Gut-Microbiota-Derived Metabolites and Probiotic Strategies in Colorectal Cancer: Implications for Disease Modulation and Precision Therapy

Abstract

The human gut microbiota significantly influences host health through its metabolic products and interaction with immune, neural, and metabolic systems. Among these, short-chain fatty acids (SCFAs), especially butyrate, play key roles in maintaining gut barrier integrity, modulating inflammation, and supporting metabolic regulation. Dysbiosis is increasingly linked to diverse conditions such as gastrointestinal, metabolic, and neuropsychiatric disorders, cardiovascular diseases, and colorectal cancer (CRC). Probiotics offer therapeutic potential by restoring microbial balance, enhancing epithelial defenses, and modulating immune responses. This review highlights the physiological functions of gut microbiota and SCFAs, with a particular focus on butyrate's anti-inflammatory and anti-cancer effects in CRC. It also examines emerging microbial therapies like probiotics, synbiotics, postbiotics, and engineered microbes. Emphasis is placed on the need for precision microbiome medicine, tailored to individual host-microbiome interactions and metabolomic profiles. These insights underscore the promising role of gut microbiota modulation in advancing preventive and personalized healthcare.

Keywords: colorectal cancer (CRC); gut microbiota; microbiome therapeutics; probiotics; short-chain fatty acids (SCFAs).

Figure 1

Butyrate-mediated regulation of epithelial differentiation and tumor suppression, showing the multifaceted roles of butyrate-producing microbial species in modulating host cellular functions. Butyrate inhibits HDACs, leading to epigenetic regulation that suppresses oncogenes (e.g., CSE1L, PLAC8) and enhances tumor suppressor gene expression. These actions contribute to cell cycle arrest, promotion of apoptosis, and inhibition of metastasis. Additionally, butyrate supports epithelial differentiation, reinforces mucosal barrier integrity, and reduces pro-inflammatory signaling, thereby maintaining tissue homeostasis and facilitating mucosal repair. HDACs, histone deacetylases; CSE1L, chromosome segregation 1 like; PLAC8, placenta-associated 8.

Figure 2

Integrated model of microbiota–SCFA–probiotic interactions and precision therapeutic strategies. This diagram synthesizes the interconnected roles of resident microbiota, therapeutic probiotics, and short-chain fatty acids (SCFAs) in maintaining gut health and modulating systemic immunity and inflammation. Microbial fermentation of dietary substrates produces SCFAs, particularly butyrate, which mediate gut barrier integrity, immune regulation, and anti-inflammatory effects. Therapeutic probiotics enhance butyrogenic taxa and support endogenous SCFA production. These mechanisms contribute to therapeutic benefits in conditions such as colorectal cancer, inflammatory bowel disease, and metabolic disorders. Future precision strategies, including dietary modulation, omics-guided stratification, and regulatory alignment, are essential to unlock the full translational potential of microbiome-based therapies.