Despite extensive investigations into the microbiome and metabolome changes associated with colon polyps and colorectal cancer (CRC), the microbiome and metabolome profiles of individuals with colonic polyposis, including those with (Gene-pos) and without (Gene-neg) a known genetic driver, remain comparatively unexplored. Using colon biopsies, polyps, and stool from patients with Gene-pos adenomatous polyposis (N = 9), Gene-neg adenomatous polyposis (N = 18), and serrated polyposis syndrome (SPS, N = 11), we demonstrated through 16S rRNA sequencing that the mucosa-associated microbiota in individuals with colonic polyposis is representative of the microbiota associated with small polyps, and that both Gene-pos and SPS cohorts exhibit differential microbiota populations relative to Gene-neg polyposis cohorts. Furthermore, we used these differential microbiota taxa to perform linear discriminant analysis to differentiate Gene-neg subjects from Gene-pos and from SPS subjects with an accuracy of 89% and 93% respectively. Stool metabolites were quantified via 1H NMR, revealing an increase in alanine in SPS subjects relative to non-polyposis subjects, and Partial Least Squares Discriminant Analysis (PLS-DA) analysis indicated that the proportion of leucine to tyrosine in fecal samples may be predictive of SPS. Use of these microbial and metabolomic signatures may allow for better diagnostric and risk-stratification tools for colonic polyposis patients and their families as well as promote development of microbiome-targeted approaches for polyp prevention.

This review delves into the complex and multi-layered mechanisms that govern the interaction between gut microbiota and T cells in the context of colorectal cancer (CRC), revealing a novel "microbiota-immune regulatory landscape" within the tumor microenvironment. As CRC progresses, the gut microbiota experiences a significant transformation in both its composition and metabolic patterns. On one hand, specific microbial entities within the gut microbiota can directly engage with T cells, functioning as "immunological triggers" that shape T-cell behavior. Simultaneously, microbial metabolites, such as short-chain fatty acids and bile acids, serve as "molecular regulators" that intricately govern T-cell function and differentiation, fine-tuning the immune response. On the other hand, the quorum-sensing mechanism, a recently recognized communication network among bacteria, also plays a pivotal role in orchestrating T-cell immunity. Additionally, the gut microbiota forms an intriguing connection with the neuro-immune regulatory axis, a largely unexplored "territory" in CRC research. Regarding treatment strategies, a diverse array of intervention approaches-including dietary modifications, the utilization of probiotics, bacteriophages, and targeted antibiotic therapies-offer promising prospects for restoring the equilibrium of the gut microbiota, thereby acting as "ecosystem renovators" that impede tumor initiation and progression. Nevertheless, the current research landscape in this field is fraught with challenges. These include significant variations in microbial composition, dietary preferences, and tumor microenvironments among individuals, a lack of large-scale cohort studies, and insufficient research that integrates tumor mutation analysis, gut microbiota investigations, and immune microenvironment evaluations. This review emphasizes the necessity for future research efforts to seamlessly incorporate multiple factors and utilize bioinformatics analysis to construct a more comprehensive "interactive map" of the gut microbiota-T cell relationship in CRC. The aim is to establish a solid theoretical basis for the development of highly effective and personalized treatment regimens, ultimately transforming the therapeutic approach to CRC.

Intestinal microbiota and the host's immune system form a symbiotic alliance that sustains normal development and function in the human gut. Changes such as dietary habits among societies in developed countries have led to the development of unbalanced microbial populations in the gut, likely contributing to the dramatic increase in inflammatory diseases in the last few decades. Recent advances in DNA sequencing technologies have tremendously helped to characterize the microbiome associated with disease, both in identifying global alterations and discovering specific biomarkers that potentially contribute to disease pathogenesis, as evidenced by animal studies. Beyond bacterial alterations, non-bacterial components such as fungi, viruses, and microbial metabolites have been implicated in these diseases, influencing immune responses and gut homeostasis. Multi-omics approaches integrating metagenomics, metabolomics, and transcriptomics offer a more comprehensive understanding of the microbiome's role in disease pathogenesis, paving the way for innovative diagnostic and therapeutic strategies. Unraveling the metagenomic profiles associated with disease may facilitate earlier diagnosis and intervention, as well as the development of more personalized and effective therapeutic strategies. This review synthesizes recent and relevant microbiome research studies aimed at characterizing the microbial signatures associated with inflammatory bowel disease, colorectal cancer, and celiac disease.

Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are synthetic chemicals known for their widespread use and environmental persistence. These compounds have been increasingly linked to hepatotoxicity and the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms by which PFAS contribute to HCC remain underexplored.

This study employs a multi-omics approach that combines network toxicology, integrated machine learning, single-cell RNA sequencing, spatial transcriptomics, experimental validation, and molecular docking simulations to uncover the mechanisms through which PFAS exposure drives HCC. We analyzed publicly available transcriptomic data from several HCC cohorts and used differential gene expression analysis to identify targets associated with both PFAS exposure and HCC. We constructed a protein-protein interaction (PPI) network and a survival risk model, the PFAS-related HCC signature (PFASRHSig), based on integrated machine learning to identify prognostic biomarkers, with the goal of identifying core targets of PFAS in HCC progression and prognosis. RT-qPCR and immunohistochemical (IHC) staining were used to validate the expression levels of the targets in both tumor and normal tissues. Molecular docking simulations were conducted to assess the binding affinities between PFAS compounds and selected target proteins.

Functional enrichment studies revealed that PFAS targets were associated with metabolic signaling pathways, which are actively involved in lipid, glucose, drug metabolism, etc. Through integrated machine learning and PPI network analysis, we identified six genes, APOA1, ESR1, IGF1, PPARGC1A, SERPINE1, and PON1, that serve as core targets of PFAS in both HCC progression and prognosis. These targets were further validated via bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomics, which revealed differential expression patterns across various cell types in the HCC tumor microenvironment. The results of RT-qPCR and IHC staining were consistent with the in silico findings. Molecular docking simulations revealed strong binding affinities between PFAS compounds and these core targets, supporting their potential roles in PFAS-induced hepatocarcinogenesis.

Our study highlights key molecular targets and pathways involved in PFAS-induced liver carcinogenesis and proposes a robust survival risk model (PFASRHSig) for HCC. These findings provide new insights into PFAS toxicity mechanisms and offer potential therapeutic targets for mitigating the health risks associated with PFAS exposure. Collectively, our findings help in advancing clinical applications by providing insights into disease mechanisms and potential therapeutic interventions.

Kombucha, a fermented beverage obtained from a Symbiotic Culture of Bacteria and Yeast, has shown potential in modulating gut microbiota, although no clinical trials have been done.

We aimed to evaluate the effects of regular black tea kombucha consumption on intestinal health in individuals with and without obesity.

A pre-post clinical intervention study was conducted lasting 8 wk. Forty-six participants were allocated into 2 groups: normal weight + black tea kombucha (n = 23); and obese + black tea kombucha (n = 23). Blood, urine, and stool samples were collected at baseline (T0) and after 8 wk of intervention (T8).

A total of 145 phenolic compounds were identified in the kombucha, primarily flavonoids (81%) and phenolic acids (19%). Kombucha favored commensal bacteria such as Bacteroidota and Akkermanciaceae, especially in the obese group. Subdoligranulum, a butyrate producer, also increased in the obese group after kombucha consumption (P = 0.031). Obesity-associated genera Ruminococcus and Dorea were elevated in the obese group at baseline (P < 0.05) and reduced after kombucha consumption, becoming similar to the normal weight group (Ruminococcus: obese T8 × normal weight T8: P = 0.27; Dorea: obese T8 × normal weight T0: P = 0.57; obese T8 × normal weight T8: P = 0.32). Fungal diversity increased, with a greater abundance of Saccharomyces in both groups and reductions in Exophiala and Rhodotorula, particularly in the obese group. Pichia and Dekkera, key microorganisms in kombucha, were identified as biomarkers after the intervention.

Regular kombucha consumption positively influenced gut microbiota in both normal and obese groups, with more pronounced effects in the obese group, suggesting that it may be especially beneficial for those individuals. This trial was registered at Brazilian Clinical Trial Registry - ReBEC as UTN code U1111-1263-9550 (https://ensaiosclinicos.gov.br/rg/RBR-9832wsx).

Colorectal cancer (CRC) is a major global health challenge. Emerging research highlights the pivotal role of the gut microbiota in influencing CRC risk, progression, and treatment response. Metagenomic approaches, especially high-throughput shotgun sequencing, have provided unprecedented insights into the intricate connections between the gut microbiome and CRC. By enabling comprehensive taxonomic and functional profiling, metagenomics has revealed microbial signatures, activities, and biomarkers associated with colorectal tumorigenesis. Furthermore, metagenomics has shown a potential to guide patient stratification, predict treatment outcomes, and inform microbiome-targeted interventions. Despite remaining challenges in multi-omics data integration, taxonomic gaps, and validation across diverse cohorts, metagenomics has propelled our comprehension of the intricate gut microbiome-CRC interplay. This review underscores the clinical relevance of microbial signatures as potential diagnostic and prognostic tools in CRC. Furthermore, it discusses personalized treatment strategies guided by this omics' approach.

Hepatocarcinogenesis is linked to environmental factors, with microplastics (MPs) emerging as a global environmental concern that may contribute to liver injury. However, the impact of MPs on the early stages of hepatocarcinogenesis has been largely ignored. Here we investigated the impact of long-term MP exposure on the formation of preneoplastic lesions during hepatocarcinogenesis induced by diethylnitrosamine (DEN) in rats. Rats were injected with DEN to induce preneoplastic lesions, and then they were orally administered with 1 µm MPs 0.5 mg/kg body weight per day for 20 weeks. The results revealed that long-term exposure to MPs did not induce the formation of glutathione S-transferase placental form (GST-P)-positive foci as preneoplastic lesions during hepatocarcinogenesis in these animals, thereby indicating non-carcinogenicity. However, MP exposure resulted in a 1-fold increase in both the number and size of GST-P-positive foci in rats initiated with DEN compared to those treated with DEN alone. Accordingly, MP exposure led to a 0.61-fold increase in the index of proliferating cell nuclear antigen (PCNA)-positive cells in DEN-initiated rats when compared to DEN treatment alone. In addition, the composition of the gut microbiota was significantly altered, accompanied by various levels of short-chain fatty acids. Our results suggest that long-term MP exposure can promote pre-neoplastic lesion formation in DEN-induced rats by increased cell proliferation as well as alterations in the gut microbiota and short-chain fatty acid levels. This highlights the potential health risks associated with hepatocarcinogenesis linked to long-term exposure to MPs.

Colorectal cancer (CRC) ranks among the top three most prevalent malignancies globally and is a leading cause of cancer-related mortality. Traditional therapeutic approaches usually cause significant adverse effects, highlighting the urgent demand for alternative, more effective treatments. Probiotics have gained attentions as potential cancer therapy due to their beneficial impacts on host health. Clostridium butyricum (Cl. butyricum) has shown anticancer properties in recent studies, though the underlying mechanisms remain inadequately understood. This study presents an integrative analysis of network pharmacology and proteomics to elucidate the key targets of Cl. butyricum in CRC treatment. The network pharmacology analysis identified 72 overlapping genes, and functional analysis of these genes indicated that most pathways were related to pathways in cancer and inflammation, and butyrate emerging as the pivotal product of Cl. butyricum due to its strong associations with the identified hub genes. In parallel, proteomics analysis revealed 168 differential expressed proteins (DEPs) in Cl. butyricum-treated HCT-116 cells, comprising 78 upregulated and 90 downregulated proteins. These DEPs were primarily enriched in apoptosis and inflammatory pathways. PPI analysis further highlighted NFKB1 as key contributors to the anticancer effects of Cl. butyricum. The integrative analysis revealed a significant convergence of pathways enrichment patterns, particularly in inflammatory and immune-related pathways. Computational and experimental validation identified NFKB1 as a pivotal molecular target in CRC intervention. These collective findings elucidate the mechanistic basis of the antitumor properties of Cl. butyricum, highlighting its regulatory effects on NFKB1 through both inflammatory and, to a lesser extent, immunoregulatory pathways.

Despite advances in metastatic colorectal cancer (mCRC) treatment, long-term survival remains poor, particularly in right-sided colorectal cancer (RCRC), which has a worse prognosis compared to left-sided CRC (LCRC). This disparity is driven by the complex biological diversity of these malignancies. RCRC and LCRC differ not only in clinical presentation and outcomes but also in their underlying molecular and genetic profiles. This article offers a detailed literature review focusing on the distinctions between RCRC and LCRC. We explore key differences across embryology, anatomy, pathology, omics, and the tumor microenvironment (TME), providing insights into how these factors contribute to prognosis and therapeutic responses. Furthermore, we examine the therapeutic implications of these differences, considering whether the conventional classification of CRC into right- and left-sided forms should be refined. Recent molecular findings suggest that this binary classification may overlook critical biological complexities. Therefore, we propose that future approaches should integrate molecular insights to better guide personalized treatments, especially anti-EGFR therapies, and improve patient outcomes.

Colorectal adenomas (CRA) are the primary precancerous lesions leading to colorectal cancer (CRC). Early detection and intervention of CRA can significantly reduce the incidence of CRC. We investigated the relationships between the gut microbiome and the expression levels of PD-L1, IL-6, and IFN-γ at different CRA stages.

Participants were divided into normal, non-advanced adenoma (NAA), and advanced adenoma (AA) groups. PD-L1 expression in collected tissues was analyzed via immunohistochemistry (IHC) and Western blotting. Serum IL-6 and IFN-γ levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). 16S rRNA gene sequencing was used to examine gut microbiota changes, with correlation analysis to assess microbial influences on CRA progression.

The main differences in bacterial composition among the three groups were found within the Firmicutes and Bacteroidetes phyla. In the normal vs. NAA comparison, Clostridium sensu stricto, Faecalimonas, Gemmiger, and Ruminococcus were more abundant in the normal group, while Solobacterium was enriched in the NAA group. For the normal vs. AA comparison, the normal group was enriched with Anaerostipes, Blautia, Clostridium sensu stricto, Intestinibacter, Phocaeicola, and Turicibacter, whereas Solobacterium was more abundant in the AA group. In the NAA vs. AA comparison, the NAA group exhibited higher levels of Blautia, Faecalimonas, and Turicibacter relative to the AA group. Anaerostipes and Blautia are positively correlated with taurine and hypotaurine metabolism, propanoate metabolism, and zeatin biosynthesis. PD-L1 protein levels progressively increase with CRA advancement. Additionally, Faecalimonas, and Solobacterium were negatively associated with IFN-γ, while Gemmiger, and Anaerostipes were positively associated with IL-6.

This study highlights the dynamic alterations in gut microbiota composition and their potential influence on the regulation of inflammatory cytokines and PD-L1 expression during CRA progression. The enrichment of protective taxa, such as Anaerostipes and Blautia, in the normal group emphasizes their potential role in mitigating adenoma progression. Dietary modulation to promote the proliferation of these beneficial bacteria could serve as a promising strategy to improve colorectal health. Future research should further explore the specific relationships between dietary components, gut microbiota, and metabolic pathways, and assess the effects of dietary interventions on gut health.

With advances in sequencing techniques, microbiota dysbiosis and pathogenic microbes that accelerate colorectal cancer progression have been identified and widely reported. However, few studies have focused on the microbiota taxa of rectal mucus in rectal cancer (RC) patients. Here, we analyzed the composition and characteristics of the rectal mucosa microbiota of RC patients from Wenzhou city, China, and compared the results with those of healthy controls.

To explore the changes in the characteristics of the rectal mucosal flora associated with RC, and identify biomarkers of microbe taxa for RC.

Rectal mucosa samples from a Chinese cohort of 72 recently diagnosed RC patients and 71 healthy controls were obtained. A validation cohort, which included 22 RC patients and 60 healthy controls, was also established. Changes in the rectal mucosal flora were observed by cultivation, 16S ribosomal DNA gene sequencing analysis and quantitative polymerase chain reaction analysis.

The 16S ribosomal DNA results demonstrated that RC patients presented increased bacterial community richness and alpha diversity as well as an altered rectal mucosal microbiota, with depletion of Proteobacteria and Thermi and enrichment of Bacteroidetes and Fusobacteria in cancerous mucosal tissues (CM) and enrichment of Firmicutes and Cyanobacteria in adjacent noncancerous mucosal tissues (AM). The culture results showed that the mean loads of Escherichia coli, Bifidobacterium, Enterococcus, and Lactobacillus were significantly reduced in RC patients. The ratios of Prevotella to Ruminococcus [areas under the receiver operating curve: 0.795 in AM vs normal control mucosa (NM), 0.77 in CM vs NM] and of Prevotella stercorea to Propionibacterium acnes (areas under the receiver operating curve: 0.808 in AM vs NM, 0.843 in CM vs NM) exhibited excellent abilities to differentiate between healthy controls and RC patients.

RC patients have an altered rectal mucosal microbiota, and the ratio of Prevotella to Ruminococcus or the ratio of Prevotella stercorea to Propionibacterium acnes may serve as a marker for RC diagnosis.

Colon cancer is a leading cause of mortality in Appalachian Kentucky. Studies suggest that the microbiome may influence cancer outcomes. We investigate differential gene expression, the tumor microbiome, and their association as potential drivers of disparities in colon cancer outcomes.

This study analyzed patients diagnosed with colon adenocarcinoma between 2010 and 2023. Demographic data were extracted from Kentucky Cancer Registry. Somatic mutations and significantly mutated genes were identified using Fisher's exact t -test. RNASeq data were processed for gene expression analysis and Holm-Bonferroni method was used to adjust p values for multiple comparisons. The STAR aligner (exotic), v2.1 pipeline, and KrakenUniq database were used to classify microbes in human samples. The R package (exotic) was then used to decontaminate the results.

The final cohort included 2,276 patients, 321 of which had available somatic mutation sequencing data. Demographic differences between Appalachian and non-Appalachian patients included marital status (p = 0.0005), race (p < 0.0001), insurance status (p = 0.0005), BMI (p = 0.001), type 2 diabetes (p < 0.0001), and Charlson Comorbidity Index (p = 0.03). There was no difference in gene mutation frequency. There was differential expression of 228 genes. Differential abundance analysis revealed differences in 381 bacterial species. Importantly, 3 microbiota significantly correlated with survival disparities between Appalachian and non-Appalachian patients: Clostridium cadaveris (adjusted p = 0.009), Ligilactobacillus salivarius (adjusted p = 0.048), and Sutterella wadsworthensis (adjusted p = 0.009).

This is the first report of the distinct tumor microbiome in Appalachian Kentucky and its impact on survival. Further studies are needed to better characterize the unique tumor and gut microbiome of Appalachian patients with colon cancer.

Bowel cancer is the third most common malignancy of tumors and one of the major causes of cancer-related death. Bowel precancerous conditions can develop without any symptoms, which either makes it difficult for early diagnosis or poses a poor prognosis/gloomy relapse. This study aimed to investigate the effects of Bifidobacterium animalis subsp. lactis TCI604 (B. lactis) on inflammatory responses, gut microbiome, and protectiveness against azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colonic precancerous lesions. The AOM/DSS-induced colonic precancerous lesion murine model was studied with 24 female C57BL/6 J mice assigned to the control group, AOM/DSS-induced colonic precancerous lesion group (AOM/DSS), AOM/DSS treated with B. lactis probiotic group (B. lactis P), and AOM/DSS treated with B. lactis cell-free supernatant group (B. lactis S). The results showed that both B. lactis P and B. lactis S could attenuate AOM/DSS-induced body weight loss and intestine damage, reduce aberrant crypt foci (ACF) and the formation of colonic polyps, and significantly inhibit pro-inflammatory cytokines and the NF-κB signaling pathway, in which the B. lactis S group outperformed others. Further analysis using 16S rDNA sequencing suggested that both B. lactis P and B. lactis S optimize gut microbiota. Several bacteria, including Muribaculaceae, Prevotellaceae_UCG-001, Anaerostipes, Ruminococcaceae, Mucispirillum, Clostridia_UCG-014, and Clostridia_vadinBB60 that were known in close relation to colonic precancerous lesions, were sequenced at taxonomic level. Our results indicated that both B. lactis P and B. lactis S improved AOM/DSS-induced colonic precancerous lesions by regulating inflammation as well as optimizing gut microbiota, thereby establishing reciprocally cooperative net benefits between probiotics/postbiotics and mice with colonic precancerous lesions. KEY POINTS: • Prophylactic administration of probiotic and postbiotic of B. lactis is capable of alleviating the AOM/DSS-induced body weight loss and colon shortening, as well as diminishing the development of colonic precancerous lesions, such as the formation of ACF and colonic polyps, in an AOM/DSS mouse model • Either probiotic or postbiotic of B. lactis has a positive role in mediating immune imbalance and colonic inflammation via suppression of inflammatory immune cells, pro-inflammatory cytokines, and the NF-κB signaling pathway • AOM/DSS-induced dysbiosis can be reversed with the probiotic and postbiotic of B. lactis supplementation.

Colon cancer (CC) is one of the most common cancers globally, which is associated with the gut microbiota intimately. In current research, exploring the complex interaction between microbiomes and CC is a hotspot. However, the information on microbiomes in most previous studies is based on fecal, which does not fully display the microbial environment of CC. Herein, we collected mucosal and tissue samples from both the tumor and normal regions of 19 CC patients and clarified the composition of mucosal microbiota by 16S rRNA and metagenomic sequencing. Additionally, RNA-Seq was also conducted to identify the different expression genes between tumor and normal tissue samples. We revealed significantly different microbial community structures and expression profiles to CC. Depending on correlation analysis, we demonstrated that 1,472 genes were significantly correlated with CC tumor microbiota. Our study reveals a significant enrichment of Campylobacter jejuni in the mucosa of CC, which correlates with bile secretion. Additionally, we observe a negative correlation between C. jejuni and immune cells CD4+ Tem and mast cells. Finally, we discovered that metabolic bacterial endosymbiont of Bathymodiolus sp., Bacillus wiedmannii, and Mycobacterium tuberculosis had a significant survival value for CC, which was ignored by previous research. Overall, our study expands the understanding of the complex interplay between microbiota and CC and provides new targets for the treatment of CC.

This study contributes to our understanding of the interaction between microbiota and colon cancer (CC). By examining mucosal and tissue samples rather than solely relying on fecal samples, we have uncovered previously unknown aspects of CC-associated microbiota. Our findings reveal distinct microbial community structures and gene expression profiles correlated with CC progression. Notably, the enrichment of Campylobacter jejuni in CC mucosa, linked to bile secretion, underscores potential mechanisms in CC pathogenesis. Additionally, observed correlations between microbial taxa and immune cell populations offer new avenues for immunotherapy research in CC. Importantly, this study introduces CC-associated microbiota with survival implications for CC, expanding therapeutic targets beyond conventional strategies. By elucidating these correlations, our study not only contributes to uncovering the potential role of gut microbiota in colon cancer but also establishes a foundation for mechanistic studies of gut microbiota in colon cancer, emphasizing the broader impact of microbiota research on cancer biology.

Colorectal cancer (CRC) poses a significant threat to human life and health. Global cancer prevalence data in 2022 indicated that the number of new cases of CRC was about 1.92 million and the deaths were around 900,000. A variety of risk factors, including genes and environment, can induce the occurrence of CRC. Previous studies have focused on the impact of dietary patterns on the development of CRC and have ignored sleep factors. Sleep deprivation is a common problem as people's work pressure increases. Sleep disorders can lead to metabolic and immune system dysregulation in people, contributing to the development and progression of many tumors. At present, there are few reports on the relationship between sleep disorders and tumors. Therefore, the purpose of this paper is to summarize and interpret the relationship between various sleep disorders and the onset and progression of CRC. This review is the first to investigate the possible mechanisms of sleep leading to CRC from the perspectives of metabolic reprogramming, intestinal microbiota disorders, and the release of inflammatory factors. In conclusion, this study highlights the rational sleep pattern and duration, which can help inhibit the occurrence of CRC.

Tumour-associated microbiota are integral components of the tumour microenvironment (TME). However, previous studies on intratumoral microbiota primarily rely on bulk tissue analysis, which may obscure their spatial distribution and localized effects. In this study, we applied in situ spatial-profiling technology to investigate the spatial distribution of intratumoral microbiota in breast cancer and their interactions with the local TME. Using 5R 16S rRNA gene sequencing and RNAscope FISH/CISH on patients' tissue, we identified significant spatial heterogeneity in intratumoral microbiota, with Fusobacterium nucleatum (F. nucleatum) predominantly localized in tumour cell-rich areas. GeoMx digital spatial profiling (DSP) revealed that regions colonized by F. nucleatum exhibit significant influence on the expression of RNAs and proteins involved in proliferation, migration and invasion. In vitro studies indicated that co-culture with F. nucleatum significantly stimulates the proliferation and migration of breast cancer cells. Integrative spatial multi-omics and co-culture transcriptomic analyses highlighted the MAPK signalling pathways as key altered pathways. By intersecting these datasets, VEGFD and PAK1 emerged as critical upregulated proteins in F. nucleatum-positive regions, showing strong positive correlations with MAPK pathway proteins. Moreover, the upregulation of VEGFD and PAK1 by F. nucleatum was confirmed in co-culture experiments, and their knockdown significantly reduced F. nucleatum-induced proliferation and migration. In conclusion, intratumoral microbiota in breast cancer exhibit significant spatial heterogeneity, with F. nucleatum colonization markedly altering tumour cell protein expression to promote progression and migration. These findings provide novel perspectives on the role of microbiota in breast cancer, identify potential therapeutic targets, and lay the foundation for future cancer treatments. KEY POINTS: Intratumoral Fusobacterium nucleatum exhibits significant spatial heterogeneity within breast cancer tissues. F. nucleatum colonization alters the expression of key proteins involved in tumour progression and migration. The MAPK signalling pathway is a critical mediator of F. nucleatum-induced breast cancer cell proliferation and migration. VEGFD and PAK1 are potential therapeutic targets to mitigate F. nucleatum-induced tumour progression.

The relationship between intraneoplastic fungi and colorectal cancer (CRC) progression remains largely unclear. Here, we investigated fungal community changes in adenoma and CRC and their correlation with host genetic mutations.

We obtained 261 tissue biopsies from two geographically distinct cohorts of CRC and adenoma patients, with each individual contributing 2-5 biopsies from lesions and 2 from adjacent normal tissues. 18S ribosomal RNA gene sequencing was used for microbial profiling. Host genetic alterations including KRAS mutations and microsatellite instability (MSI) were detected concurrently.

Intra-neoplastic fungal composition significantly differed between CRC and adenoma in two independent cohorts, with enrichment of highly variable fungi (HVF) in CRC. Six HVFs exhibited higher abundances in adenoma and CRC compared to adjacent normal tissues with Malassezia showing a progressive increase from adenoma to CRC. Fungi intratumoral heterogeneity index also increased from adenoma through stages I to IV of CRC. Intra-tumoral fungi-fungi co-abundance analysis indicated stronger positive interactions in CRC than in adenoma, with increasingly robust links among intra-tumoral fungi along adenoma-CRC progression, primarily driven by Malassezia and Aspergillus. Furthermore, fungal heterogeneity was significantly correlated with host genetic mutations, with higher risk indices in CRC tissues harboring KRAS and MSI mutations. Thirteen fungi stratified CRC samples with KRAS mutations, achieving an area under the curve (AUC) of 0.86, while those associated with MSI status showed an AUC of 0.89.

This study demonstrates that intraneoplastic fungal community alterations occur between adenoma and CRC, with increasing heterogeneity associated with host genetic mutations, emphasizing the role of fungal dysbiosis in CRC.

This work was supported by RGC Research Impact Fund Hong Kong (R4032-21F); RGC-CRF (C4008-23W); Strategic Seed Funding Collaboration Research Scheme CUHK (3133344); Strategic Impact Enhancement Fund CUHK (3135509); Impact case for RAE CUHK (3134277).

Although studies are available on the impact of gallbladder disease on the risk of colorectal neoplasia (CRN), the results are still debatable. We conducted a meta-analysis to summarize the correlation between gallbladder diseases and CRN. Eligible studies up to June 2024 were screened and retrieved using PubMed and Web of Science as well as by performing a manual review of references. Subgroup analyses stratified by region, location, and pathology of CRN were performed. Subgroup analyses stratified by classification and size of gallbladder disease were also performed. The pooled odd ratios (ORs) with 95% confidence intervals (CIs) were calculated. Sensitivity analyses were also performed. Begg's test was conducted to determine the publication bias. A total of twenty studies were included. The results showed that gallbladder disease significantly increased the risk of CRN (OR = 1.20, 95%CI, 1.11-1.29, P < 0.001). Subgroup analyses showed that subjects with gallstones (OR = 1.14, 95%CI, 1.05-1.25, P = 0.003) or gallbladder polyps (OR = 1.23, 95%CI, 1.15-1.31, P < 0.001) had a significantly higher risk of developing CRN. Asians (OR = 1.21, 95%CI, 1.11-1.31, P < 0.001) with gallstones were more likely to develop CRN. Patients with larger gallbladder polyps (≥ 0.5 cm) were at a greater risk of developing CRN (OR = 1.96, 95%CI, 1.41-2.73, P < 0.001). Gallbladder polyps and gallstones increase the risk of CRN. Therefore, colonoscopy should be performed in patients with gallbladder disease, especially in those of Asian descent, as well as in people with large gallbladder polyps.

Microbial dysbiosis, characterized by an imbalanced microbial community structure and function, has been linked to hypertension. While prior research has primarily focused on differential abundances, our study highlights the role of non-differential microbes in hypertension. We propose that non-differential microbes contribute to hypertension through their ecological interactions, as defined by co-abundances (pairs of microbes exhibiting correlated abundance patterns). Using gut microbiome data from the Guangdong Gut Microbiome Project, which includes 2355 hypertensive and 4644 non-hypertensive participants across 14 regions, we identified replicable hypertension-related microbial interactions. Notably, most co-abundances involved non-differential microbes, which were found to correlate with both hypertension severity and hypertension-related microbial metabolic pathways. These findings emphasize the importance of microbial interactions in hypertension pathogenesis and propose a novel perspective for microbiome-based therapeutic strategies.

We have previously identified increased levels of distinct bacterial taxa within mucosal biopsies from colorectal cancer (CRC) patients. Following prior research, the aim of this study was to investigate the detection of the same CRC-associated bacteria in fecal samples and to evaluate the suitability of fecal samples as a non-invasive material for the detection of CRC-associated bacteria. Next-generation sequencing (NGS) of the 16S ribosomal RNA (rRNA) V4 region was performed to evaluate the detection of the CRC-associated bacteria in the fecal microbiota of cancer patients, patients with adenomatous polyp and healthy controls. Furthermore, 19 novel species-specific quantitative PCR (qPCR) assays were established to detect the CRC-associated bacteria. Approximately, 75% of the bacterial taxa identified in biopsies were reflected in fecal samples. NGS failed to detect low-abundance CRC-associated taxa in fecal samples, whereas qPCR exhibited high sensitivity and specificity in identifying all targeted taxa. Comparison of fecal microbial composition between the different patient groups showed enrichment of Fusobacterium nucleatum, Parvimonas micra, and Gemella morbillorum in cancer patients. Our findings suggest that low-abundance mucosa-associated bacteria can be detected in fecal samples using sensitive qPCR assays.

Highly frequent colorectal cancer (CRC) is predicted to have 3.2 million novel cases by 2040. Tumor microenvironment (TME) bacteriome and metabolites are proposed to be involved in CRC development. In this regard, we aimed to investigate the bacteriome and metabolites of healthy, adenomatous polyp, and CRC tissues.

Sixty samples including healthy (H), adenomatous polyps (AP), adenomatous polyps-adjacent (APA), cancer tumor (CT), and cancer tumor-adjacent (CA) tissues were collected and analyzed by 16 S rRNA sequencing and 1H NMR spectroscopy.

Our results revealed that the bacteriome and metabolites of the H, AP, and CT groups were significantly different. We observed that the Lachnospiraceae family depleted concomitant with acetoacetate and beta-hydroxybutyric acid (BHB) accumulations in the AP tissues. In addition, some bacterial species including Gemella morbillorum, and Morganella morganii were enriched in the AP compared to the H group. Furthermore, fumarate was accumulated concomitant to Aeromonas enteropelogenes, Aeromonas veronii, and Fusobacterium nucleatum subsp. animalis increased abundance in the CT compared to the H group.

These results proposed that beneficial bacteria including the Lachnospiraceae family depletion cross-talk with acetoacetate and BHB accumulations followed by an increased abundance of driver bacteria including G. morbillorum, and M. morganii may reprogram polyp microenvironment leading to tumor initiation. Consequently, passenger bacteria accumulation like A. enteropelogenes, A.veronii, and F. nucleatum subsp. animalis cross-talking fumarate in the TME may aggravate cancer development. So, knowledge of TME bacteriome and metabolites might help in cancer prevention, early diagnosis, and a good prognosis.

Introduction: Recent studies have discovered that lung cancer subtypes possess distinct microbiome profiles within their tumor microenvironment. Additionally, the tumor-associated microbiome exhibits altered bacterial pathways, suggesting that certain bacterial families are more capable of facilitating tumor progression than others. We hypothesize that there exists a crosstalk between lung adenocarcinoma (LUAD) cells and bacterial cells. Methods and Materials: RNA sequencing (RNA-seq) was performed on LUAD cell lines to explore the paracrine signaling effects of bacterial biomolecules. Based on our RNA-seq data, we investigated glycolysis by measuring glucose uptake and lactate production, invasive potential through invasion assays, and epithelial-to-mesenchymal transition (EMT) markers. Since lipopolysaccharides (LPS), abundant on the cell walls of Gram-negative bacteria, can activate toll-like receptor 4 (TLR4), we inhibited TLR4 with C34 to assess its relationship with the observed phenotypic changes. To identify the bacterial biomolecules responsible for these changes, we treated the media with RNAse enzyme, charcoal or dialyzed away molecules larger than 3 kDa. Results and Discussion: RNA-seq revealed 948 genes upregulated in the presence of E. coli biomolecules. Among these, we observed increased expression of Hexokinase II (HKII), JUN proto-oncogene, and Snail Family Transcriptional Repressor 1. We verified the elevation of glycolytic enzymes through Western blot and saw elevation of 2-deoxyglucose uptake and lactate production in LUAD cell lines incubated in E. coli biomolecules. In addition to E. coli elevating glycolysis in LUAD cell lines, E. coli exposure enhanced invasive potential as demonstrated by Boyden chamber assays. Notably, inhibition of TLR4 did not reduce the impact of E. coli biomolecules on glycolysis or the invasive potential of LUAD. Modulating the E. coli-supplemented media with RNAse enzyme or dextran-coated charcoal or using a spin column to remove biomolecules smaller than 3 kDa resulted in changes in HKII and Claudin protein expression. These findings suggest a direct relationship between E. coli and LUAD, wherein several cancer hallmarks are upregulated. Future studies should further investigate these bacterial biomolecules and their role in the tumor microenvironment to fully understand the impact of microbial shifts on cancer progression.

Lynch syndrome (LS)-associated colorectal cancer (CRC) always ascribes to pathogenic germline mutations in mismatch repair (MMR) genes. However, the penetrance of CRC varies among those with the same MMR gene mutation. Thus, we hypothesized that the gut microbiota is also involved in CRC development in LS families.

This prospective, observational study was performed from December 2020 to March 2023. We enrolled 72 individuals from 9 LS families across six provinces in China and employed 16S rRNA gene amplicon sequencing to analyze the fecal microbiota components among LS-related CRC patients (AS group), their spouses (BS group), mutation carriers without CRC (CS group), and non-mutation carriers (DS group) using alpha and beta diversity indices.

There were no apparent differences in age or gender among the four groups. Alpha and beta diversity indices exhibited no significant differences between the AS and BS groups, verifying the role of germline mutations in the occurrence of CRC in LS families. Beta diversity analysis exhibited significant differences between the AS and CS groups, revealing the importance of the gut microbiota for the occurrence of CRC in LS families. A greater difference (both alpha and beta diversity indices) was shown between the AS and DS groups, demonstrating the combined impact of the gut microbiota and genetic germline mutations on the occurrence of CRC in LS families. Compared with those in the CS and DS groups, we identified ten microbial genera enriched in the AS group, and one genus (Bacteroides) decreased in the AS group. Among the elevated genera in the AS group, Agathobacter, Coprococcus and Prevotellaceae_NK3B31_group were butyrate-producing genera.

This study found the development of CRC in the LS families can be attributed to the combined effects of gene germline mutations as well as the gut microbiota and provided novel insights into the prevention and treatment of CRC in the LS families.

The probiotic gut microbiome and its metabolites are pivotal in regulating host metabolism, inflammation, and immunity. Host genetics, colonization at birth, the host lifestyle, and exposure to diseases and drugs determine microbial composition. Dysbiosis and disruption of homeostasis in the beneficial microbiome have been reported to be involved in the tumorigenesis and progression of colorectal cancer (CRC). However, the influence of bacteria-secreted metabolites on CRC growth is yet to be fully elucidated. In this study, we compared the microbial composition of CRC patients to healthy controls to identify distinct patterns of microbiota-derived metabolites in CRC patients. Metagenomic analysis demonstrated that beneficial bacteria strains; Blautia producta, Bifidobacterium adolescentis, and Bifidobacterium longum decreased, while Parabacteroides distasonis and Bacteroides ovatus were more prevalent in the CRC patient group. Treatment of cancer organoid lines with microbial culture supernatants from Blautia producta, Bifidobacterium adolescentis, and Bifidobacterium longum showed remarkable inhibition of cancer growth. This study demonstrates that the bacterial metabolites depleted in CRC patients may inhibit cancer growth and highlights the effects of microbiome-derived metabolites on CRC growth.

The current understanding of colorectal carcinogenesis is based on the adenoma-carcinoma sequence, where genetics, intestinal microbiota changes and local immunity shifts seem to play the key roles. Despite the emerging evidence of dysbiotic intestinal state and immune-cell infiltration changes in patients with colorectal adenocarcinoma, early and advanced adenoma as precursors of colorectal cancer, and carcinoma in situ as the following progression, are rather less studied. The newly colon-site adapted AI-based analysis of immune infiltrates is able to predict long-term outcomes of colon carcinoma. Though it could also facilitate the pathologic evaluation of precancerous lesion's potential to progress. Therefore, the purpose of this prospective cohort study (MIMICA-1) is, firstly, to identify the intestinal microbiota and immune infiltration patterns around the normal bowel tissue, early and advanced adenoma, carcinoma in situ, and adenocarcinoma, and secondly, to analyze the immune - microbiome interplay along the steps of conventional colorectal tumorigenesis.

This study aims to prospectively recruit 40 patients (10 per group) with confirmed colorectal dysplasia undergoing endoscopic polypectomy, endoscopic mucosal resection for colorectal small (≤1cm), and large (>1cm) adenoma or carcinoma in situ, or biopsy and subsequent colon resection for invasive colorectal cancer, and 10 healthy patients undergoing screening colonoscopy. Stool samples will be collected prior to bowel preparation for the analysis of fecal (luminal) microbiota composition. Biopsy specimens will be taken from the terminal ileum, right colon, left colon, and a pathological lesion in the colon (if present) to assess mucosa-associated microbiota composition and intestinal immunity response. DNA will be extracted from all samples and sequenced using the Illumina MiSeq platform. Unifrac and Bray-Curtis methods will be used to assess microbial diversity. The intestinal immune system response will be examined using digital image analysis where primarily immunohistochemistry procedures for CD3, CD8, CD20 and CD68 immune cell markers will be performed. Thereafter, the count, density and distribution of immunocompetent cells in epithelial and stromal tissue compartments will be evaluated using AI-based platform. The interaction between the microbial shifts and intestinal immune system response in adenoma-carcinoma sequence and the healthy patients will be examined. In addition, fecal samples will be explored for gut microbiota's composition, comparing fecal- and tissue-derived bacterial patterns in healthy gut and along the adenoma-carcinoma sequence.

We hypothesize that changes within the human gut microbiota led to detectable alterations of the local immune response and correlate with the progression from normal mucosa to colorectal adenoma and invasive carcinoma. It is expectable to find more severe gut immune infiltration at dysplasia site, though analyzing invasive colorectal cancer we expect to detect broader mucosa-associated and luminal microbiota changes with subsequent local immune response at near-lesion site and possibly throughout the entire colon. We believe that specific compositional differences detected around premalignant colorectal lesions are critically important for its primary role in initiation and acceleration of colorectal carcinogenesis. Thus, these microbial patterns could potentially supplement fecal immunohistochemical tests for the early non-invasive detection of colorectal adenoma. Moreover, AI-based analysis of immune infiltrates could become additional diagnostic and prognostic tool in precancerous lesions prior to the development of colorectal cancer.

The study is registered at the Australian New Zealand Clinical Trials Registry (ACTRN12624000976583) https://www.anzctr.org.au/.

The rapidly aging population is fueling a surge in diabetes, especially Type 2, which heightens colorectal cancer (CRC) risk. Colorectal adenoma, a precursor, compounds this trend. Although alpha-glucosidase inhibitors are effective hypoglycemic drugs working in the GI tract, the link between them and colorectal adenoma formation remains unexplored. A retrospective cross-sectional study was conducted on type 2 diabetes patients aged 60 and above using data from Wenzhou Central Hospital from January 2021 to May 2024. We used multivariable logistic regression and propensity score matching analysis (PSM) to calculate adjusted ORs for colorectal adenoma, controlling for potential confounders. A total of 311 subjects were enrolled in the study, with a mean age of 67.55 years. 138 (44.4%) were diagnosed with colorectal adenoma. Multivariate logistic regression analysis revealed that the AGI (Alpha-glucosidase inhibitor) Group had an adjusted OR of 0.399 (95% CI = 0.22-0.723, p = 0.002) compared to those with AGI free people. A similar trend was also observed in the PSM analysis (OR = 0.362, 95% CI = 0.176-0.744, p = 0.004). Subgroup analysis reveals hypertension as a potential modulator of the inverse relationship between AGI and colorectal adenoma occurrence post-PSM (p = 0.049). And AGI reduces serum iron levels, both before (p = 0.01) and after PSM (p = 0.028). In summary, our findings indicate that AGI significantly mitigates the risk of colorectal adenoma among individuals aged 60 and above, particularly among those afflicted with hypertension. Additionally, it substantially decreases serum iron levels.

It is a well-known fact that cancer is considered the second leading cause of mortality across the globe. Although the human oral cavity and intestine are the natural habitat of thousands of microbes, dysbiosis results in malignancies, such as oral squamous cell carcinoma and colorectal cancer. Amongst the intestinal microbes, H. pylori is a deadly carcinogen. Also, causative pathogens for the development of pancreatic and colorectal cancer are found in the oral cavity, such as Fusobacterium nucleatum and Porphyromonas gingivalis. Many periodontopathic micro- organisms, like Streptococcus sp., Peptostreptococcus sp., Prevotella sp., Fusobacterium sp., Porphyromonas gingivalis, and Capnocytophaga gingivalis, strongly have an impact on the development of oral cancers. Three basic mechanisms are involved in pathogen-mediated cancer development, like chronic inflammation-mediated angiogenesis, inhibition of cellular apoptosis, and release of carcinogenic by-products. Microbiota has a dichotomous role to play in cancer, i.e., microbiota can be used for cancer management too. Shreds of evidence are there to support the fact that microbiota enhances the chemotherapeutic drug efficacy. This review presents the possible mechanism of the oncogenic effect of microbiota with emphasis on the oral microbiome and also attempts to explain the intricate role of microbiota in cancer management.

Colorectal cancer (CRC) is a multifaceted disease whose development and progression varies depending on tumor location, age of patients, infiltration of immune cells within cancer lesions, and the tumor microenvironment. These pathophysiological characteristics are additionally influenced by sex-related differences. The gut microbiome plays a role in initiation and progression of CRC, and shapes anti-tumor immune responses but how responsiveness of the immune system to the intestinal microbiota may contribute to sexual dimorphism of CRC is largely unknown. We studied survival, tumor-infiltrating immune cell populations and tumor-associated microbiome of a cohort of n = 184 male and female CRC patients through high-dimensional single-cell flow cytometry and 16S rRNA gene sequencing. We functionally tested the immune system-microbiome interactions in in-vivo and in-vitro models of the disease. High-dimensional single-cell flow cytometry showed that female patients are enriched by tumor-infiltrating invariant Natural Killer T (iNKT) cells but depleted by cytotoxic T lymphocytes. The enrichment of oral pathobionts and a reduction of β-glucuronidase activity are distinctive traits characterizing the gut microbiome of female patients affected by CRC. Functional assays using a collection of human primary iNKT cell lines demonstrated that the gut microbiota of female patients functionally impairs iNKT cell anti-tumor functions interfering with the granzyme-perforin cytotoxic pathway. Our results highlight a sex-dependent functional relationship between the gut microbiome, estrogen metabolism, and the decline of cytotoxic T cell responses, contributing to the sexual dimorphism observed in CRC patients with relevant implications for precision medicine and the design of targeted therapeutic approaches addressing sex bias in cancer.

The aim of this study was to investigate the biomarkers of salivary and fecal microbiota in Colorectal cancer (CRC). Initially, the study scrutinized the microbial community composition disparities among groups. Utilizing Lasso analysis, it sifted through operational taxonomic units (OTUs) to pinpoint distinctive features. Subsequently, by intersecting feature OTUs across groups, it curated a set of core-shared OTUs and devised a corresponding network. Concluding with functional enrichment analysis, the research delved into the divergent biological functions of these microbial communities within the studied groups. Analysis revealed higher bacterial diversity in saliva compared to feces, with distinct differences at both phylum and genus levels. Feces primarily contained Firmicutes, while saliva was dominated by Bacteroidetes and Proteobacteria. Notably, Escherichia-Shigella and Fusobacterium in feces and Streptococcus in saliva showed increasing abundance from average to adenoma to colorectal cancer. Specific dominant flora was identified within and between groups, including CRC and adenomas across different stages. Seventeen core shared OTUs were identified, and networks of shared OTUs were constructed for each group. Functional enrichment analysis highlighted distinct microbial community functions among the groups. This study's findings on characteristic OTUs in saliva and fecal samples offer valuable insights for distinguishing between healthy individuals, adenoma patients, and those with colorectal cancer. This study identified distinctive OTUs in saliva and feces to distinguish between healthy individuals, adenoma patients, and those with CRC, offering a valuable diagnostic reference.

The discoveries of the oncomicrobiome (intratumoral microbiome) and oncomicrobiota (intratumoral microbiota) represent significant advances in tumor research and have rapidly become of key interest to the field. Within tumors, microorganisms such as bacteria, fungi, viruses, and archaea form the oncomicrobiota and are primarily found within tumor cells, immunocytes, and the intercellular matrix. The oncomicrobiome exhibits marked heterogeneity and is associated with tumor initiation, progression, metastasis, and treatment response. Interactions between the oncomicrobiome and the immune system can modulate host antitumor immunity, influencing the efficacy of immunotherapies. Oncomicrobiome research also faces numerous challenges, including overcoming methodological issues such as low target abundance, susceptibility to contamination, and biases in sample handling and analysis methods across different studies. Furthermore, studies of the oncomicrobiome may be confounded by baseline differences in microbiomes among populations driven by both environmental and genetic factors. Most studies to date have revealed associations between the oncomicrobiome and tumors, but very few have established mechanistic links between the two. This review introduces the relevant concepts, detection methods, sources, and characteristics of the oncomicrobiome. We then describe the composition of the oncomicrobiome in common tumors and its role in shaping the tumor microenvironment. We also discuss the current problems and challenges to be overcome in this rapidly progressing field.

Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant 'window-of-opportunity' trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance.

Colorectal cancer (CRC) is a common cancer, with a concerning rise in early-onset CRC cases, signalling a shift in disease epidemiology. Whilst our understanding of the molecular underpinnings of CRC has expanded, the complexities underlying its initiation remain elusive, with emerging evidence implicating the microbiome in CRC pathogenesis. This review synthesizes current knowledge on the intricate interplay between the microbiome, tumour microenvironment (TME), and molecular pathways driving CRC carcinogenesis. Recent studies have reported how the microbiome may modulate the TME and tumour immune responses, consequently influencing cancer progression, and whilst specific bacteria have been linked with CRC, the underlying mechanisms remains poorly understood. By elucidating the functional links between microbial landscapes and carcinogenesis pathways, this review offers insights into how bacteria orchestrate diverse pathways of CRC development, shedding light on potential therapeutic targets and personalized intervention strategies.