S‐Allylcysteine Inhibits PhIP/DSS‐Induced Colon Carcinogenesis through Mitigating Inflammation, Targeting Keap1, and Modulating Microbiota Composition in Mice

Abstract

The objective of the present study is to investigate whether edible S-allylcysteine (SAC) has chemoprophylactic effects on inflammation-associated colon carcinogenesis induced in mice through 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) exposure and promoted by dextran sodium sulfate (DSS) and whether its cancer-prevention effects are related to the modulation of gut microbiota composition. Methods and results: Dietary administration of 0.05% SAC in mice for 18 weeks prevents shortening of the colon length and reduces the number of colon polyps. The SAC supplementation markedly decreases PhIP/DSS-induced plasma and colon tissue pro-inflammatory cytokines. These changes are accompanied by the suppression of inducible nitric oxide synthase, COX-2, and MMP-2 protein expression in colon tissue. In addition, the dietary administration of SAC increases heme oxygenase-1 expression through activation of the NF-E2-related factor 2 pathway, thus abating PhIP/DSS-induced colitis. The 16S rRNA gene sequence data indicate that SAC counteracted the PhIP/DSS-induced gut dysbiosis, resulting in a microbiota composition similar to the control group. Conclusion: The results indicate that SAC can suppress PhIP/DSS-induced colorectal carcinogenesis. Hence, SAC may merit further clinical investigation as a chemoprevention strategy for retarding colitis-associated colon cancer in humans.

S‐Allylcysteine Potently Protects against PhIP‐Induced DNA Damage via Nrf2/AhR Signaling Pathway Modulation in Normal Human Colonic Mucosal Epithelial Cells

“…These results suggested that SAC may mitigate PhIP-induced mutagenic effects by mediating the Nrf2 antioxidant signaling pathway at the initiation stage of colon cancer. [29] In the present study, we used CETSA experiments to provide evidence supporting the supposition that SAC could engage with Keap1 in normal human colonic mucosal epithelial cells. Furthermore, SAC inhibited p38 and increased AKT and ERK phosphorylation, consequently reinforcing Nrf2 signaling and upregulating HO-1 expression in NCM460 cells.…”

“…The amounts of SAC and PhIP used were based on previous studies. [28,29,54,55] NCM460 cells treated with 0.5% DMSO served as vehicle controls. The cells were seeded at a density of 2 × 10 5 cells mL −1 into 96-well plates and grown 12 h, the cells were treated either with or without PhIP (50 μM) in the presence and absence of SAC (5 or 20 mM).…”

“…[ 27,28 ] Moreover, in our previous study, we found that dietary supplementation with SAC abated PhIP/DSS‐induced colon tumorigenesis in Institute of Cancer Research (ICR) mice. [ 29 ] The inhibitory effect of SAC against colonic DNA damage may be mediated by antioxidant signaling or detoxification pathways. This provides protection against early cellular mutations and DNA damage caused by PhIP during the initiation of carcinogenesis.…”

Dietary Tangeretin Alleviated Dextran Sulfate Sodium-Induced Colitis in Mice via Inhibiting Inflammatory Response, Restoring Intestinal Barrier Function, and Modulating Gut Microbiota

“…1 IBD has been found to show an increasing incidence, which compromises healthy life and span, and increases the risk of colorectal cancer. 2 Crohn's Disease (CD) and Ulcerative Colitis (UC) are two major types of IBD that have been commonly diagnosed globally. 3 They have unique clinical, histopathological, radiological, and endoscopic characteristics.…”

“…Inflammatory bowel disease (IBD), a relapsing and chronic intestinal inflammation that leads to the damage of gastrointestinal tract, usually causes weight loss, abdominal pain, persistent diarrhea, cramps, and rectal bleeding . IBD has been found to show an increasing incidence, which compromises healthy life and span, and increases the risk of colorectal cancer . Crohn’s Disease (CD) and Ulcerative Colitis (UC) are two major types of IBD that have been commonly diagnosed globally .…”