The gut microbiota has emerged as a central player in the pathogenesis of colorectal cancer, bridging metabolic reprogramming, immune dysregulation, and epithelial transformation. Accumulating evidenc

The gap

Consensus across the literature

Supporting evidence — 3 representative gaps

• The microbiota–metabolite–immune axis in colorectal cancer: mechanistic insights and emerging clinical applications (2026) · doi

  The gut microbiota has emerged as a central player in the pathogenesis of colorectal cancer, bridging metabolic reprogramming, immune dysregulation, and epithelial transformation. Accumulating evidence highlights that microbial metabolites are not just by-prod- ucts of bacterial activity; rather, they are powerful bioactive mediators that regulate host signaling networks involved in inflammation, DNA integrity, and tumor immunity. The dynamic interplay among SCFAs, secondary bile acids, and tryptophan metabolites exemplifies how microbial metabolism can either sustain intestinal homeostasis or promote malignant transformation, depending on contextual cues within the tumor microenvironment. Despite significant progress, several key challenges persist. The causal hierarchy connecting specific microbial taxa, metabolites, and host signaling pathways in CRC remains incompletely under- stood. Interindividual microbiome heterogeneity, metabolic redun- dancy, and the impacts of diet and genetics complicate the interpretation of mechanisms and the translation of therapies. Future research should focus on integrating multi-omics profiling, spatial microbiome mapping, and advanced organ Additionally, interindividual oid or immune co-culture models to unravel these complex networks with both temporal and spatial precision. Ultimately, the microbiota–metabolite–immune axis represents a promising frontier for CRC prevention and therapy. Personalized strategies—combining dietary modulation, probiotics, prebiotics, postbiotics, or FMT—with conventional treatments may offer synergistic benefits. A deeper understanding of microbial metabo- lism and immune crosstalk will pave the way for microbiome-based precision medicine. This advancement will transform the manage- ment of colorectal cancer from generalized interventions to indi- vidualized microbial modulation.

  Keywords: microbial immune metabolites microbiome microbiota colorectal cancer metabolic transformation host signaling networks tumor interindividual spatial
• Synergistic antitumor and immunomodulatory effects of Bifidobacterium animalis subsp. lactis V9 combined with anti–PD-1 therapy (2026) · doi

  immune checkpoint blockade, several should be acknowledged. First, although multiple murine tumor models were employed, inherent differences in tumor evolution, immune system composition, and gut microbiota structure between mice and humans may constrain the direct translation of these findings to clinical applications. Second, as a gut-acting microbial‐ derived agent, the causal pathways linking B. lactis V9 to enhanced immunotherapy responses remain insufficiently defined. While this study suggests that B. lactis V9 may mitigate immune-related tissue injury and modulate host immunity, mechanistic insights into how influences gut microbial metabolism, host metabolic it reprogramming, and tumor immune microenvironment remodel- ing are still lacking. Comprehensive multi-omics approaches will be necessary to delineate the specific molecular and metabolic axes through which B. lactis V9 exerts its immunomodulatory effects. Third, at the clinical level, larger and well-designed prospective trials are required to determine whether B. lactis V9 combined with anti–PD-1 therapy can improve objective response rates, progres- sion-free survival, and other clinically meaningful outcomes. Parallel monitoring of dynamic changes in patients’ gut microbiota will also be essential to validate its utility as a microbiome-based immunotherapy adjuvant. In conclusion, B. lactis V9 augments anti–PD-1 efficacy in colorectal and breast cancer models and mitigates immune-related toxicity by harmonizing innate immune activation and remodeling the tumor microenvironment. Its stable colonization after antibiotic exposure and favorable high-dose safety further support its trans- lational promise as a microbiome-based adjunct to immunotherapy. These findings provide both strain-level and mechanistic under- pinnings for LBP–ICI combination strategies and lay a foundation for the clinical translation of “gut microbiota modulation of tumor immunity.

  Keywords: immune tumor lactis microbiota clinical immunotherapy models translation ndings microbial related host immunity mechanistic metabolic
• Gut microbial metabolites in colorectal cancer: dual roles in tumorigenesis, immune crosstalk, and therapeutic innovation (2026) · doi

  While this review outlines the role of microbial metabolites in CRC, several methodological limitations in the current field must be acknowl- edged. While such research provides key insights into molecular and cellular processes, it often fails to reflect the full complexity of human physiology and disease. First, most mechanistic insights come from preclinical mouse models, which do not fully reflect the genetic, microbial, and tumor microenvironmental complexity of human CRC (Gates et al., 2025). Cell models also cannot replicate the complex microenvironment or inter-tissue communication seen in vivo. Despite genetic similarities, human immune regulation and cognitive functions are more advanced. Human diseases develop over decades, whereas animal models show rapid progression. Patient-specific factors like genetic variation, comorbidities, and environmental exposures are difficult to fully reproduce experimentally. Second, the tumor immune microenvironment and direct interactions between gut microbes and immune cells in CRC progression and treatment response were not a central focus. To address this, multi-omics approaches integrating metabolomics, proteomics, and genomics should be used. Experimental tools such as fecal microbiota transplantation, germ-free animal models, and in vitro co-culture systems can help clarify how microbes regulate immune function. Multimodal bioinformatics can further dissect the molecular mechanisms of microbe-immune interac- tions. Third, although strong associations exist between microbial metabolites and CRC development, a more comprehensive understand- ing requires combining metabolomics with immune profiling to study tumor metabolic reprogramming at a systems level (Chen et al., Frontiers in Cellular and Infection Microbiology 14 frontiersin.org Jin et al. 10.3389/fcimb.2026.1693161 2025).Finally, safety is critical when translating microbial metabolites into clinical use. Mechanistic studies often use surrogate endpoints, such as reduced tumor size that may not correlate with clinical benefits like longer survival or improved quality of life. Therefore, caution is needed when applying preclinical findings to clinical practice. This involves rigorous toxicological testing, dose-escalation studies in vitro, in animals, and in early-phase trials. Attention must also be paid to metabolite sources, contamination risks, and active safety monitoring, including for allergic reactions and drug stability in vivo. Manufacturing processes must meet regulatory standards. However, current agencies lack a dedicated framework for evaluating microbial metabolite-based thera- pies, creating major barriers to clinical translation. Addressing these gaps is essential for developing safe and effective treatments.

  Keywords: immune microbial human models tumor clinical metabolites must genetic current insights molecular cellular processes often