Diabetes-Associated Colorectal Cancer: The Emerging Role of Microbiota

Abstract

Diabetes mellitus (DM) is a critical global health concern significantly contributing to morbidity and mortality due to its complexity in affecting the body’s metabolism and energy use. Disrupting these important functions has a wide range of consequences on body organs. Recent data has highlighted a link between type 2 diabetes and colorectal cancer (CRC). CRC, the third most diagnosed cancer globally, is classified as an unconventional complication of DM. A cascade of physiological alterations that act as risk factors for colorectal cancer (CRC) are linked to DM. Chronic inflammation, increased insulin resistance, and elevated oxidative stress observed in DM can ultimately result in CRC. Diabetes also alters the gastrointestinal environment and thus the host's microbiota, resulting in an imbalance termed dysbiosis. Dysbiosis of the gut microbiota, whether caused by diabetes or dietary modification, is a major risk factor for developing CRC. In this study, we aimed to investigate the effect of gut dysbiosis on the pathogenesis and progression of diabetes and CRC. A set of experiments were carried out to study our aim. The first study included FVB/NJ, MKR, which spontaneously develop type 2 diabetes, and CRC mice. CRC was chemically induced by treating mice with azoxymethane followed by dextran sulfate sodium. In parallel experiments, three animal models were used, comprising FVB/NJ, MKR, and CRC groups. Each group was inoculated with FMT from either healthy, MKR, or CRC mice after depleting their microbiota. Sham group was used as controls. Fecal samples were collected at different time points, the 1st and 2nd being before and after depleting the microbiota and the 3rd taken right before sacrifice. Urine collection was also performed. At sacrifice, blood was withdrawn, and colons were harvested for histological and molecular analysis. Our results show that treatment of T2DM mice or CRC mice with healthy FMT decreased colon injury, inflammatory markers including TNF-a and IL-6, and oxidative stress as assessed NADPH oxidase activity. Additionally, alterations in the gut microbiota of T2DM and CRC mice with CRC and T2DM FMT respectively increased collagen deposition and fibrosis, upregulated inflammatory markers including TNF-a and IL-6, and increased NADPH oxidase activity contributing to oxidative stress. These results suggest that alteration in gut microbiota affect the pathogenesis and progression of T2DM and CRC. Of interest, our data also suggests that microbiota depletion has an adverse impact on the pathogenesis of mice colons’ health. Gut microbiota dysbiosis is a major contributor to T2DM and CRC. To target these alterations, fecal samples compromising healthy microbiota could be used to restore colon health. FMT is a potential therapeutic intervention designed to alleviate dysbiosis-associated dysregulations caused by T2DM and CRC.