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Altering Gut Microbiota to Enhance Therapeutic Efficacy in Resistant Colon Cancer by Natural Agents

Tumor recurrence, a common phenomenon in allmalignancies, is observed in nearly 50% of patients with colorectal cancer(CRC) and is thought to be due to re‐emergence of chemotherapy‐resistant cancerstem cells (CSCs), accompanied by dysfunction of the gut microbiota, resultingin alterations in microbial metabolites. Thus,development of preventive/therapeutic strategies that specifically target CSCs and are non‐toxic should be effective in reducing the risk of relapse. We have examinedthe effectiveness of the combination of ETO‐Curcumin (ETO‐Cur; curcumincomplexed with essential turmeric oil) and TRF, tocotrienol‐rich fractionof palm oil in inhibiting the growth of SCID micexenograft of chemo‐resistant (CR) colon cancer cells and whether thisinhibition could be attributed to alterations in gut and tumor microbiome andtheir metabolites. Indeed, feeding of ETO‐Cur (5 mg/kg) together with TRF (2mg/kg) or the vehicle (control) in SCID mice, initiated after 20 days of inoculationof CR colon cancer cells and continued for 45 days resulted in inhibition of growth of colon tumor that became apparent after about 30 days of treatment. At 40‐ and 45 days, differences in tumor growth between the two groups were highly significant. This inhibition of growth was associated with a significant down‐regulation of β‐catenin and TNF‐α in the tumor and alterations in gutmicrobiota. The latter was evidenced by an overlap of 340 bacterial species between the control and ETO‐Cur/TRF‐treated mice, and 216 and 120 species being different in ETO‐Cur/TRF treated and control mice, respectively. ETO‐Cur/TRF treatment also caused a significant reduction in the expression of 7‐α‐dehydroxylase, an enzyme that catalyzes the conversion of primary to secondary bile acids. Since secondary bile acids, specifically deoxycholic acid (DCA) and lithocholic acid(LCA) are known for their co‐carcinogenic activity and to induce CSCs in the colon, we postulate that the decreased conversion of primary bile acids in the gut to secondary bile acids DCA and/or LCA by ETO‐Cur/TRF may have contributed to the suppression of growth of colon tumors.