing on how it influences the tumorigenesis processes linked to CRC. Additionally, we go over CRC treatment strategies involving the manipulation of the gut microbiota. Furthermore, we investigated how a nutritious diet can prevent CRC by reestablishing the colonic epithelium’s ability to function.

Relationship between CRC and gut microbiome

As global dietary patterns shift toward a more Westernized style, there is a projected steady rise in the incidence of CRC, with an estimated 2.2 million new cases anticipated by 2030. 16 Research indicates that around 90% of CRC cases occur sporadically, with the remaining cases attributed to genetic factors or exposure to specific environmental influences.17,18 Lifestyle choices, including physical inactivity, smoking history, adherence to a Western diet, low fiber intake, alcohol consumption, and obesity, play pivotal roles in CRC development.19–22 Lifestyle factors such as smoking, alcohol consumption, diet, and obesity significantly influence cancer risk and the microbial/immune system. Smoking and alcohol impair immune function and alter the microbiome, leading to increased cancer susceptibility. A diet rich in fruits and vegetables supports a healthy immune system and microbiome, reducing cancer risk, while high consumption of red/processed meats, sugar, and high-fat foods promotes obesity and related cancers. Obesity itself contributes to chronic inflammation, immune dysfunction, and microbial imbalances, further elevating cancer risk.23–26 Notably, these lifestyle factors often trigger alterations in the gut microbiota.27–29 Numerous studies have demonstrated that changes in the gut microbiome contribute to susceptibility to CRC or impact tumor progression, triggering inflammation, DNA damage, or the production of metabolites by microorganisms.30,31

Numerous investigations have suggested a strong correlation between the gut microbiome and host physiology in CRC development. Utilizing high-throughput microbiome sequencing, researchers have examined microbial communities in both tumor-affected and healthy colon tissues, thereby enhancing our comprehension of the differences in the gut microbiome between CRC patients and those without the disease. Studies have revealed a decrease in the diversity and abundance of the gut microbiome in individuals with CRC. Analysis of the gut microbiome in CRC patients has highlighted significant alterations in specific microbial groups, potentially influencing mucosal immune responses in CRC patients compared to healthy individuals. Notably, certain operational taxonomic units linked to genera such as Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus, and Peptostreptococcus were found to be more prevalent in CRC patients’ gut microbiota, while others, including Roseburia and other butyrate-producing bacteria from the Lachnospiraceae family, were less abundant. Additionally, dysbiosis, characterized by microbial imbalance, was observed in the gut microbiome of CRC patients. Dysbiosis, coupled with heightened intestinal permeability, may incite colonic inflammation, potentially exacerbating or accelerating CRC. Notably, Fusobacterium nucleatum presence was significantly elevated in human CRC compared to healthy counterparts. Moreover, discrepancies in microbiome composition were noted between early-stage CRC patients (advanced adenoma) and those with advanced-stage CRC (established CRC).32–36 These studies underscore a closely intertwined relationship between CRC and the gut microbiome, although further research is essential for a comprehensive understanding of the gut microbiome’s impact on CRC.

Effect of diet on gut microbiome and CRC development

Dietary components such as fibers, fats, and proteins play a vital role in fueling bacterial metabolisms in the gut. This not only aids in digestion but also results in the synthesis of byproducts that hold significant functional importance for the host. For example, bacteria residing in the colon play a crucial role in synthesizing essential co-factors like B vitamins, which are vital for host energy metabolism and gene expression regulation. Additionally, these microorganisms can biotransform plant-derived polyphenols with beneficial properties, such as antioxidant, anticancer, and anti-inflammatory effects. This transformation by the gut microbiota enhances the absorption of these compounds by the host, amplifying their potential health benefits. It underscores the importance of maintaining a healthy balance of gut bacteria for overall well-being.37–39 However, an imbalance in this equilibrium can lead to the generation of toxic metabolites by gut microbes, causing cytotoxic and genotoxic effects. Additionally, diets rich in prebiotics and probiotics have the potential to enhance the microbiome’s richness by fostering microbial diversity and supporting existing microbiota.40,41 In the contemporary era of increased processed food consumption, gut biodiversity and chemical composition are substantially impacted, leading to chronic colonic inflammation and an elevated risk of CRC.2,30,42–44

Eating processed meat has been associated with a higher chance of developing CRC. The chemicals used in processing red meat can combine to form carcinogenic N-nitroso compounds. Besides poor dietary habits, factors like obesity, heme iron consumption, and changes in the gut microbiota contribute to cancer-related changes in the colon lining. Notably, consuming emulsifiers like carboxymethylcellulose and polysorbate 80 has been linked to changes in the gut microbiome, potentially increasing the risk of intestinal inflammation and the formation of adenomas. The intake of emulsifiers can alter the abundance of specific groups of microbes, potentially affecting how the immune system in the colon responds in individuals with CRC compared to those without the disease.45–48 Moreover, the imbalance observed in the gut microbiome of individuals with CRC disturbs the microbial equilibrium, triggering inflammation in the colon and facilitating the advancement of CRC. Notably, there is a significant increase in F. nucleatum levels in human CRC patients compared to those who are healthy, indicating its potential involvement in CRC development.49,50

While evidence suggests a close relationship between red and processed meat consumption, gut microbiota alterations, and CRC, epidemiological support is limited. Red meat, rich in Neu5Gc, can trigger chronic inflammation, potentially contributing to cancers. Nonetheless, the relationship between red meat and CRC is not strong, and certain food combinations can change how the colonic microbiome influences this. For example, consuming red meat alongside high amylose-resistant starch can change how the gut processes food, possibly reducing the risk of CRC. Include alterations in the production of SCFAs in the gut. SCFAs, such as butyrate, acetate, and propionate, are produced by the fermentation of dietary fiber by gut bacteria. These SCFAs have been associated with several beneficial effects, including promoting colon health, reducing inflammation, and potentially inhibiting the growth of cancerous cells in the colon. Additionally, this dietary combination may also influence the composition and activity of the gut microbiota, leading to a favorable gut environment that is less conducive to CRC development.51–53

Empirical Dietary inflammatory pattern (EDIP) scoring system assesses the inflammatory potential of foods, assessed by, influences F. nucleatum abundance in CRC patients. Higher EDIP scores, indicating inflammatory effects, are associated with CRC positivity for F. nucleatum, Consumption of anti-inflammatory foods like whole grains is associated with a reduced likelihood of developing F. nucleatum-positive CRC.54–57 Fermented foods like yogurt contribute to colonic mucosal protection and stabilizing microbial diversity, potentially reducing CRC.58,59

Antioxidant consumption is crucial for the survival of certain gut bacterial strains. Supplementation of antioxidants enhances the survival of anaerobic microbes, leading to the synthesis of protective SCFAs like butyrate that have a positive impact on CRC. Additionally, legume consumption by CRC survivors increases the production of beneficial metabolites, potentially detoxifying carcinogens and reducing oxidative stress. This has been linked to heightened production of beneficial metabolites, including piperidine, N-methylpipecolate, vanillate, and 2-aminoadipate. These metabolites are generated through the metabolism of indigestible substrates present in navy beans by gut microbes, resulting in a total of 237 beneficial metabolites. Notably, individuals who consume navy beans exhibit a 5.25-fold increase in ophthalmic acid levels, which play a pivotal role in glutathione metabolism. Ophthalmic acid is crucial for detoxifying xenobiotics such as carcinogens and reducing oxidative stress, thereby conferring protective effects against cancer. This underscores the significance of dietary choices in modulating gut microbiota metabolism and subsequently influencing overall health outcomes.60–63

Alcohol consumption alters the gut microbiota and accelerates CRC carcinogenesis. The microbiota in alcoholics exhibits a decrease in beneficial organisms and an increase in harmful ones, potentially contributing to genotoxic insults on the colonic mucosa. Restricting alcohol consumption could be a preventive measure against such genotoxic effects on the colon.64–66

In summary, the combination of specific foods in one’s diet plays a crucial role in mitigating toxicity on the colonic epithelium, consequently reducing the risk of CRC development. Dietary constituents significantly influence chronic inflammation by modulating the immune response, and various foods have been related with either increased or decreased risk of CRC.

The impact of dietary measure on CRC

Dietary fibers derived from diet rich in plant foods undergo minimal digestion by human intestinal enzymes, reaching the colon in an unchanged state. Enzymes that metabolize and ferment soluble dietary fibers into beneficial metabolites like SCFAs possessed by colonic bacteria, which play a crucial role in reducing inflammation in the colonic mucosa, consequently lowering the risk of CRC.67,68 Butyrate, a prominent SCFA, inhibits histone deacetylases (HDAC) enzymes, promoting the expression of genes that arrest the cell cycle. 69 Furthermore, butyrate functions as a fuel source for healthy enterocytes, whereas CRC cells, which proliferate rapidly, prioritize glycolysis over utilizing butyrate for their energy requirements. 70 Co-cultivating specific bacterial strains in animal models has been shown to enhance butyrate production, offering SCFA-mediated protection against CRC. For instance, when Faecalibacterium prausnitzii ATCC 27768 strain is co-cultured with Bifidobacterium catenulatum KCTC 3221 and supplemented with fructooligosaccharides in anaerobic conditions, there is a significant increase in butyrate production, suggesting potential protective effects. 70 This co-culture’s supernatant, when exposed to colon cancer cells and macrophages, exhibited anti-inflammatory effects in vitro, and when administered in a dextran sodium sulfate (DSS)-induced colitis mice model, it increased SCFA levels and decreased gene expression of pro-inflammatory cytokines. 71 Butyrate was observed to enhance the abundance of tight junction protein complexes in an Apcmin/+ mice model, underscoring its potential in lowering CRC risk. Phytochemicals obtained from dietary sources, like polyphenols and flavonoids, also play a role in safeguarding the colonic mucosa.72,73 Most polyphenols ingested through plant-based diets reach the colon unaltered and are metabolized by intestinal bacteria into more active substances that decrease oxidative stress, inflammation, and tumorigenesis. 74 Polyphenols also interact with the gut microbiota, promoting the growth of beneficial strains like Lactobacillus and Bifidobacterium, which inhibit inflammation, alleviate colitis, and reduce CRC risk. 75 Examples include epigallocatechin-3-O-gallate and theaflavins from tea extracts, which exhibit anti-inflammatory effects on F. nucleatum-induced inflammatory bowel disorders, consequently lowering CRC risk. 76 Berries, rich in polyphenols, act as prebiotics, enhancing microbial richness and decreasing CRC growth. Mango pulp, containing gallotannins and gallic acid, demonstrates anti-inflammatory effects on the intestinal mucosa, reducing pro-inflammatory cytokines and increasing the abundance of beneficial bacteria like Lactobacillus. 77 Date palms, another source of polyphenols and fibers, may not significantly alter gut microbiota but decrease genotoxicity and fecal ammonia levels, contributing to a decreased risk of CRC.78,79 Green tea extracts rich in polyphenols enhance the Firmicutes to Bacteroidetes ratio and the presence of SCFA-producing gut microbes. Polyphenols, therefore, play a crucial role in reshaping the gut microbiome and potentially decreasing CRC risk. Curcumin, a polyphenol from the Curcuma longa plant, significantly decreases inflammation, oxidative stress, and alterations in the gut microbiome.80,81 The breakdown of curcumin by gut bacteria yields beneficial metabolites that offer protection against CRC, as indicated by enhanced taxonomic profiles of gut microbiota observed in IL-10-deficient CRC mice models fed a diet rich in curcumin. This enhancement was linked to a decrease in both tumor size and visible macroscopic lesions. Additionally, a combination of essential turmeric oil-curcumin and tocotrienol-rich fraction of vitamin E isomers demonstrated antiproliferative effects on colon cells in vitro studies and suppressed the growth of mice xenografts formed of colon cells in vivo studies. The intervention increased the abundance of anti-inflammatory bacterial genus and decreased harmful microbes, supporting curcumin’s potential role in reducing CRC risk.82–85 Flavonoids, which are another set of beneficial polyphenols found abundantly in fruits and vegetables, are transformed by gut microbiota into active compounds with anti-inflammatory, antioxidant, and anticancer properties. 86 For example, neohesperidin, a flavonoid plentiful in citrus fruits, demonstrates cancer-killing effects in models of CRC in mice, altering the composition of gut microbiota and reducing the formation of tumors in the colon. 87 Likewise, anthocyanins found in black raspberries, which are a type of flavonoid, reduce tumor formation in mice with colitis-associated CRC by prompting epigenetic alterations. These flavonoids, commonly present in plant-centered diets, enhance the diversity of gut microbes and inhibit the growth of CRC. 88

Olive oil, a prominent element of the Mediterranean diet, containing abundant monounsaturated fatty acids, squalene, phytosterols, and phenols, exhibits favorable effects on mucosal cells in comparison to other oils. Consumption of extra virgin olive oil (EVOO) has been linked to reduced levels of harmful microbes and disruptions in gut microbiota, along with inflammatory alterations, highlighting its potential in preventing CRC. N-3 polyunsaturated fatty acids (PUFA), when combined with fermentable dietary fibers, play a protective role in pathways associated with programmed cell death and epigenetic irregularities observed in CRC. However, careful selection of dietary lipids, particularly EVOO and n-3 PUFA, is essential for optimizing a healthy colonic mucosa, as the benefits of n-3 PUFA may only be significant when sourced from marine origins and consumed alongside dietary fibers. Overall, a combination of dietary fibers and various diet-derived components such as phytochemicals, essential fatty acids, as well as prebiotics, probiotics, and postbiotics collectively forms a multifaceted protective strategy against CRC.89–91

Generally, in vitro studies highlight that the diet can influence the gut microbiome by regulating molecular events in the colonic mucosa through controlled experiments with cultured cells. In vivo studies further show that these dietary effects translate into significant changes in gut health in animal models. Human studies have confirmed these findings, demonstrating that dietary habits significantly impact the gut microbiome and CRC risk in human populations.

Impact of the gut microbiome on CRC formation

While much remains unknown about the development of CRC, the onset of CRC is often associated with chronic inflammation, with around 20% of colon malignancies thought to be preceded by prolonged inflammation. Throughout the process of carcinogenesis, cancer cells release inflammatory proteins known as cytokines and chemokines. These molecules attract immature myeloid cells and pro-inflammatory helper T cells, fostering a microenvironment conducive to tumor growth. This environment is marked by the production of growth factors and angiogenic factors, the activation of enzymes involved in tissue remodeling, and the suppression of the body’s antitumor T-cell responses.92,93

The role of the gut microbiome in the development of CRC was initially acknowledged in the early 1970s. Studies involving germ-free mice exposed to the carcinogen 1,2-dimethylhydrazine showed a notable decrease in CRC occurrence. Further investigations utilizing different CRC models consistently highlighted the substantial impact of intestinal microbes, whether present or absent, on the formation of colon cancer. Advanced techniques such as high-throughput microbiome sequencing have pinpointed specific microorganisms within the intestines that exert influence over the development of CRC.94–97

Streptococcus bovis has been identified as a CRC risk factor, with its proinflammatory proteins playing a role in colon carcinogenesis. 98 F. nucleatum is associated with CRC tumor formation and early carcinogenesis, producing a protein, Fusobacterium adhesin A (FadA), that activates the oncogenic b-catenin signaling pathway. Enterococcus faecalis increases CRC risk by inducing DNA damage to intestinal epithelial cells.99–103

Enterotoxigenic Bacteroides fragilis (ETBF) accelerates tumor growth by upregulating signal transducer and activator of transcription 3 (STAT3) and stimulating the Th17 immune response during the development of colon tumors. Peptostreptococcus anaerobius fosters a proinflammatory environment and facilitates tumor formation in the intestine by heightening levels of reactive oxygen species (ROS) and promoting cholesterol synthesis.15,104–106

Salmonella and Campylobacter jejuni have been linked to chronic infections that increase the risk of gastrointestinal diseases, including CRC. Sulfate-reducing bacteria can stimulate CRC progression by producing hydrogen sulfide (H2S), inducing DNA damage and disrupting the gut barrier.73,107–110

Current research endeavors are focused on unraveling the connections between additional intestinal microorganisms and the development of CRC, highlighting the intricate interplay between the gut microbiome and CRC formation.

Gut microbiome’s impact on CRC progression

The gut microbiome doesn’t just impact the onset of colon cancer; it also plays a role in its progression.111,112 Research indicates that various bacteria play a role in the development and progression of tumors. In CRC patients, F. nucleatum is linked to a poorer prognosis, as it facilitates the development of colonic tumors by suppressing the adaptive immune response mediated by anti-tumor T cells.113–115 ETBF contributes to the advancement of cancer by triggering the recruitment and multiplication of CD4+CCR6+IL17A+ Th17 cells through the IL-17 signaling pathway. P. anaerobius fosters the development of CRC by activating the oncogenic PI3K-Akt signaling pathway, which boosts the proliferation of tumor cells.116–118

Escherichia coli is closely related to CRC growth, with pathogenic strains correlating with inflammation, ROS production, and tumor infiltration. Colibactin, a genotoxin produced by certain E. coli strains, significantly impacts tumor growth.119–124

Certain intestinal strains, such as F. prausnitzii, Lactobacillus rhamnosus GG, and Bifidobacterium lactis Bb12, induce protective effects against CRC by downregulating proinflammatory pathways, preventing abnormal epithelial proliferation, and improving the intestinal epithelial barrier. In CRC mouse models, probiotics such as Lactobacilli and Bifidobacteria impede tumor advancement and reduce tumor size by enhancing the production of SCFAs, promoting apoptosis, and inhibiting tumor cell proliferation.125–129

In conclusion, the gut microbiome plays a multifaceted role in both the formation and progression of CRC, with specific bacterial strains influencing various pathways and processes in the complex landscape of CRC development.

Gut microbiome on CRC treatment

The close association between the gut microbiome and CRC has prompted extensive research into its impact on CRC treatment. This area constitutes a vital component of cancer-microbiome research, with numerous studies exploring its integration with diverse treatment modalities for clinical application. Beyond traditional chemotherapy or radiotherapy, emerging insights reveal synergistic effects of the gut microbiome with immune checkpoint inhibitors (ICIs).130,131

Chemotherapy

The gut microbiota plays a crucial role in determining the effectiveness of traditional chemotherapy. Certain gut bacteria can modulate cytotoxicity by engaging in the metabolic pathways of anticancer medications. For example, antibiotics-treated mice show reduced efficacy of platinum-based chemotherapeutic drugs like oxaliplatin, leading to decreased cytokine secretion and ROS production, ultimately resulting in diminished tumor necrosis in a mouse model of colon tumor transplantation. 132 Similarly, gemcitabine’s anticancer potency diminishes in the presence of certain gammaproteobacteria in the tumor, emphasizing the microbial influence on chemotherapy effectiveness.133,134 Antibiotic administration in CRC mouse models also reduces the anticancer effect of 5-fluorouracil (5-FU) administration, indicating the microbiota’s role in chemotherapy response.135,136 F. nucleatum, previously associated with both the onset and advancement of tumors, influences treatment responses, as elevated levels of F. nucleatum are associated with less-favorable outcomes to 5-FU and oxaliplatin treatments in CRC patients.49,137

Radiotherapy

Radiation therapy-induced dysbiosis can adversely impact other CRC treatment modalities. After radiation treatment, there is a decline in commensal bacteria and an increase in potentially tumor-promoting microbiota, leading to impaired gut barrier function and additional inflammatory responses. These changes highlight the potential consequences of radiation therapy on the gut microbiome and its subsequent impact on CRC treatment outcomes.138–140

Immunotherapy

Certain intestinal microbes play a role in regulating the immune response and, consequently, tumor growth. Research has aimed to understand how intestinal microbes influence the efficacy of immunotherapeutic agents. Commensal gut microbiota have been shown to enhance the antitumor efficacy of ICIs like programmed death-ligand 1 (PD-L1) inhibitors. The gut microbiota composition influences the efficacy of ICIs, including CTLA-4 and PD-L1 inhibitors, with bacterial species such as Bacteroides, Akkermansia, Faecalibacterium, Clostridiales, and Bifidobacterium spp. being associated with improved antitumor effects.141–145 The modulation of ICIs extends to direct interactions between host immune cells and specific bacteria, such as Akkermansia muciniphila and Bacteroides spp., demonstrating their role in enhancing the effectiveness of immunotherapeutic agents. The microbial metabolites, such as SCFAs like butyrate and propionate, have also been implicated in the antitumor effects observed in response to ICIs.145–147

Potential clinical utilizations of the gut microbiome

The potential roles of the gut microbiome in addressing CRC are diverse. It can serve as a screening, prognostic, and/or predictive biomarker, and it can also influence CRC prevention and the effectiveness of systemic treatments. As a screening marker, the gut microbiota acts as a detector for high-risk adenomas or CRC in asymptomatic individuals. Specific bacterial strains, like F. nucleatum, can act as screening markers, with their higher abundance in adenomas and CRC patients detectable in fecal samples. Other screening markers, such as metabolic and genotoxic by-products of certain strains, may aid in the early detection of CRC. As a prognostic and/or predictive biomarker, the gut microbiome has the potential to predict patients’ clinical outcomes, treatment responses, and potential treatment-related adverse effects. Potential biomarkers may include microbial genes, metabolites, and microbiota-related serological markers detectable in blood, tumor tissue, feces, and samples from the oral cavity. Modulating the gut microbiome offers opportunities for preventing CRC in high-risk populations, improving responses to chemotherapy and immunotherapy, and reducing potential adverse effects. This modulation can be achieved through dietary interventions, prebiotics, probiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT).31,148–150

Gut microbiota modulation

The makeup of the gut microbiome can be changed through dietary adjustments, which may involve consuming prebiotics such as dietary fiber, cutting back on fat consumption, following a plant-based diet, minimizing or eliminating red and processed meat intake, or boosting the intake of probiotics and postbiotics (microbial fermentation byproducts, like SCFAs). These dietary practices should be coupled with weight reduction and regular exercise. Probiotics, live microorganisms administered in adequate amounts, play a role in improving or restoring gut flora. In CRC, preclinical studies highlight certain bacteria like Bifidobacterium and Lactobacillus spp., exhibiting anticancer properties. These include inhibiting cell proliferation, inducing cancer cell apoptosis, modulating host immunity, deactivating carcinogenic toxins, and producing anticarcinogenic compounds like butyrate. Although widely used as a food supplement, the effectiveness of probiotics in preventing or treating diseases, including acute antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea, remains inconclusive in both preclinical and clinical studies. Questions persist regarding the selection, ratio, activities, colonization, physiological effects, interactions with the intestinal microbiome, safety issues, and overall impact on the host. Prebiotics defined as nondigestible food ingredients that selectively stimulate the growth and/or activity of specific bacteria in the colon, can be combined with probiotics to induce beneficial changes in the fecal microbiota. For instance, inulin, in combination with L. rhamnosus GG and B. lactis Bb12 probiotics, increases beneficial Lactobacillus and Bifidobacterium strains while decreasing harmful Clostridium strains.148–154

Postbiotics, which include microbial fermentation components such as metabolites, SCFAs, microbial cell fractions, and functional proteins, enhance the potency of prebiotics. Oncomicrobiotics, a potential postbiotic, represents a mixture of bacteria or bacterial products that enhance the immune response.155,156

Selective antibiotics can be pivotal in preventing CRC by inhibiting cancer-associated bacteria, boosting beneficial microbes to improve cancer therapies, or acting as small molecule inhibitors to alleviate treatment side effects. Notably, targeting cancer-associated F. nucleatum with antibiotics like β-lactams, metronidazole, and clindamycin offers a specific treatment option, although combining these antibiotics with other methods to modulate the gut microbiome is crucial for optimal outcomes. FMT, which involves introducing healthy microbiota from a donor into a patient’s intestine, represents a direct manipulation of the gut microbiome. FMT has shown remarkable success in treating C. difficile infection, with a cure rate exceeding 90%, and it is governed by stringent international guidelines. Its potential applications extend beyond intestinal diseases to include metabolic, neurological, cardiovascular, and rheumatological conditions. Innovative strategies for modulating the gut microbiome encompass bioengineering the gut microbiota, developing genetically engineered probiotics, and using bacteriocins or bacteriophages to modify the gut microbiota.31,148,149,157–160

Limitation of the study

The review compellingly demonstrates the significant influence of diet-modulated gut microbiota on CRC development and progression through diverse molecular mechanisms, providing an illuminating exposé on this complex relationship. However, as a narrative review, it lacks the methodological rigor of a systematic review or meta-analysis. Additionally, the reliance on preclinical and observational human data makes it difficult to infer causality from the reported associations. Addressing these limitations in future research will enhance the understanding and applicability of the findings.

Conclusion

CRC is a global health concern, with lifestyle choices, particularly dietary habits, playing a pivotal role in its development. The gut microbiome, a complex ecosystem of microorganisms residing in the GIT, is closely linked to CRC, influencing various stages from initiation to progression. Several studies on animals and humans have shown that modifications to the gut microbiota can influence the emergence of precancerous lesions and the advancement of cancer. Research suggests that dysbiosis is more common in CRC patients than in healthy individuals, suggesting that CRC is particularly affected by these alterations. An increase in opportunistic pathogens, intestinal inflammation, and a decrease in butyrate-producing bacteria are the hallmarks of dysbiosis. According to epidemiological studies, dietary factors that have been linked to the development of CRC include low-fiber intake and a Western diet. The gut microbiota plays a part in this process. Dietary fiber is fermented by intestinal bacteria into SCFA, such as butyrate, which has been demonstrated in animal studies to influence the development and spread of cancer. Moreover, the gut microbiome may shed light on the association between antibiotic use and an increased risk of CRC. Our knowledge of this intricate system is still lacking, despite the fact that numerous published studies have demonstrated the importance of the gut microbiota in controlling CRC. In order to treat and prevent CRC, more research is required to clarify the underlying mechanisms and investigate methods for altering the gut microbiota. The goal of this review is to give a general overview of the mechanisms underlying the various gut microbiome strains implicated in each stage of carcinogenesis. This review paves the way for further research into the connection between the gut microbiome and CRC by identifying the microbiota species most likely linked to CRC.

None.

Author contributions: HTE: conceived the design, searching the literature, drafting the article; WBA, FSH, WT, EYT, YYS, TA, and HTE: searching literature, supervising and critical review of the article. All authors read and approved the final article for publication.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval: Not applicable.

Informed consent: Not applicable.

ORCID iD: Hiwot Tezera Endale https://orcid.org/0000-0002-4672-0551
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References

1 Lee J-Y Tsolis RM Bäumler AJ. The microbiome and gut homeostasis. Science 2022; 377 (6601 ): eabp9960.
2 Hanus M Parada-Venegas D Landskron G , et al . Immune system, microbiota, and microbial metabolites: the unresolved triad in colorectal cancer microenvironment. Front Immunol 2021; 12 : 612826.33841394
3 Choi J Jia G Wen W , et al . Healthy lifestyles, genetic modifiers, and colorectal cancer risk: a prospective cohort study in the UK Biobank. Am J Clin Nutr 2021; 113 (4 ): 810–820.33675346
4 Conti L Del Cornò M Gessani S. Revisiting the impact of lifestyle on colorectal cancer risk in a gender perspective. Crit Rev Oncol Hematol 2020; 145 : 102834.31790930
5 Vujkovic-Cvijin I Sklar J Jiang L , et al . Host variables confound gut microbiota studies of human disease. Nature 2020; 587 (7834 ): 448–454.33149306
6 Ağagündüz D Cocozza E Cemali Ö , et al . Understanding the role of the gut microbiome in gastrointestinal cancer: a review. Front Pharmacol 2023; 14 : 1130562.
7 Walter J Ley R. The human gut microbiome: ecology and recent evolutionary changes. Annu Rev Microbiol 2011; 65 : 411–429.21682646
8 Almeida A Mitchell AL Boland M , et al . A new genomic blueprint of the human gut microbiota. Nature 2019; 568 (7753 ): 499–504.30745586
9 Afzaal M Saeed F Shah YA , et al . Human gut microbiota in health and disease: unveiling the relationship. Front Microbiol 2022; 13 : 999001.36225386
10 Peng K Xia S Xiao S , et al . Short-chain fatty acids affect the development of inflammatory bowel disease through intestinal barrier, immunology, and microbiota: a promising therapy? J Gastroenterol Hepatol 2022; 37 (9 ): 1710–1718.35906780
11 Caetano MAF Castelucci P . Role of short chain fatty acids in gut health and possible therapeutic approaches in inflammatory bowel diseases. World J Clin Cases 2022; 10 (28 ): 9985.36246826
12 Littman DR Pamer EG. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 2011; 10 (4 ): 311–323.22018232
13 De Filippis F Vitaglione P Cuomo R , et al . Dietary interventions to modulate the gut microbiome—how far away are we from precision medicine. Inflamm Bowel Dis 2018; 24 (10 ): 2142–2154.29668914
14 Daschner PJ Ross S Seifried H , et al . Nutrition and microbiome interactions in human cancer. J Acad Nutr Diet 2023; 123 (3 ): 504–514.36208721
15 Karpiński TM Ożarowski M Stasiewicz M (eds.). Carcinogenic microbiota and its role in colorectal cancer development. Semin Cancer Biol 2022; 86 (Pt 3 ): 420–430.
16 Mikaeel RR . Towards an understanding of the growing incidence of colorectal cancer and appendiceal neoplasms in young adults. 2022.
17 Sawicki T Ruszkowska M Danielewicz A , et al . A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers 2021; 13 (9 ): 2025.33922197
18 Valle L de Voer RM Goldberg Y , et al . Update on genetic predisposition to colorectal cancer and polyposis. Mol Aspects Med 2019; 69 : 10–26.30862463
19 Dahham SS Majid AMA . The impact of life style and nutritional components in primary prevention of colorectal cancer. J Appl Pharm Sci 2016; 6 (9 ): 237–244.
20 Carr PR Weigl K Jansen L , et al . Healthy lifestyle factors associated with lower risk of colorectal cancer irrespective of genetic risk. Gastroenterology 2018; 155 (6 ): 1805–1815.e5.
21 Mehta M Shike M. Diet and physical activity in the prevention of colorectal cancer. J Natl Compr Cancer Netw 2014; 12 (12 ): 1721–1726.
22 Degen LP Phillips SF. Variability of gastrointestinal transit in healthy women and men. Gut 1996; 39 (2 ): 299–305.8977347
23 Islami F Guerra CE Minihan A , et al . American Cancer Society’s report on the status of cancer disparities in the United States, 2021. CA Cancer J Clin 2022; 72 (2 ): 112–143.34878180
24 Klein WM Jacobsen PB Helzlsouer KJ. Alcohol and cancer risk: clinical and research implications. JAMA 2020; 323 (1 ): 23–24.31834355
25 Clinton SK Giovannucci EL Hursting SD. The world cancer research fund/American institute for cancer research third expert report on diet, nutrition, physical activity, and cancer: impact and future directions. J Nutr 2020; 150 (4 ): 663–671.31758189
26 Avgerinos KI Spyrou N Mantzoros CS , et al . Obesity and cancer risk: emerging biological mechanisms and perspectives. Metabolism 2019; 92 : 121–135.30445141
27 Zhang M Lv Y Hou S , et al . Differential mucosal microbiome profiles across stages of human colorectal cancer. Life 2021; 11 (8 ): 831.34440574
28 Vacante M Ciuni R Basile F , et al . Gut microbiota and colorectal cancer development: a closer look to the adenoma-carcinoma sequence. Biomedicines 2020; 8 (11 ): 489.33182693
29 García-González AP Ritter AD Shrestha S , et al . Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics. Cell 2017; 169 (3 ): 431–441.e8.
30 Dalal N Jalandra R Bayal N , et al . Gut microbiota-derived metabolites in CRC progression and causation. J Cancer Res Clin Oncol 2021; 147 : 3141–3155.34273006
31 Wong SH Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol 2019; 16 (11 ): 690–704.31554963
32 Zwezerijnen-Jiwa FH Sivov H Paizs P , et al . A systematic review of microbiome-derived biomarkers for early colorectal cancer detection. Neoplasia 2023; 36 : 100868.36566591
33 Saffarian A Mulet C Regnault B , et al . Crypt-and mucosa-associated core microbiotas in humans and their alteration in colon cancer patients. MBio 2019; 10 (4 ): e01315-19.
34 Yang T-W Lee W-H Tu S-J , et al . Enterotype-based analysis of gut microbiota along the conventional adenoma-carcinoma colorectal cancer pathway. Sci Rep 2019; 9 (1 ): 10923.31358825
35 Liu W Zhang X Xu H , et al . Microbial community heterogeneity within colorectal neoplasia and its correlation with colorectal carcinogenesis. Gastroenterology 2021; 160 (7 ): 2395–2408.33581124
36 Coker OO Nakatsu G Dai RZ , et al . Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut 2019; 68 (4 ): 654–662.30472682
37 Biesalski HK. Nutrition meets the microbiome: micronutrients and the microbiota. Ann N Y Acad Sci 2016; 1372 (1 ): 53–64.27362360
38 Ozdal T Sela DA Xiao J , et al . The reciprocal interactions between polyphenols and gut microbiota and effects on bioaccessibility. Nutrients 2016; 8 (2 ): 78.26861391
39 Ray SK Mukherjee S. Evolving interplay between dietary polyphenols and gut microbiota—an emerging importance in healthcare. Front Nutr 2021; 8 : 634944.34109202
40 Davis EC Dinsmoor AM Wang M , et al . Microbiome composition in pediatric populations from birth to adolescence: impact of diet and prebiotic and probiotic interventions. Dig Dis Sci 2020; 65 : 706–722.32002758
41 Collins MD Gibson GR. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 1999; 69 (5 ): 1052s–1057s.
42 Vipperla K O’Keefe SJ. Diet, microbiota, and dysbiosis: a “recipe” for colorectal cancer. Food Funct 2016; 7 (4 ): 1731–1740.26840037
43 Siddiqui R Boghossian A Alharbi AM , et al . The pivotal role of the gut microbiome in colorectal cancer. Biology 2022; 11 (11 ): 1642.36358343
44 Mohseni AH Taghinezhad-S S Fu X. Gut microbiota-derived metabolites and colorectal cancer: new insights and updates. Microb Pathog 2020; 149 : 104569.33075518
45 Hur SJ Jo C Yoon Y , et al . Controversy on the correlation of red and processed meat consumption with colorectal cancer risk: an Asian perspective. Crit Rev Food Sci Nutr 2019; 59 (21 ): 3526–3537.29999423
46 Abu-Ghazaleh N Chua WJ Gopalan V. Intestinal microbiota and its association with colon cancer and red/processed meat consumption. J Gastroenterol Hepatol 2021; 36 (1 ): 75–88.32198788
47 Mizutani S Yamada T Yachida S. Significance of the gut microbiome in multistep colorectal carcinogenesis. Cancer Sci 2020; 111 (3 ): 766–773.31910311
48 DeDecker L Coppedge B Avelar-Barragan J , et al . Microbiome distinctions between the CRC carcinogenic pathways. Gut Microbes 2021; 13 (1 ): 1–12.
49 Chen Y Chen Y Zhang J , et al . Fusobacterium nucleatum promotes metastasis in colorectal cancer by activating autophagy signaling via the upregulation of CARD3 expression. Theranostics 2020; 10 (1 ): 323.31903123
50 Zhang S Cai S Ma Y. Association between Fusobacterium nucleatum and colorectal cancer: progress and future directions. J Cancer 2018; 9 (9 ): 1652.29760804
51 Alexander DD Weed DL Miller PE , et al . Red meat and colorectal cancer: a quantitative update on the state of the epidemiologic science. J Am Coll Nutr 2015; 34 (6 ): 521–543.25941850
52 Aglago EK Cross AJ Riboli E , et al . Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study. Br J Cancer 2023; 128 (8 ): 1529–1540.36759722
53 Nielsen TS Bendiks Z Thomsen B , et al . High-amylose maize, potato, and butyrylated starch modulate large intestinal fermentation, microbial composition, and oncogenic miRNA expression in rats fed a high-protein meat diet. Int J Mol Sci 2019; 20 (9 ): 2137.31052187
54 Pignatelli P Iezzi L Pennese M , et al . The potential of colonic tumor tissue Fusobacterium nucleatum to predict staging and its interplay with oral abundance in colon cancer patients. Cancers 2021; 13 (5 ): 1032.33804585
55 Liu L Tabung FK Zhang X , et al . Diets that promote colon inflammation associate with risk of colorectal carcinomas that contain Fusobacterium nucleatum. Clin Gastroenterol Hepatol 2018; 16 (10 ): 1622–1631.e3.
56 Borozan I Zaidi SH Harrison TA , et al . Molecular and pathology features of colorectal tumors and patient outcomes are associated with Fusobacterium nucleatum and its subspecies animalis. Cancer Epidemiol Biomarkers Prev 2022; 31 (1 ): 210–220.34737207
57 Mehta RS Nishihara R Cao Y , et al . Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol 2017; 3 (7 ): 921–927.28125762
58 Jin S Kim Y Je Y. Dairy consumption and risks of colorectal cancer incidence and mortality: a meta-analysis of prospective cohort studies. Cancer Epidemiol Biomarkers Prev 2020; 29 (11 ): 2309–2322.32855265
59 Sun J Song J Yang J , et al . Higher yogurt consumption is associated with lower risk of colorectal cancer: a systematic review and meta-analysis of observational studies. Front Nutr 2022; 8 : 789006.35047546
60 Gao J Azad MA Han H , et al . Impact of prebiotics on enteric diseases and oxidative stress. Curr Pharm Des 2020; 26 (22 ): 2630–2641.32066357
61 Pham VT Fehlbaum S Seifert N , et al . Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome—a pilot study. Gut Microbes 2021; 13 (1 ): 1875774.33615992
62 Riaz Rajoka MS Thirumdas R Mehwish HM , et al . Role of food antioxidants in modulating gut microbial communities: novel understandings in intestinal oxidative stress damage and their impact on host health. Antioxidants 2021; 10 (10 ): 1563.34679698
63 Million M Armstrong N Khelaifia S , et al . The antioxidants glutathione, ascorbic acid and uric acid maintain butyrate production by human gut clostridia in the presence of oxygen in vitro. Sci Rep 2020; 10 (1 ): 7705.32382092
64 Lee E Lee J-E. Impact of drinking alcohol on gut microbiota: recent perspectives on ethanol and alcoholic beverage. Curr Opin Food Sci 2021; 37 : 91–97.
65 Rossi M Jahanzaib Anwar M Usman A , et al . Colorectal cancer and alcohol consumption—populations to molecules. Cancers 2018; 10 (2 ): 38.29385712
66 Tsuruya A Kuwahara A Saito Y , et al . Ecophysiological consequences of alcoholism on human gut microbiota: implications for ethanol-related pathogenesis of colon cancer. Sci Rep 2016; 6 (1 ): 27923.27295340
67 Guz M Jeleniewicz W Malm A , et al . A crosstalk between diet, microbiome and microRNA in epigenetic regulation of colorectal cancer. Nutrients 2021; 13 (7 ): 2428.34371938
68 Fu J Zheng Y Gao Y , et al . Dietary fiber intake and gut microbiota in human health. Microorganisms 2022; 10 (12 ): 2507.36557760
69 Salek Farrokhi A Mohammadlou M Abdollahi M , et al . Histone deacetylase modifications by probiotics in colorectal cancer. J Gastrointest Cancer 2020; 51 : 754–764.31808058
70 Hou H Chen D Zhang K , et al . Gut microbiota-derived short-chain fatty acids and colorectal cancer: ready for clinical translation? Cancer Lett 2022; 526 : 225–235.34843863
71 Kim H Jeong Y Kang S , et al . Co-culture with Bifidobacterium catenulatum improves the growth, gut colonization, and butyrate production of Faecalibacterium prausnitzii: in vitro and in vivo studies. Microorganisms 2020; 8 (5 ): 788.32466189
72 Zhang W An Y Qin X , et al . Gut microbiota-derived metabolites in colorectal cancer: the bad and the challenges. Front Oncol 2021; 11 : 739648.34733783
73 Cueva C Silva M Pinillos I , et al . Interplay between dietary polyphenols and oral and gut microbiota in the development of colorectal cancer. Nutrients 2020; 12 (3 ): 625.32120799
74 Esmeeta A Adhikary S Dharshnaa V , et al . Plant-derived bioactive compounds in colon cancer treatment: an updated review. Biomed Pharmacother 2022; 153 : 113384.35820317
75 Han D Wu Y Lu D , et al . Polyphenol-rich diet mediates interplay between macrophage-neutrophil and gut microbiota to alleviate intestinal inflammation. Cell Death Dis 2023; 14 (10 ): 656.37813835
76 Wang S-T Cui W-Q Pan D , et al . Tea polyphenols and their chemopreventive and therapeutic effects on colorectal cancer. World J Gastroenterol 2020; 26 (6 ): 562.32103869
77 Kim H Castellon-Chicas MJ Arbizu S , et al . Mango (Mangifera indica L.) Polyphenols: anti-inflammatory intestinal microbial health benefits, and associated mechanisms of actions. Molecules 2021; 26 (9 ): 2732.34066494
78 Alasalvar C Chang SK Kris-Etherton PM , et al . Dried fruits: bioactives, effects on gut microbiota, and possible health benefits—an update. Nutrients 2023; 15 (7 ): 1611.37049451
79 Metwally AM Yousef W Abdel-Latif GA , et al . Impact of Palm dates fruit intake in the alleviation of gastrointestinal manifestations of autistic children: A randomized clinical trial. Research Square 2023. DOI: 10.21203/rs.3.rs-2511698/v1.
80 Kon R Ikarashi N Yamaguchi A , et al . Green tea extract prevents CPT-11-induced diarrhea by regulating the gut microbiota. Sci Rep 2023; 13 (1 ): 6537.37085597
81 Enayati A Soghi A Butler AE , et al . The effect of curcumin on the gut-brain axis: therapeutic implications. J Neurogastroenterol Motil 2023; 29 (4 ): 409.37814431
82 Guo X Xu Y Geng R , et al . Curcumin alleviates dextran sulfate sodium-induced colitis in mice through regulating gut microbiota. Mol Nutr Food Res 2022; 66 (8 ): 2100943.
83 McFadden R-MT Larmonier CB Shehab KW , et al . The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention. Inflamm Bowel Dis 2015; 21 (11 ): 2483–2494.26218141
84 Gholipour F Amini M Baradaran B , et al . Anticancer properties of curcumin-treated Lactobacillus plantarum against the HT-29 colorectal adenocarcinoma cells. Sci Rep 2023; 13 (1 ): 2860.36801895
85 Farhana L Sarkar S Nangia-Makker P , et al . Natural agents inhibit colon cancer cell proliferation and alter microbial diversity in mice. PLoS One 2020; 15 (3 ): e0229823.
86 Afshari K Haddadi NS Haj-Mirzaian A , et al . Natural flavonoids for the prevention of colon cancer: a comprehensive review of preclinical and clinical studies. J Cell Physiol 2019; 234 (12 ): 21519–21546.31087338
87 Gong Y Dong R Gao X , et al . Neohesperidin prevents colorectal tumorigenesis by altering the gut microbiota. Pharmacol Res 2019; 148 : 104460.31560944
88 Chen T Shi N Afzali A. Chemopreventive effects of strawberry and black raspberry on colorectal cancer in inflammatory bowel disease. Nutrients 2019; 11 (6 ): 1261.31163684
89 Memmola R Petrillo A Di Lorenzo S , et al . Correlation between olive oil intake and gut microbiota in colorectal cancer prevention. Nutrients 2022; 14 (18 ): 3749.36145125
90 Sain A Sahu S Naskar D. Potential of olive oil and its phenolic compounds as therapeutic intervention against colorectal cancer: a comprehensive review. Br J Nutr 2022; 128 (7 ): 1257–1273.34338174
91 Chapkin RS Navarro SL Hullar MA , et al . Diet and gut microbes act coordinately to enhance programmed cell death and reduce colorectal cancer risk. Dig Dis Sci 2020; 65 : 840–851.32006211
92 Fantini MC Guadagni I. From inflammation to colitis-associated colorectal cancer in inflammatory bowel disease: pathogenesis and impact of current therapies. Dig Liver Dis 2021; 53 (5 ): 558–565.33541800
93 Chen J Pitmon E Wang K (eds.). Microbiome, inflammation and colorectal cancer. Semin Immunol 2017; 32 : 43–53.28982615
94 Reddy BS Narisawa T Weisburger JH. Colon carcinogenesis in germ-free rats with intrarectal 1, 2-dimethylhydrazine and subcutaneous azoxymethane. Cancer Res 1976; 36 (8 ): 2874–2876.1277197
95 Goldin BR Gorbach SL. Effect of antibiotics on incidence of rat intestinal tumors induced by 1, 2-dimethylhydrazine dihydrochloride. J Natl Cancer Inst 1981; 67 (4 ): 877–880.6944555
96 Biondi A Basile F Vacante M. Familial adenomatous polyposis and changes in the gut microbiota: new insights into colorectal cancer carcinogenesis. World J Gastrointest Oncol 2021; 13 (6 ): 495.34163569
97 Son JS Khair S Pettet DW III , et al . Altered interactions between the gut microbiome and colonic mucosa precede polyposis in APCMin/+ mice. PLoS One 2015; 10 (6 ): e0127985.
98 Galdy S. Streptococcus bovis and colorectal cancer. In: Shurin MR Thanavala Y Ismail N , (eds) Infection and Cancer: Bi-Directorial Interactions. Cham: Springer International Publishing, 2015, pp. 231–241.
99 Şahin T Kiliç Ö Acar A , et al . A review: the role of Streptococcus bovis in colorectal cancer. Arts Humanit Open Access J 2023; 5 : 165–173.
100 Justesen US Nielsen SL Jensen TG , et al . Bacteremia with anaerobic bacteria and association with colorectal cancer: a population-based cohort study. Clin Infect Dis 2022; 75 (10 ): 1747–1753.35380653
101 Pasquereau-Kotula E Martins M Aymeric L , et al . Significance of Streptococcus gallolyticus subsp. gallolyticus association with colorectal cancer. Front Microbiol 2018; 9 : 614.29666615
102 Wang S Liu Y Li J , et al . Fusobacterium nucleatum acts as a pro-carcinogenic bacterium in colorectal cancer: from association to causality. Front Cell Dev Biol 2021; 9 : 710165.34490259
103 Wang X Huycke MM. Colorectal cancer: role of commensal bacteria and bystander effects. Gut Microbes 2015; 6 (6 ): 370–376.26727419
104 Cheng Y Ling Z Li L. The intestinal microbiota and colorectal cancer. Front Immunol 2020; 11 : 615056.33329610
105 Abdulla M-H Agarwal D Singh JK , et al . Association of the microbiome with colorectal cancer development. Int J Oncol 2021; 58 (5 ): 1–12.33649821
106 Wang Y Li H. Gut microbiota modulation: a tool for the management of colorectal cancer. J Transl Med 2022; 20 (1 ): 178.35449107
107 Kato I Minkevitch J Sun J. Oncogenic potential of Campylobacter infection in the gastrointestinal tract: narrative review. Scand J Gastroenterol 2023; 58 (12 ): 1453–1465.37366241
108 El Tekle G Garrett WS . Bacteria in cancer initiation, promotion and progression. Nat Rev Cancer 2023; 23 (9 ): 600–618.37400581
109 Xiao A Liu C Li J. The role of H2S in the gastrointestinal tract and microbiota. Adv Exp Med Biol 2021; 1315 : 67–98.34302689
110 Fang Y Yan C Zhao Q , et al . The roles of microbial products in the development of colorectal cancer: a review. Bioengineered 2021; 12 (1 ): 720–735.33618627
111 Sánchez-Alcoholado L Ramos-Molina B Otero A , et al . The role of the gut microbiome in colorectal cancer development and therapy response. Cancers 2020; 12 (6 ): 1406.32486066
112 Nistal E Fernández-Fernández N Vivas S , et al . Factors determining colorectal cancer: the role of the intestinal microbiota. Front Oncol 2015; 5 : 220.26528432
113 Pignatelli P Nuccio F Piattelli A , et al . The role of Fusobacterium nucleatum in oral and colorectal carcinogenesis. Microorganisms 2023; 11 (9 ): 2358.37764202
114 Yin H Miao Z Wang L , et al . Fusobacterium nucleatum promotes liver metastasis in colorectal cancer by regulating the hepatic immune niche and altering gut microbiota. Aging (Albany NY) 2022; 14 (4 ): 1941.35212644
115 Wu J Li Q Fu X. Fusobacterium nucleatum contributes to the carcinogenesis of colorectal cancer by inducing inflammation and suppressing host immunity. Transl Oncol 2019; 12 (6 ): 846–851.30986689
116 Chorawala MR Postwala H Prajapati BG , et al . Impact of the microbiome on colorectal cancer development. In: Prajapati BG Philip AK Bhattacharya S , editors. Colorectal Cancer: Academic Press, 2024, pp. 29–72.
117 Deng Z Mu J Tseng M , et al . Corrigendum: enterobacteria-secreted particles induce production of exosome-like S1P-containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis. Nat Commun 2016; 7 : 11348.27063505
118 Peng C Ouyang Y Lu N , et al . The NF-κB signaling pathway, the microbiota, and gastrointestinal tumorigenesis: recent advances. Front Immunol 2020; 11 : 1387.
119 Li S Liu J Zheng X , et al . Tumorigenic bacteria in colorectal cancer: mechanisms and treatments. Cancer Biol Med 2022; 19 (2 ): 147.
120 Nouri R Hasani A Shirazi KM , et al . Escherichia coli and colorectal cancer: unfolding the enigmatic relationship. Curr Pharm Biotechnol 2022; 23 (10 ): 1257–1268.34514986
121 Feizi H Rezaee MA Ghotaslou R , et al . Gut microbiota and colorectal cancer risk factors. Curr Pharm Biotechnol 2023; 24 (8 ): 1018–1034.36200153
122 Veziant J Gagnière J Jouberton E , et al . Association of colorectal cancer with pathogenic Escherichia coli: focus on mechanisms using optical imaging. World J Clin Oncol 2016; 7 (3 ): 293.27298769
123 Chat H Dalmasso G Godfraind C , et al . Cytotoxic necrotizing factor 1 hinders colon tumorigenesis induced by colibactin-producing Escherichia coli in ApcMin/+ mice. Gut Microbes 2023; 15 (1 ): 2229569.37417545
124 Faïs T Delmas J Barnich N , et al . Colibactin: more than a new bacterial toxin. Toxins 2018; 10 (4 ): 151.29642622
125 Kvakova M Kamlarova A Stofilova J , et al . Probiotics and postbiotics in colorectal cancer: prevention and complementary therapy. World J Gastroenterol 2022; 28 (27 ): 3370.36158273
126 Darbandi A Mirshekar M Shariati A , et al . The effects of probiotics on reducing the colorectal cancer surgery complications: a periodic review during 2007–2017. Clin Nutr 2020; 39 (8 ): 2358–2367.31831184
127 Chopra H Goyal R Baig AA , et al . Synbiotics in colon cancer. In: Mishra N Bhatt S Paudel KR , et al . (eds) Synbiotics for the management of cancer. Singapore: Springer Nature Singapore, 2023, pp. 115–133.
128 Lee HA Kim H Lee K-W , et al . Dead nano-sized Lactobacillus plantarum inhibits azoxymethane/dextran sulfate sodium-induced colon cancer in Balb/c mice. J Med Food 2015; 18 (12 ): 1400–1405.26595186
129 Ghanavati R Akbari A Mohammadi F , et al . Lactobacillus species inhibitory effect on colorectal cancer progression through modulating the Wnt/β-catenin signaling pathway. Mol Cell Biochem 2020; 470 : 1–13.32419125
130 Inamura K (ed.). Gut microbiota contributes towards immunomodulation against cancer: new frontiers in precision cancer therapeutics. Semin Cancer Biol 2021; 70 : 11–23.32580023
131 Roy S Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 2017; 17 (5 ): 271–285.28303904
132 Matson V Chervin CS Gajewski TF. Cancer and the microbiome—influence of the commensal microbiota on cancer, immune responses, and immunotherapy. Gastroenterology 2021; 160 (2 ): 600–613.33253684
133 Anfossi S Calin GA. Gut microbiota: a new player in regulating immune-and chemo-therapy efficacy. Cancer Drug Resist 2020; 3 (3 ): 356.33062956
134 Sayin S Rosener B Li CG , et al . Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy. bioRxiv 2022. DOI: 10.1101/2022.09.07.506952.
135 Geller LT Barzily-Rokni M Danino T , et al . Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 2017; 357 (6356 ): 1156–1160.28912244
136 Yeung CY Chiang Chiau JS Cheng ML , et al . Modulations of probiotics on gut microbiota in a 5-fluorouracil-induced mouse model of mucositis. J Gastroenterol Hepatol 2020; 35 (5 ): 806–814.31674687
137 Zhang S Yang Y Weng W , et al . Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. J Exp Clin Cancer Res 2019; 38 : 1–13.30606223
138 Li Y Zhang Y Wei K , et al . Effect of gut microbiota and its metabolite SCFAs on radiation-induced intestinal injury. Front Cell Infect Microbiol 2021; 11 : 577236.34307184
139 Bai J Barandouzi ZA Rowcliffe C , et al . Gut microbiome and its associations with acute and chronic gastrointestinal toxicities in cancer patients with pelvic radiation therapy: a systematic review. Front Oncol 2021; 11 : 5237.
140 Oh B Eade T Lamoury G , et al . The gut microbiome and gastrointestinal toxicities in pelvic radiation therapy: a clinical review. Cancers 2021; 13 (10 ): 2353.34068216
141 Andrews MC Duong CP Gopalakrishnan V , et al . Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med 2021; 27 (8 ): 1432–1441.34239137
142 Kaźmierczak-Siedlecka K Roviello G Catalano M , et al . Gut microbiota modulation in the context of immune-related aspects of Lactobacillus spp. and Bifidobacterium spp. in gastrointestinal cancers. Nutrients 2021; 13 (8 ): 2674.34444834
143 Peng Z Cheng S Kou Y , et al . The gut microbiome is associated with clinical response to anti–PD-1/PD-L1 immunotherapy in gastrointestinal cancer. Cancer Immunol Res 2020; 8 (10 ): 1251–1261.32855157
144 Davar D Dzutsev AK McCulloch JA , et al . Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients. Science 2021; 371 (6529 ): 595–602.33542131
145 Routy B Le Chatelier E Derosa L , et al . Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 2018; 359 (6371 ): 91–97.29097494
146 Hayase E Jenq RR. Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer. Genome Med 2021; 13 (1 ): 107.34162429
147 Zhao H Wang D Zhang Z , et al . Effect of gut microbiota-derived metabolites on immune checkpoint inhibitor therapy: enemy or friend? Molecules 2022; 27 (15 ): 4799.35956752
148 Liu Y Lau HC-H Cheng WY , et al . Gut microbiome in colorectal cancer: clinical diagnosis and treatment. Genomics Proteomics Bioinformatics 2023; 21 (1 ): 84–96.35914737
149 Pandey H Tang DW Wong SH , et al . Gut microbiota in colorectal cancer: biological role and therapeutic opportunities. Cancers 2023; 15 (3 ): 866.36765824
150 McQuade JL Daniel CR Helmink BA , et al . Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol 2019; 20 (2 ): e77–e91.
151 Fong W Li Q Yu J. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene 2020; 39 (26 ): 4925–4943.32514151
152 Montassier E Valdés-Mas R Batard E , et al . Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner. Nat Microbiol 2021; 6 (8 ): 1043–1054.34226711
153 Davani-Davari D Negahdaripour M Karimzadeh I , et al . Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods 2019; 8 (3 ): 92.30857316
154 Saus E Iraola-Guzmán S Willis JR , et al . Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential. Mol Aspects Med 2019; 69 : 93–106.31082399
155 Ranjbar M Salehi R Haghjooy Javanmard S , et al . The dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review. Cancer Cell Int 2021; 21 : 1–24.33397383
156 Wang N Fang J-Y. Fusobacterium nucleatum, a key pathogenic factor and microbial biomarker for colorectal cancer. Trends Microbiol 2023; 31 (2 ): 159–172.36058786
157 Song M Chan AT Sun J . Influence of the gut microbiome, diet, and environment on risk of colorectal cancer. Gastroenterology 2020; 158 (2 ): 322–340.31586566
158 Biazzo M Deidda G. Fecal microbiota transplantation as new therapeutic avenue for human diseases. J Clin Med 2022; 11 (14 ): 4119.35887883
159 Quaranta G Sanguinetti M Masucci L. Fecal microbiota transplantation: a potential tool for treatment of human female reproductive tract diseases. Front Immunol 2019; 10 : 2653.
160 Waller KM Leong RW Paramsothy S. An update on fecal microbiota transplantation for the treatment of gastrointestinal diseases. J Gastroenterol Hepatol 2022; 37 (2 ): 246–255.34735024
