The field of colorectal cancer (CRC) research is increasingly focused on understanding how gut microbiota and their metabolites influence therapeutic outcomes. While CRC remains a major cause of global cancer mortality, a significant barrier to patient survival is the development of resistance to standard treatments such as chemotherapy, immunotherapy, and targeted therapies. Recent studies demonstrate that the gut microbial ecosystem, through its ever-changing composition and metabolic output, interacts extensively with both tumor cells and the host. Bioactive metabolites produced by these microbes—including short-chain fatty acids, secondary bile acids, and polyamines—play multifaceted roles, regulating oxidative stress, epigenetic modifications, immune responses, and cell death pathways that are now recognized as key contributors to both resistance and sensitivity to cancer therapies. Notably, accumulating evidence also reveals the therapy itself can induce changes in the gut microbiome, establishing a complex feedback loop that complicates clinical management. Despite this emerging knowledge, the precise molecular mechanisms underpinning microbiome-metabolite crosstalk in CRC resistance, as well as how these interactions could be harnessed for therapeutic benefit, remain incompletely characterized and demand further investigation.

This Research Topic aims to elucidate the mechanistic and translational roles played by the gut microbiota and their metabolites in contributing to, or mitigating, drug resistance in colorectal cancer. Key objectives include identifying microbial and metabolic signatures predictive of therapy response, clarifying how microbial metabolism modulates tumor and immune cell behavior, and exploring interventions—from dietary modulation to targeted microbiome therapies—that could restore or enhance treatment efficacy. The collection also seeks to foster a multidisciplinary dialogue on how microbiome-metabolite research can inform biomarker development and precision oncology in CRC care.

This Research Topic is limited to investigations centered on the interplay between gut microbiota, their metabolites, and mechanisms of resistance in colorectal cancer therapy, excluding unrelated microbiome or cancer settings. We welcome articles addressing, but not limited to, the following themes:

- Mechanisms by which microbial metabolites contribute to chemoresistance and immunotherapy evasion
- Host-microbiome metabolic interactions and their impact on tumor progression
- Effects of cancer therapies on gut microbial ecology (therapy-induced dysbiosis)
- Microbiota-derived biomarkers for monitoring treatment response or predicting resistance
- Preclinical and clinical evaluation of microbiome-targeted strategies to overcome resistance

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Microbiome-Metabolite Crosstalk in Colorectal Cancer Therapy Resistance