Diabetes changes the microbiota of the host, a condition known as dysbiosis. Dysbiosis have emerged to be an important contributing factor for the pathogenesis of diabetes and diabetes-associated colorectal cancer. In this study we tangled some of the molecular mechanisms that links diabetes to CRC that are in tune relation with dysbiosis. To test our hypothesis, MKRmice that can spontaneously develop type 2 diabetes were used in our work. For CRC induction, another subset of mice was treated with azoxymethane (AOM) and dextran sulfate sodium. (DSS), to identify the link between both diabetes and CRC. In parallel experiments, a subset of control mice was depleted of their microbiota after weaning, then mice were inoculated with fecal microbial transplant (FMT) from diabetic mice and mice with CRC. After 5 weeks of transplantation, all mice groups were treated with AOM and DSS. Further, a subset of the diabetic mice and diabetic mice with CRC were treated with probiotics or butyrate. At the end of the treatment, 16S rRNA sequencing was performed to identify different microbial communities in the fecal samples. Besides, at sacrifice, blood was collected, and colons were harvested for molecular, and biochemical analysis. Our preliminary results show that diabetes is associated with a defined microbial signature characterized by reduction of butyrate-forming bacteria which is associated with gastrointestinal complications.These changes are reversed upon treatment with probiotics or butyrate. Inoculation of control mice with diabetic microbiota and cancer microbiota resulted in the development of more aggressive CRC. Our data also show that IL-1βand NOX4 are over-expressed in diabetic mice as a result of activation of HDAC3 in colon tissue. Collectively our data suggest that diabetes is associated with dysbiosis characterized by lower abundance of butyrate-forming bacteria leading to less butyrate production and activation of HDAC3 resulting in over-expression of IL-1βand NOX4 leading to CRC.


M.H. Noureldein: None. A.A. Eid: None.

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