Phloretin-induced modulation in gut microbiome, mitigates colonic inflammation and alleviates colitis-associated colorectal cancer in mice

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Colitis associated colorectal cancer (CAC) is the fourth common cancer known to cause significant mortalities worldwide. Phloretin is a dihydrochalcone naturally found in apple, pear and strawberry. It exhibited different biological activities, namely anti-inflammatory, anticancer and anti-microbial. In the present study, the role of phloretin towards alleviating colonic inflammation and regulating gut microbiota was explored. The treatment of phloretin led to the reduction in the intestinal inflammation and maintained colon length-weight ratio by decreasing the total number of tumor nodules. We registered reduction in the colonic inflammatory cytokines levels namely TNFα, IL1β, IFNγ, and IL6 as well as expression of HSP90, Cox2, and Src found decreased. Results highlighted the restoration in the levels of tight junction proteins and the expression of Muc2 and Muc3. Further, role of phloretin in inducing apoptosis of tumor cells and the deregulation β-catenin pathway was studied. The histopathological analysis revealed normal colonic structure by decreasing leukocyte infiltration, as well as, circumvention in the reduction of the numbers of goblet cell, crypt abscess and ulceration in phloretin and 5-ASA (5-aminosalicylic acid) treated animals, compared to the diseased group. Metagenomic analysis of the gut microbiome in CAC mice revealed that phloretin significantly increased the abundance of Lactobacillus species, which exert probiotic effects and inhibit synchronous colon tumor growth by modulating β-catenin signaling. The increased abundance of L. reuteri and L. murinus was associated with regulated cellular proliferation, reduced TNF-α production, and decreased expression of COX-2, cyclin D1, and Bcl-2. In conclusion, the results obtained signify the nutraceutical potential of phloretin in restoring the intestinal barrier, maintaining the beneficial gut microbial population, and amelioration of CAC in mice.