Bibliometric and visualization analysis of cancer associated with intestinal flora through genetics and epigenetics from 1991 to 2024

Introduction

Malignant tumors, as a serious health threat to humans, are showing an increasing incidence and mortality rate year by year. According to reports from the World Health Organization, cancer has become the first leading cause of death worldwide. Despite significant advancements in the diagnosis and treatment of cancer, its etiology and pathogenesis have not yet been fully elucidated. In recent years, an increasing number of studies have focused on the relationship between the intestinal flora and malignant tumors (1), especially gut microbes influence the development of cancer through epigenetic inheritance. This article aims to explore the role of the intestinal flora in the occurrence and development of malignant tumors and its possible mechanisms.

The gut microbiota, located within the human gastrointestinal system, constitutes an intricate and multifaceted assembly of microorganisms. Typically, this gut microbiota engages in a symbiotic association with the host, contributing to the modulation of numerous bodily functions such as immune response, metabolic processes, and nutrient absorption. Nevertheless, should the equilibrium of the gut microbiota be disturbed, it could precipitate the development of a range of illnesses, encompassing gastrointestinal disorders, metabolic imbalances, cardiovascular conditions, and cancerous growths (2). Apart from the straight communication between the gastrointestinal microbiota and the central nervous system, these microorganisms and their metabolic derivatives have the ability to influence epigenetic modifications, such as changes in DNA methylation patterns, histone alterations, and the governance of non-coding RNA molecules. Recent scholarly work has revealed a significant link between the composition of the gut flora and the development of cancerous growths (3). On one hand, the intestinal flora participates in the occurrence and development of malignant tumors by influencing the body’s immune surveillance, inflammatory responses, and metabolic activities (4,5). One the other hand, the occurrence and development of malignant tumors can also affect the composition and function of the intestinal flora. Metabolic products, cytokines, and other substances produced by tumor cells can alter the intestinal microenvironment, thereby affecting the balance of the intestinal flora (6).

Overall, an intricate relationship exists between the gut microbiome and cancerous growths. Comprehensive investigation into the association between gut flora and malignant tumors has the potential to elucidate the underlying mechanisms of tumor development and offer novel perspectives for cancer prevention, detection, and therapy. This paper is dedicated to examining the correlation between gut microbiota and cancer, delving into the associated pathways and advancements in research, with the intent of furnishing a theoretical foundation for future endeavors in cancer control and management. We present this article in accordance with the BIBLIO reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-13/rc).

Methods

Data source and search strategy

The Web of Science Core Collection (WoSCC), a database provided by Clarivate Analytics, is regarded as a premier and exhaustive repository, housing over 12,000 scholarly periodicals from around the world. For the purpose of our bibliometric examination, drawing on the findings of earlier research, we selected this database to gather comprehensive academic insights. We retrieved all published works from the WoSCC, spanning a period from January 1, 1991 to September 1, 2024. The search criteria employed in our investigation were: Topic = cancer *AND Topic = gut microbiota AND Publication Year = (1991-2024) AND Article Type = (article or review) AND Language = (English). Within the WoSCC, the specifics of individual nations or areas were delineated by the country index. Furthermore, the literature’s pertinent details, such as publication year, title, author, nationality, institution, abstract, keywords, and journal title, were preserved in the download.txt format within the WoSCC database. Discrepancies were addressed through expert consultation to arrive at a unified decision. In the final stages, the collaborative authors processed and examined the data using Origin 2021 and GraphPad Prism 8 software consecutively.

Bibliometric analysis and visualization

The core purpose of the WoSCC is to delve into the essential features of the pertinent literature. As such, it mirrors the volume of publications along with their respective citation frequencies. The Relative Research Interest (RRI) is defined as the ratio of the number of publications within a specific domain annually to the total number of publications in that domain. The global map was generated utilizing a combination of R software and the Python libraries including numpy, scipy, and matplotlib. A publication timeline was constructed, influenced by earlier scholarly works. For the purposes of this study, we utilized VOSviewer to build and render a visual representation of the bibliometric network of the publications. VOSviewer was also employed for in-depth analyses of bibliographic coupling, co-citation, and co-occurrence. Additionally, the R package “bibliometrix” was chosen to depict the dissemination of publications across various countries, to illustrate a collaborative international research map, and to visualize the findings of the three-field diagram analysis.

Results

Overall performance of global literatures

Following the established search criteria, a dataset comprising 1,362 items was gathered, covering a period from 1991 through to 2024. Following this, the selection was narrowed down to include only those documents sourced from the WoSCC, with conference abstracts, along with other non-peer-reviewed materials such as proceedings and revised book chapters, being removed from the count. This refining process yielded a final tally of 1,006 documents (Figure 1).

Figure 1 Flowchart depicting the article selection process.

When examining the distribution by year, the volume of documents published prior to 2013 was notably low, with an annual output of less than 20 publications. However, from 2013 onwards, there was a noticeable annual upsurge in the number of publications, culminating in a zenith in the years 2022 and 2023 (with the data for 2024 reflecting only the first 9 months), signifying a growing interest in this field among researchers (Figure 2).

Figure 2 The annual number of publications related to intestinal flora and cancer.

Analysis of countries

Across various nations, there are 86 countries or territories that house research entities which have authored and released scholarly articles on the subject. Leading the pack in terms of publication volume is China, with the United States in close pursuit, followed by Italy, India, the United Kingdom, Germany, Spain, and France. Nevertheless, when assessing the impact of these publications based on citations per article to determine the overall connectivity strength, the United States assumes the top position, with China taking the runner-up spot. The standing of other nations undergoes a minor shift, suggesting that the research outputs from American institutions are more frequently cited, indicative of their superior research quality (Figure 3).

Figure 3 A world map depicting the distribution of publication.

Analysis of institutions and authors

The evaluation of academic institutions revealed that the Harvard Medical School occupies the top position comprehensively. While Zhejiang University boasts a greater volume of publications, it assumes the second position based on citation numbers. Not far behind are the Chinese Academy of Sciences and Zhejiang Chinese Medical School. Moreover, the Harvard T.H. Chan School of Public Health in Boston and Massachusetts General Hospital are also among the leading ranks. The findings align with the global trend, where China leads in terms of quantity, yet American institutions excel in the realm of publication quality and citation impact (Figure 4).

Figure 4 Mapping of institutions associated with intestinal flora and cancer. Analysis was based on VOSviewer.

The study’s authorship evaluation identifies the Luigi Santacroce group at the Interdisciplinary Department of Medicine, specializing in Microbiology and Virology within the School of Medicine at the University of Bari “Aldo Moro” in Bari, Italy, as the top-ranked. Similarly, the Jun Yu group at the Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, and Shenzhen Research Institute, located in the Hong Kong Special Administrative Region, is on par with them in publication volume. Trailing these are the teams led by Loannis Alexandros Charitos, Amedeo Amedei, and Antonio Taddei, respectively (Figure 5).

Figure 5 Mapping of the identified authors in this field.

Upon examining the frequency of document citations, the trio of most referenced articles were all featured in the “Science” publication. Leading the list is the study titled “Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors” by Bertrand Routy and colleagues (7), which appeared in “Science” in 2018. This research primarily explores how immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have generated sustained clinical responses in a notable subset of cancer patients, and that primary resistance to these therapies may be linked to an altered gut microbiome composition. The potential of PD-1 inhibition can be enhanced through fecal microbiota transplantation (FMT) and the oral intake of Akkermansia muciniphila. In the second position is the article “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy” by Ayelet Sivan and associates, published in “Science” in 2015. The article primarily posits that gut microbiota can modulate the response to cancer immunotherapy, with the ingestion of Bifidobacterium bolstering dendritic cell activity and facilitating the activation and accumulation of CD8⁺ T cells within the tumor microenvironment, thereby enhancing tumor control akin to PD-L1-targeted antibody treatments. Securing the third rank is the scholarly work “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota” by Marie Vétizou and team, also published in “Science” in 2015. This study mainly asserts that the therapeutic impact of CTLA-4 inhibition is contingent on specific Bacteroides strains, with Bacteroides fragilis (B. fragilis) being pivotal in modulating the immune response to therapy, and that the therapeutic efficacy in antibiotic-treated or germ-free mice can be rejuvenated through supplementation with this bacterium (Figures 6,7).

Figure 6 Network visualization diagram of the cocited authors of the publications.

Figure 7 Mapping of the cocited references related to this field.

In conclusion, the gastrointestinal microbiota is pivotal in the therapeutic approach to cancer using ICI treatments, with particular microbes like Akkermansia muciniphila, Bifidobacterium species, and B. fragilis having the capacity to affect the therapeutic outcomes of PD-1 and CTLA-4 inhibitory strategies.

Analyzing the connectivity between authors, the 2023 article “Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila” (8) by Pandey et al. ranks first in total link strength, indicating a significant level of influence (Figure 8).

Figure 8 Network visualization diagram of the co-cited authors of the publications.

Further analysis of the authors’ keywords reveals that the top two keywords are “gut microbiota” and “cancer”, followed by “probiotics”, “inflammation”, “colorectal cancer”, “Fusobacterium nucleatum”, “dysbiosis”, “chain fatty-acids”, “risk”, “colon cancer”, “immunotherapy”, and “diet”. The ranking and frequent occurrence of these keywords indicate that the following themes and concepts have received significant attention in current scientific research and public health fields: “gut microbiota” as the top keyword suggests that the study of the gut microbiome is a hot topic in biomedical research. Scientists are exploring how the microorganisms in the gut affect the host’s health and disease. The ranking of “probiotics” suggests it may be related to improving the balance of the gut microbiota and their role in preventing or treating cancer. Inflammation is a key factor in many diseases, including cancer, indicating that scientists are studying how the gut microbiota can affect cancer development by triggering or regulating inflammatory responses. “Colorectal cancer” is a specific type of cancer mentioned in the keywords, indicating that this is a key area of research into the association between the gut microbiota and cancer. “Fusobacterium nucleatum (Fn)” is a specific bacterium that studies have shown is associated with the development of colorectal cancer (CRC), making it a research focus. “Dysbiosis” refers to an imbalance in the gut microbiota and is thought to be related to the onset of various diseases, including cancer. “Chain Fatty-Acids” may be related to the metabolic products of the gut microbiota, which may affect the risk of cancer. “Colon cancer”, similar to CRC, is also a focus of research on the association between the gut microbiota and cancer. “Immunotherapy” suggests that researchers are exploring how the gut microbiota can affect immune responses and whether they can be used to enhance the effectiveness of cancer immunotherapy. “Diet” is an important factor influencing the composition of the gut microbiota, and research may focus on how dietary interventions can prevent or treat cancers associated with dysbiosis. These keywords indicate that the connection between the gut microbiota and cancer is being widely researched, particularly focusing on regulating the gut microbiota through probiotics, diet, immunotherapy, and other means to prevent or treat cancer (Figure 9).

Figure 9 Clustering analysis of the keyword network based on CiteSpace.

Discussion

In the past few years, significant new advancements have been made in the field of CRC and gut microbiota research, providing a richer context for our discussion.

The association between the microbiome and CRC

Microbiome dysbiosis and CRC risk

Gut microbiome dysbiosis is characterized by a decrease in beneficial bacteria, an increase in harmful bacteria, and a reduction in bacterial diversity. Study has found a positive correlation between microbiome dysbiosis and the risk of CRC (9). Dysbiosis in the microbiome may promote the onset of CRC through the following pathways: (I) production of carcinogens: certain harmful bacteria can produce carcinogens such as nitrites and hydrogen sulfide, which can directly damage the intestinal mucosa and increase the risk of CRC (10); (II) impact on intestinal immune function: beneficial bacteria can regulate intestinal immune function and suppress inflammatory responses. Dysbiosis may lead to immune dysfunction, promoting tumor growth (11); (III) influence on intestinal metabolism: dysbiosis may result in abnormalities of metabolic products such as short-chain fatty acids (SCFAs) and bile acids, which in turn affect the proliferation, differentiation, and apoptosis of intestinal cells, increasing the risk of CRC (12,13).

The relationship between specific microorganisms and CRC

Study indicates that certain specific microorganisms are closely related to the onset of CRC (14). These microorganisms may promote the occurrence of CRC through the following pathways:

Inducing genetic mutations

Helicobacter pylori (H. pylori) infection can lead to genetic mutations in gastric mucosal epithelial cells, increasing the risk of CRC (15).

Regarding H. pylori, germline pathogenic variants in homologous-recombination genes (Apc, Atm, Brca1/2) and H. pylori infection synergistically increase gastric cancer risk [relative excess risk due to the interaction (RERI) =16.01], with carriers of both having a 45.5% cumulative risk by the age 85 years versus 14.4% in infected non-carriers, per analyses of 10,426 cases and 38,153 controls (16).

Regarding Escherichia coli (E. coli), chronic exposure of human intestinal organoids to colibactin-producing polyketide synthase-positive (pks⁺) E. coli induces a unique mutational signature—later identified in 5,876 human cancers (primarily colorectal)—demonstrating for the first time that gut bacteria can directly drive oncogenic mutations via bacterial genotoxins (17). A low-carbohydrate diet exacerbates pks⁺E. coli-induced colorectal polyposis in IL10^−/− mice by promoting mucosal inflammation, reducing PPAR-γ signaling, and increasing luminal nitrate—effects reversible by PPAR-γ agonists or fiber supplementation—while mismatch-repair deficiency further potentiates tumorigenesis via senescence-associated secretory phenotypes, revealing diet-host-microbe interplay in oncogenesis (18).

Gut microbiota—including CRC-promoting pathogens [Fn, E. coli] and protective species (Clostridium butyricum, Lacticaseibacillus paracasei)—interact with host cells via metabolites (carcinogenic bile acids vs. anti-tumor butyrate), influencing CRC development, early-onset patterns, and therapeutic responses, highlighting their dual roles as diagnostic biomarkers and treatment modulators (19).

Promoting inflammatory responses

Pathogens such as Fn can induce intestinal inflammation, and chronic inflammation over a long period can promote tumor development (20).

(I) Epidemiological associations with cancer development

Multiple lines of evidence from large-scale genomic and population studies have established Fn as an oncogenic bacterium with multi-organ tropism. Initial investigations demonstrated significant enrichment of Fn in CRC tissues compared to adjacent normal mucosa (21,22), with subsequent validation across international cohorts revealing a 20–30% prevalence in CRC cases (23,24). Clinically, Fn-positive CRCs exhibit more aggressive phenotypes, including reduced survival (25,26) and increased lymph node metastasis (27). Epidemiological study further identifies important diet-microbe interactions, with Western dietary patterns showing significant association with Fn-positive CRC subtypes (28). While CRC remains the best-characterized malignancy, emerging data implicate Fn in pancreatic (29) and breast cancers (30), suggesting broader oncogenic potential.

(II) Molecular mechanisms of Fn-mediated carcinogenesis

Fn orchestrates tumorigenesis through multifaceted mechanisms: immune modulation includes Fap2-mediated inhibition of natural killer and T cell cytotoxicity (31), and TLR4/NF-κB-mediated PD-L1 upregulation (32). Epithelial reprogramming involves miR-21 activation and Wnt/β-catenin pathway dysregulation, along with induction of proinflammatory cytokines (IL-8, TNF-α) through monocyte activation (33). Microenvironment remodeling encompasses biofilm formation that confers chemoresistance (34) and recruitment of immunosuppressive myeloid-derived suppressor cells (35).

(III) Translational implications

Fn’s association with mesenchymal/CMS4 CRC subtypes (36) supports its dual utility as: (I) a diagnostic biomarker for early detection (37), and (II) a therapeutic target through antibiotic regimens (metronidazole in preclinical models) and emerging immunotherapies targeting Fn adhesins (Fap2-neutralizing antibodies) (38).

(IV) Critical knowledge gaps and future directions

Despite advances, key questions remain unresolved: (I) whether Fn eradication prevents tumor initiation requires testing in intervention trials; (II) subspecies animals exhibits heightened oncogenicity (39); and (III) potential cooperation with pks⁺E. coli or H. pylori in tumor microenvironment.

Microbiome as a target for CRC diagnosis and treatment

The gut microbiome, with its individual differences and stability, holds promise as a target for the diagnosis and treatment of CRC (40). Study has found that characteristic changes in the gut microbiome of CRC patients, such as the enrichment or depletion of certain bacterial genera, can serve as biomarkers for the diagnosis of CRC (41). Additionally, adjusting the gut microbiome, for example, by using probiotics, prebiotics, and other means, may provide new strategies for the prevention and treatment of CRC (42).

The role of microbial metabolites

The relationship between microbial metabolites and tumor initiation

Study has found that an imbalance of gut microbial metabolites is closely related to the onset of cancer (43). Specifically, the levels of certain harmful bacterial metabolites, such as secondary bile acids, hydrogen sulfide, and lipopolysaccharides, are elevated in tumor tissues, and these substances have been proven to have a carcinogenic effect (44). This finding is consistent with previous research results, suggesting that gut microbial metabolites may be one of the key factors in tumor initiation.

The carcinogenic mechanisms of microbial metabolites

• The role of bile acids: the levels of secondary bile acids are significantly increased in cancer patients. They promote tumor cell proliferation by activating the FXR receptor and affecting the cell cycle and apoptosis pathways (45). Additionally, secondary bile acids may also increase the risk of cancer by inducing DNA damage and inflammatory responses (46).
• The role of hydrogen sulfide: hydrogen sulfide, as a gaseous signaling molecule, plays a role in promoting angiogenesis and inhibiting immune surveillance in the tumor microenvironment (47).
• The role of lipopolysaccharides: lipopolysaccharides are components of the cell walls of intestinal bacteria. They can activate immune cells in the tumor microenvironment, releasing pro-inflammatory cytokines, thus promoting tumor growth (48).

Microbial metabolites as potential targets for cancer treatment

Regulating gut microbial metabolites may become a new strategy for cancer treatment (40). Here are some potential therapeutic directions. Microbiota modulation: modulating the composition of the gut microbiota through the use of probiotics, prebiotics, or FMT to reduce the production of harmful metabolites may help prevent tumor initiation. Targeting metabolites: developing drugs that target specific harmful metabolites, such as bile acid sequestrants, hydrogen sulfide inhibitors, etc., may help slow down tumor growth. Immunotherapy: by reducing the levels of immune-activating substances like lipopolysaccharides, it may be possible to improve the efficacy of immunotherapy and reduce immune-related adverse reactions.

Gut microbiota and immunotherapy

The composition and diversity of the gut microbiota significantly impact the efficacy of immunotherapy (49). Specifically, patients who respond well to immunotherapy tend to have a richer and more diverse gut microbiota, whereas non-responders show a decrease in microbiota diversity. The gut microbiota may serve as an important predictive factor for immunotherapy response.

Mechanisms by which gut microbiota affects immunotherapy

• Microbiota and ICIs: certain gut bacteria can regulate the expression of immune checkpoint molecules such as PD-1 and CTLA-4 (50,51). These bacteria may influence the efficacy of immunotherapy by producing specific metabolites or by directly interacting with immune cells.
• Microbiota and immune cell infiltration: changes in the gut microbiota may affect the infiltration and function of immune cells in the tumor microenvironment. For example, certain beneficial bacteria can promote the activation of T cells, while harmful bacteria may suppress the anti-tumor activity of immune cells (49).
• Microbiota and immune metabolism: alterations in the metabolic activity of the gut microbiota may affect the metabolic state of immune cells, thereby influencing their function (11). For instance, microbiota-derived metabolites such as SCFAs have been shown to regulate the activity and inflammatory responses of immune cells.

Interaction between genetic and environmental factors

The development of CRC is a result of the combined effects of genetic and environmental factors. Here are some key points of interaction

• Genetic variations and gut microbiota: recent studies suggest that genetic variations may influence an individual’s response to the gut microbiota. For example, certain genetic variations may lead to changes in the composition of the gut microbiota, which could increase the risk of CRC (52).
• Genetic variations and dietary habits: dietary habits are significant factors affecting the risk of CRC. Studies indicate that individuals carrying specific genetic variations may respond differently to certain food components (such as fat and red meat), thereby influencing the onset of CRC (53).
• Genetic variations and lifestyle: in addition to diet, lifestyle factors such as smoking (12), alcohol consumption, and lack of physical activity are also associated with the risk of CRC (54). Genetic variations may affect the degree to which these lifestyle factors impact the risk of CRC (55).

The interaction between genetic and environmental factors may affect the onset of CRC through the following mechanisms

• Immune response: genetic variations may influence an individual’s immune response, thereby affecting the regulation of the gut microbiota and tumor surveillance (56);
• Toxin metabolism: genetic variations may affect an individual’s ability to metabolize environmental toxins, influencing the accumulation of toxins and the risk of CRC (57);
• Inflammatory pathways: genetic variations may affect the activity of inflammatory pathways, and chronic inflammation is one of the key factors in the development of CRC (5).

Impact on prevention, diagnosis, and treatment

Understanding the interaction between genetic and environmental factors is of great significance for the prevention, diagnosis, and treatment of CRC. Personalized prevention: by identifying high-risk genetic variations, personalized prevention strategies can be developed for specific populations, such as altering dietary habits or increasing the intake of specific nutrients (40). Early diagnosis: combining genetic information with environmental exposure data can lead to the development of more accurate tools for assessing the risk of CRC, enabling early diagnosis. Targeted treatment: understanding the mechanisms of gene-environment interaction can help in developing treatments that target specific genetic backgrounds and environmental factors (11).

Environmental and lifestyle factors influencing microbial carcinogenesis

Impact of environmental and lifestyle factors on microbial-driven carcinogenesis

Emerging evidence highlights how environmental exposures and lifestyle habits modulate the microbiome to influence cancer risk and progression. These factors contribute to inter-individual variability in disease outcomes by altering microbial composition and function:

Dietary patterns

• Western diet (high-fat, low-fiber): promotes Fn and pks+ E. coli enrichment, linked to CRC via pro-inflammatory and genotoxic mechanisms (28);
• Mediterranean diet (high-fiber, polyphenol-rich): associated with anti-inflammatory Faecalibacterium prausnitzii and reduced CRC risk (58).

Antibiotic use

Disrupts gut microbial balance, increasing susceptibility to Fn-associated CRC (27). Early-life antibiotics correlate with later-life CRC, possibly due to persistent dysbiosis (59).

Smoking and alcohol

Smoking alters oral/intestinal microbiota, favoring Fn and Porphyromonas gingivalis (linked to oral/CRC cancers) (60). Heavy alcohol intake depletes Bacteroides, increasing pathogenic Enterobacteriaceae (61).

Obesity

Obesity-associated dysbiosis promotes Fn and Bacteroides fragilis toxin-driven carcinogenesis (62).

These factors may vary in each person differentially, which can explain differences in disease outcomes.

Molecular pathological epidemiology (MPE): bridging lifestyle, microbes, and cancer subtypes

MPE is an interdisciplinary field that combines molecular pathology and epidemiology to study disease heterogeneity. It recognizes that each individual’s disease develops uniquely due to interactions between environmental exposures and host factors, leading to distinct molecular and pathological subtypes (63). Metagenomic studies reveal that altered gut microbiome compositions—including enriched E. coli, Bacteroides fragilis, and oral microbes—interact with host genetics, immunity, and environmental factors to influence gastrointestinal carcinogenesis, prompting the integration of microbiology into MPE (microbiology-MPE) to unravel these complex interactions and guide microbiome-targeted prevention and therapies (64).

MPE integrates environmental exposures, host molecular signatures, and microbial biomarkers to decipher heterogeneous cancer etiologies (65). Personalized microbial biomarkers: Fn and pks⁺E. coli stratify CRC into molecular subtypes (CMS4 with poor prognosis) (36). Microbial signatures (Fap2 gene in Fn) may predict immunotherapy response (35). By analyzing 5,959 individuals’ genotypes, gut microbiomes, and health data, we identified 567 host genetic-microbial associations, including dairy-dependent lactase gene (LCT)-Bifidobacterium links, ABO-blood-group-Faecalicatena interactions, and a MED13L-Enterococcus association potentially relevant to CRC, while Mendelian randomization suggested Morganella’s causal role in depression, collectively revealing complex host-microbiome-disease interplay (66). A recent study reveals that glioblastoma human leukocyte antigen (HLA) molecules present bacterial peptides, and tumor-infiltrating lymphocytes (TILs) recognize these microbial antigens alongside tumor antigens, demonstrating cross-reactivity between commensal/pathogenic bacteria and tumor immunity, with implications for personalized cancer vaccines (67). A sex-specific dietary pattern high in processed foods and low in fiber was associated with increased CRC risk [hazard ratio (HR) comparing the highest quintile (Q5) to the lowest quintile (Q1) dependent (HRQ5vsQ1) =1.25], particularly for tumors harboring Fn (HR =2.51), pks⁺ E. coli (HR =1.68), or enterotoxigenic Bacteroides fragilis (HR =2.06), suggesting microbiome-mediated dietary influences on carcinogenesis across 259,200 participants over 6.4 million person-years (68). A meta-analysis of eight global fecal metagenomic studies (n=768) identified 29 consistently CRC-enriched microbial species (false discovery rate <1×10⁻⁵) with improved diagnostic accuracy when cross-validated, revealing CRC-specific depletion of carbohydrate degradation genes and enrichment of protein/mucin catabolism and secondary bile acid pathways, establishing generalizable microbiome signatures for future diagnostics (58). MPE research that can investigate those lifestyle factors and biomarkers and clinical outcomes. Findings from MPE can be used in research and clinical practice.

Research limitations and prospects

Although this study conducted a comprehensive bibliometric analysis of the literature related to CRC and the gut microbiota, there are still some limitations. First, the literature search strategy may have missed some relevant studies, affecting the accuracy of the results. Second, this study did not evaluate the quality of the literature, which may have led to the inclusion of some low-quality studies in the analysis. Future research can be expanded in the following aspects:

• Improve the literature search strategy to increase the coverage of literature;
• Conduct quality evaluations of the included literature to enhance the reliability of the research results;
• Further explore the mechanisms of action between the gut microbiota and CRC to provide new targets for clinical treatment;
• Carry out multi-center, large-sample clinical studies to validate the role of gut microbiota interventions in the prevention of CRC.

To overcome these limitations, future research should:

• Utilize metagenomics and metabolomics technologies to conduct deeper analyses of microbial functions;
• Implement prospective cohort studies to better understand the temporal relationship between changes in the gut microbiota and the onset of CRC;
• Explore biomarkers based on the gut microbiota for early diagnosis and prognostic assessment of CRC;
• Design clinical trials to test the feasibility of improving the efficacy of CRC treatment by regulating the gut microbiota;
• Consider the combined impact of environmental factors, dietary habits, and lifestyle on the gut microbiota and the risk of CRC. Through these in-depth studies, we hope to make significant breakthroughs in the prevention, diagnosis, and treatment of CRC.

In summary, this study provides a useful reference for the field of CRC and gut microbiota research. With the continuous development of science and technology, we have reason to believe that the role of the gut microbiota in the prevention and treatment of CRC will be further studied and applied.

Conclusions

Visual analysis of research trends

Through the visualization charts of time series analysis, we found that since 2010, the number of studies on CRC and the gut microbiota has significantly increased (Figure 2). This trend reflects the growing research interest in the field and also indicates that the role of the gut microbiota in the occurrence of CRC is gradually being recognized.

Through a bibliometric analysis of studies related to CRC and the gut microbiota, we have found that research in this field has shown a rapid growth trend in recent years. This indicates that the relationship between the gut microbiota and CRC has become a hot topic of research both domestically and internationally. Especially driven by microbiomics and precision medicine, researchers have delved into the mechanisms of action of the gut microbiota in the onset and development of CRC.

Regional and institutional collaboration

Through the geographic distribution heatmap, we observed that research on CRC and the gut microbiota is unevenly distributed worldwide (Figure 3). The quantity and quality of research in North America and Europe are generally higher than in other regions. This finding suggests that international collaboration and knowledge dissemination are crucial for promoting the development in this field.

From the bibliometric analysis results, China has a relatively high volume of publications and influence in the research area of CRC and the gut microbiota. However, compared to international advanced levels, there is still room for improvement in collaborative research within this field in China. In the future, researchers in China should actively engage in international collaborations and enhance the level of research to provide stronger theoretical support for the prevention and treatment of CRC.

The social network graph showcases the collaboration between different research institutions (Figures 6-8). We found that while there are some core research institutions, the overall collaboration network is relatively dispersed. This result indicates that strengthening cross-institutional and interdisciplinary collaboration is essential for a deeper understanding of the relationship between CRC and the gut microbiota.

Research hotspots and key areas

We constructed a keyword co-occurrence network map that displays the main hotspots in the field of CRC research (Figure 9). The key nodes in the map, such as “gut microbiota dysbiosis”, “inflammatory bowel disease”, “microbial metabolites”, and “intestinal barrier”, reveal the close connections between these areas and CRC. This result supports our hypothesis that changes in the gut microbiota play a significant role in the development of CRC.

The results of the visual analysis indicate that gut microbiota dysbiosis, inflammatory bowel disease, intestinal microbial metabolites, and intestinal barrier function are key areas in CRC research. These research hotspots provide important clues for uncovering the pathogenesis of CRC. For example, gut microbiota dysbiosis may lead to intestinal inflammatory responses, thereby increasing the risk of CRC. Additionally, the role of intestinal microbial metabolites such as SCFAs and bile acids in the occurrence of CRC has also received widespread attention.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-13/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-13/prf

Funding: This work was supported by the National Key Research and Development Project of China (No. 2022YFC2704300), Zhejiang Provincial Administration of Traditional Chinese Medicine Co-construction Science and Technology Plan Project (No. GZY-ZJ-KJ-24083), Scientific Research Foundation of the Education Department of Zhejiang Province (No. Y202249581), Guangdong Medical Science and Technology Research Fund Project (No. A2024305) and Dongguan Comprehensive Prevention and Control of Birth Defects Project (No. 441900210000272762).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-13/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Wong-Rolle A, Wei HK, Zhao C, et al. Unexpected guests in the tumor microenvironment: microbiome in cancer. Protein Cell 2021;12:426-35. [Crossref] [PubMed]
2. Park EM, Chelvanambi M, Bhutiani N, et al. Targeting the gut and tumor microbiota in cancer. Nat Med 2022;28:690-703. [Crossref] [PubMed]
3. Sepich-Poore GD, Zitvogel L, Straussman R, et al. The microbiome and human cancer. Science 2021;371:eabc4552. [Crossref] [PubMed]
4. Gunjur A, Shao Y, Rozday T, et al. A gut microbial signature for combination immune checkpoint blockade across cancer types. Nat Med 2024;30:797-809. [Crossref] [PubMed]
5. Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022;30:289-300. [Crossref] [PubMed]
6. Chen H, Tong T, Lu SY, et al. Urea cycle activation triggered by host-microbiota maladaptation driving colorectal tumorigenesis. Cell Metab 2023;35:651-666.e7. [Crossref] [PubMed]
7. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91-7. [Crossref] [PubMed]
8. Pandey A, Galeone A, Han SY, et al. Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila. Nat Commun 2023;14:5667. [Crossref] [PubMed]
9. Yuan X, Chen B, Duan Z, et al. Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics. Gut Microbes 2021;13:1987779. [Crossref] [PubMed]
10. Stanfill SB, Hecht SS, Joerger AC, et al. From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications. Crit Rev Toxicol 2023;53:658-701. [Crossref] [PubMed]
11. Fernandes MR, Aggarwal P, Costa RGF, et al. Targeting the gut microbiota for cancer therapy. Nat Rev Cancer 2022;22:703-22. [Crossref] [PubMed]
12. Bai X, Wei H, Liu W, et al. Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites. Gut 2022;71:2439-50. [Crossref] [PubMed]
13. Guo X, Okpara ES, Hu W, et al. Interactive Relationships between Intestinal Flora and Bile Acids. Int J Mol Sci 2022;23:8343. [Crossref] [PubMed]
14. Zhang H, Wu J, Li N, et al. Microbial influence on triggering and treatment of host cancer: An intestinal barrier perspective. Biochim Biophys Acta Rev Cancer 2023;1878:188989. [Crossref] [PubMed]
15. Barouki R, Samson M, Blanc EB, et al. The exposome and liver disease - how environmental factors affect liver health. J Hepatol 2023;79:492-505. [Crossref] [PubMed]
16. Usui Y, Taniyama Y, Endo M, et al. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. N Engl J Med 2023;388:1181-90. [Crossref] [PubMed]
17. Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, et al. Mutational signature in colorectal cancer caused by genotoxic pks(+) E. coli. Nature 2020;580:269-73. [Crossref] [PubMed]
18. Thakur BK, Malaise Y, Choudhury SR, et al. Dietary fibre counters the oncogenic potential of colibactin-producing Escherichia coli in colorectal cancer. Nat Microbiol 2025;10:855-70. [Crossref] [PubMed]
19. Qu R, Zhang Y, Ma Y, et al. Role of the Gut Microbiota and Its Metabolites in Tumorigenesis or Development of Colorectal Cancer. Adv Sci (Weinh) 2023;10:e2205563. [Crossref] [PubMed]
20. Yang X, Guo Y, Chen C, et al. Interaction between intestinal microbiota and tumour immunity in the tumour microenvironment. Immunology 2021;164:476-93. [Crossref] [PubMed]
21. Kostic AD, Gevers D, Pedamallu CS, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 2012;22:292-8. [Crossref] [PubMed]
22. Castellarin M, Warren RL, Freeman JD, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012;22:299-306. [Crossref] [PubMed]
23. Ito M, Kanno S, Nosho K, et al. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. Int J Cancer 2015;137:1258-68. [Crossref] [PubMed]
24. Li YY, Ge QX, Cao J, et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol 2016;22:3227-33. [Crossref] [PubMed]
25. Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 2016;65:1973-80. [Crossref] [PubMed]
26. Kosumi K, Baba Y, Yamamura K, et al. Intratumour Fusobacterium nucleatum and immune response to oesophageal cancer. Br J Cancer 2023;128:1155-65. [Crossref] [PubMed]
27. Kawamura H, Ugai T, Takashima Y, et al. Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status. Ann Surg 2025;282:319-27. [Crossref] [PubMed]
28. 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;3:921-7. [Crossref] [PubMed]
29. Joo JE, Chu YL, Georgeson P, et al. Intratumoral presence of the genotoxic gut bacteria pks(+) E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer. Br J Cancer 2024;130:728-40. [Crossref] [PubMed]
30. 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;31:210-20. [Crossref] [PubMed]
31. Mima K, Sukawa Y, Nishihara R, et al. Fusobacterium nucleatum and T Cells in Colorectal Carcinoma. JAMA Oncol 2015;1:653-61. [Crossref] [PubMed]
32. Yang Y, Weng W, Peng J, 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 2017;152:851-866.e24. [Crossref] [PubMed]
33. Luo K, Zhang Y, Xv C, et al. Fusobacterium nucleatum, the communication with colorectal cancer. Biomed Pharmacother 2019;116:108988. [Crossref] [PubMed]
34. Zhang S, Cai S, Ma Y. Association between Fusobacterium nucleatum and colorectal cancer: Progress and future directions. J Cancer 2018;9:1652-9. [Crossref] [PubMed]
35. Hamada T, Zhang X, Mima K, et al. Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status. Cancer Immunol Res 2018;6:1327-36. [Crossref] [PubMed]
36. Takeda K, Koi M, Okita Y, et al. Fusobacterium nucleatum Load Correlates with KRAS Mutation and Sessile Serrated Pathogenesis in Colorectal Adenocarcinoma. Cancer Res Commun 2023;3:1940-51. [Crossref] [PubMed]
37. Nosho K, Sukawa Y, Adachi Y, et al. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World J Gastroenterol 2016;22:557-66. [Crossref] [PubMed]
38. Park CH, Han DS, Oh YH, et al. Role of Fusobacteria in the serrated pathway of colorectal carcinogenesis. Sci Rep 2016;6:25271. [Crossref] [PubMed]
39. Ye X, Wang R, Bhattacharya R, et al. Fusobacterium Nucleatum Subspecies Animalis Influences Proinflammatory Cytokine Expression and Monocyte Activation in Human Colorectal Tumors. Cancer Prev Res (Phila) 2017;10:398-409. [Crossref] [PubMed]
40. Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023;20:429-52. [Crossref] [PubMed]
41. Kong C, Liang L, Liu G, et al. Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer. Gut 2023;72:1129-42. [Crossref] [PubMed]
42. Suez J, Zmora N, Segal E, et al. The pros, cons, and many unknowns of probiotics. Nat Med 2019;25:716-29. [Crossref] [PubMed]
43. Ternes D, Tsenkova M, Pozdeev VI, et al. The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab 2022;4:458-75. [Crossref] [PubMed]
44. Cui W, Guo M, Liu D, et al. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition. Nat Cell Biol 2024;26:124-37. [Crossref] [PubMed]
45. Clifford BL, Sedgeman LR, Williams KJ, et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab 2021;33:1671-1684.e4. [Crossref] [PubMed]
46. Fu T, Coulter S, Yoshihara E, et al. FXR Regulates Intestinal Cancer Stem Cell Proliferation. Cell 2019;176:1098-1112.e18. [Crossref] [PubMed]
47. Hyer ML, Milhollen MA, Ciavarri J, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med 2018;24:186-93. [Crossref] [PubMed]
48. Wang A, Liu Y, Zeng S, et al. Dietary Plant Polysaccharides for Cancer Prevention: Role of Immune Cells and Gut Microbiota, Challenges and Perspectives. Nutrients 2023;15:3019. [Crossref] [PubMed]
49. Jia D, Wang Q, Qi Y, et al. Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer. Cell 2024;187:1651-1665.e21. [Crossref] [PubMed]
50. Wu H, Leng X, Liu Q, et al. Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma. Cancer Res 2023;83:3131-44. [Crossref] [PubMed]
51. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350:1079-84. [Crossref] [PubMed]
52. Yu Z, Coorens THH, Uddin MM, et al. Genetic variation across and within individuals. Nat Rev Genet 2024;25:548-62. [Crossref] [PubMed]
53. Yang J, Wei H, Zhou Y, et al. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites. Gastroenterology 2022;162:135-149.e2. [Crossref] [PubMed]
54. Zhang X, Coker OO, Chu ES, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut 2021;70:761-74. [Crossref] [PubMed]
55. Kim CH. Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity. Cell Mol Immunol 2023;20:341-50. [Crossref] [PubMed]
56. Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet 2021;53:156-65. [Crossref] [PubMed]
57. Clay SL, Fonseca-Pereira D, Garrett WS. Colorectal cancer: the facts in the case of the microbiota. J Clin Invest 2022;132:e155101. [Crossref] [PubMed]
58. Wirbel J, Pyl PT, Kartal E, et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat Med 2019;25:679-89. [Crossref] [PubMed]
59. Reyman M, van Houten MA, Watson RL, et al. Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial. Nat Commun 2022;13:893. [Crossref] [PubMed]
60. Fan J, Zhou Y, Meng R, et al. Cross-talks between gut microbiota and tobacco smoking: a two-sample Mendelian randomization study. BMC Med 2023;21:163. [Crossref] [PubMed]
61. Shen M, Zhao H, Han M, et al. Alcohol-induced gut microbiome dysbiosis enhances the colonization of Klebsiella pneumoniae on the mouse intestinal tract. mSystems 2024;9:e0005224. [Crossref] [PubMed]
62. Liu R, Hong J, Xu X, et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med 2017;23:859-68. [Crossref] [PubMed]
63. Hamada T, Keum N, Nishihara R, et al. Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis. J Gastroenterol 2017;52:265-75. [Crossref] [PubMed]
64. Mima K, Kosumi K, Baba Y, et al. The microbiome, genetics, and gastrointestinal neoplasms: the evolving field of molecular pathological epidemiology to analyze the tumor-immune-microbiome interaction. Hum Genet 2021;140:725-46. [Crossref] [PubMed]
65. Ogino S, Nowak JA, Hamada T, et al. Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology. Annu Rev Pathol 2019;14:83-103. [Crossref] [PubMed]
66. Qin Y, Havulinna AS, Liu Y, et al. Author Correction: Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat Genet 2024;56:554. [Crossref] [PubMed]
67. Naghavian R, Faigle W, Oldrati P, et al. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma. Nature 2023;617:807-17. [Crossref] [PubMed]
68. Wang K, Lo CH, Mehta RS, et al. An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk. Gastroenterology 2024;167:1371-1383.e4. [Crossref] [PubMed]