Gut modulation to regulate NF-κB in colorectal and gastric cancer therapy and inflammation

The nuclear factor-kappa B (NF-κB) pathway plays a pivotal role in cancer progression, immune regulation, and inflammation. Aberrant activation of this pathway, often driven by gut microbiota dysbiosis, contributes to tumorigenesis, therapy resistance, and chronic inflammation. Emerging evidence highlights the bidirectional interaction between gut microbiota and NF-κB signalling, suggesting that microbiota modulation may enhance cancer treatment efficacy and reduce treatment-induced inflammation. This review explores the mechanistic underpinnings of gut microbiota-mediated NF-κB regulation, focusing on microbial metabolites such as short-chain fatty acids (SCFAs) and microbial-associated molecular patterns, including lipopolysaccharides (LPS). It examines how conventional cancer treatments, chemotherapy, radiotherapy, and immune checkpoint inhibitors, exacerbate dysbiosis and NF-κB-driven inflammation, further complicating treatment outcomes. Additionally, this review evaluates the therapeutic potential of gut-targeted interventions, including probiotics, prebiotics, faecal microbiota transplantation (FMT), and dietary modifications, in restoring microbial homeostasis and modulating NF-κB signalling. Despite promising findings, challenges remain regarding the clinical translation of microbiota-based therapies, including the need for standardised microbiota profiling, regulatory frameworks, and long-term safety assessments. Advances in metagenomics and metabolomics are proposed as essential tools to personalise gut-targeted interventions and optimise cancer treatment strategies. Integrating gut modulation into oncology represents a paradigm shift, offering a holistic, patient-centric approach to cancer therapy. However, further research is required to validate these strategies and ensure their efficacy in clinical applications. [Abstract copyright: © 2025. The Author(s).]