Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

Abstract

Previously, a synbiotic combination of probiotic Lactobacillus gasseri 505 (LG) and a new prebiotic, Cudrania tricuspidata leaf extract (CT) in fermented milk, designated FCT, showed an in vitro immunomodulatory effect and antioxidant activity. Although synbiotic combination might have cancer-protective effects, these activities have not been fully validated in vivo. Ten-week treatment of LG, CT, or FCT to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colorectal cancer (CAC) mouse model reduced both the incidence of colonic tumors and damage to the colonic mucosa effectively, suggesting a cancer-protective effect. To understand these, biomarkers associated with inflammation, colon barrier, apoptosis, and cancer cell proliferation were monitored in AOM/DSS group versus LG/CT/FCT groups. A synbiotic combination (FCT) downregulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) and inflammation-associated enzymes (iNOS and COX-2), and up-regulated anti-inflammatory cytokines (IL-4 and IL-10). In addition, colon barrier experiment revealed that biomarkers of mucus layer (MUC-2 and TFF3) and tight junction (occludin and ZO-1) were up-regulated. Subsequent apoptosis experiment showed that pro-apoptotic factors (p53, p21, and Bax) were up-regulated and anti-apoptotic factors (Bcl-2 and Bcl-xL) were down-regulated. Furthermore, comparative metagenome analysis of gut microbiota revealed that Staphylococcus decreased but Lactobacillus, Bifidobacterium, and Akkermansia increased, supporting their protective effects, accompanied by increased short-chain fatty acids (SCFAs). Taken together, the FCT administration showed cancer-protective effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Consequently, the synbiotic combination (FCT) could be a novel potential health-protective natural agent against CAC.

The inhibitory effects of probiotics on colon cancer cells: in vitro and in vivo studies

“…This suggests that there is a special connection between probiotics and CRC. In fact, numerous studies have demonstrated the anti-tumor effects of probiotics such as L. acidophilus, L. casei, L. plantarum, and B. longum (13,14). However, before a specific probiotic strain can be considered part of a cancer treatment regimen, its function needs to be assessed in detail (15).…”

Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases

“…In contrast, high-sugar diet was shown to enhance susceptibility to DSS-colitis via depletion of luminal short chain fatty acids [ 181 ]. Similar to dietary fibers, several probiotics and symbiotic supplementations with dietary fibers also ameliorated disease activity, changed the gut microbiota, and showed SCFA-supporting effects [ 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 ]. These promising reports inspired further studies on the direct effect of SCFA supplementation on experimental colitis.…”

Role of Gut Microbiota and Probiotics in Colorectal Cancer: Onset and Progression

“…In an AOM/DSS model, this treatment ameliorated the effects of cancer by downregulating pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) and anti-apoptotic factors (Bcl-2 and Bcl-xL), and upregulating anti-inflammatory cytokines (IL-4 and IL-10) and pro-apoptotic factors (p53, p21, and Bax). Furthermore, synbiotic treatment decreased the expression of the inflammation-associated enzymes iNOS and COX-2 [ 115 ]. These effects were corroborated by work in a mouse model that demonstrated the ability of this combination to prevent the hepatic toxicity induced by CRC [ 116 ].…”