Food-derived dietary alkaloids: structure-biofunctionality relationships in modulating gut microbial biofilms for...

Colorectal cancer (CRC) is the second most common cancer across the globe, accounting for 10% cancer-related deaths annually. CRC has been recognized as a consequence of microbial (such as F. nucleatum, E. coli (pks⁺ strains) biofilms, inflammatory signaling, and redox imbalance in the human gut. Hence, natural bioactive substances as a part of the daily diet are crucial for the downregulation of biofilm-mediated CRC. Dietary alkaloids, nitrogen-containing secondary metabolites, have been identified as potential chemotherapeutic agents that can inhibit biofilm formation through quorum-sensing inhibition, modulating the tumor microenvironment, including redox and inflammatory pathway regulation. The present review primarily focuses on the alkaloids' structure-function relationships, microbial biotransformation, and inhibition of pathogenic biofilms, through downregulation of NF-κB, IL-6, STAT3-mediated inflammatory cascades, apoptosis, induction of autophagy, and balancing the redox-oxidative homeostasis. Further, the synergistic effect of alkaloids with dietary fiber, short-chain fatty acid (SCFA)-mediated synergy, and polyphenol compounds is essential for microbial-epithelial barrier activity and metabolic homeostasis regulation. However, the integration of dose windows, dietary patterns, and regulatory landscapes is essential to establish dietary alkaloids as a functional food in biofilm-mediated CRC prevention. Moreover, bioavailability of dietary alkaloids is a potential challenge, and nano-enabled delivery, specifically lipid and polymeric nano carriers, is considered for the controlled delivery, mucosal bioactivity, and reduced systemic exposure of alkaloid carriers for colon mucosa bioactivity. Overall, the integration of microbiome with dietary alkaloids as bioactive food components, to modulate biofilm and tumor micro-niches, underlines the translational potential of dietary alkaloids for CRC prevention.