Postbiotics, defined as a preparation of inanimate microorganisms and/or their components, including metabolic byproducts, have gained recognition as promising modulators of gut health and disease, offering advantages over probiotics in terms of safety, stability, and formulation. This systematic review investigates the therapeutic potential of postbiotics derived from functional foods in the context of colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide. Despite encouraging preclinical findings, translation into clinical practice remains limited due to a paucity of robust human trials, revealing a significant gap and the need for further translational research. Key bioactive categories of postbiotics are described, alongside their anti-inflammatory, immunomodulatory, and chemopreventive mechanisms. Through comprehensive literature mapping, this review uniquely categorizes research according to the experimental models employed, i.e., in vitro, in silico, in vivo, and ex vivo, and advanced models such as organoids and organ-on-chip platforms. The latter offers greater physiological relevance by closely mimicking human tissue architecture and microenvironment. These models help demonstrate how postbiotics may influence tumorigenesis through mechanisms involving inflammation, apoptosis, epigenetic regulation, and the maintenance of gut barrier integrity. Finally, the review summarizes recent innovations in their delivery strategies and calls for comprehensive mechanistic studies and high-quality clinical trials to validate postbiotics as safe and effective adjuncts in CRC prevention, therapy, and management.

Postbiotics, defined as non-viable microbial cells, their components, or metabolic byproducts, have gained recognition as promising modulators of gut health and disease, offering advantages over probiotics in terms of safety, stability and formulation. This systematic review explores the therapeutic potential of postbiotics derived from functional foods in the context of colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide. Key bioactive categories of postbiotics, including short-chain fatty acids, exopolysaccharides, enzymes, cell wall fragments and cell-free supernatants are described, along with their mechanisms of action such as anti-inflammatory, immunomodulatory, and chemopreventive effects. Particular emphasis is laid on preclinical studies, in vitro, in silico, in vivo, ex vivo and advanced models such as organoids and organ-on-chip systems, that demonstrate how postbiotics may impact on tumorigenesis through pathways involving apoptosis, epigenetic regulation and gut barrier integrity. Recent advances in postbiotic delivery strategies are also summarized. Despite encouraging preclinical results, translation to clinical practice remains limited by the scarcity of human trials. This review draws attention to the need for further mechanistic research and robust clinical studies to validate the role of postbiotics as safe, effective adjuncts in CRC prevention therapy and management.

Short-chain fatty acids (SCFAs), such as butyrate, acetate, and propionate, are the result of microbial fermentation and have been demonstrated to exert anticancer effects in different experimental models. We systematically reviewed 27 studies on postbiotics in colorectal cancer models, enclosing a range of study types including cell lines, animal models, and organoids. Eight studies that focused specifically on SCFAs were identified and analyzed. SCFAs promoted apoptosis through caspase activation, influenced NF-κB and MAPK signaling, increased mucin expression, and strengthened barrier function. Butyrate has also been demonstrated to induce autophagy via LKB1–AMPK signaling. Studies using SCFA-containing supernatants showed similar effects, although the presence of multiple biomolecules limited attribution. Overall, these findings provide a robust foundation for further research, particularly in the context of translational studies that can bridge the gap between preclinical and clinical research.