Chemoprevention of Colorectal Cancer by Anthocyanidins and Mitigation of Metabolic Shifts Induced by Dysbiosis of the Gut Microbiome

Diets rich in fat, smoking, as well as exposure to environmental pollutants and dysbiosis of gut microbiota, increase the risk of developing colorectal cancer. Much progress has been made in combating colorectal cancer. However, options for chemoprevention from environmental insult and dysbiosis of gut microbiota remain elusive. We investigated the influence of berry-derived anthocyanidins (Anthos), with and without encapsulating them in bovine milk-derived exosomes (ExoAnthos), on the chemoprevention of bacteria-driven colon tumor development. Anthos and ExoAnthos treatment of colon cancer cells showed dose-dependent decreases in cell viability. Calculated selectivity index (SI) values for Anthos and ExoAnthos suggest that both treatments selectively targeted cancer over normal colon cells. In addition, ExoAnthos treatment yielded higher SI values than Anthos. Anthos and ExoAnthos treatment of Apc(Min/+) mice inoculated with enterotoxigenic Bacteriodes fragilis (ETBF) bacteria led to significant decreases in colon tumor numbers over mice receiving vehicle treatments. Western blot analysis of normal colon, colon tumor, and liver tissue lysates showed that mice inoculated with ETBF featured increased expression of phase I enzymes in normal colon tissue and decreased expression of phase II enzymes in liver tissue. Treatment with the Anthos and ExoAnthos reverted the modulation of phase I and phase II enzymes, respectively; no significant changes in phase II enzyme expression occurred in colon tumor tissue. Treatment of HCT-116 cells with the ubiquitous carcinogen, benzo[a]pyrene (B[a]P) led to similarmodulation of phase I and II enzymes, which was partially mitigated by treatment with Anthos. These results provide a promising outlook on the impact of berry Anthos for prevention and treatment of bacteria- and B[a]P-driven colorectal cancer.