Sucralose Promotes Colitis-Associated Colorectal Cancer Risk in a Murine Model Along With Changes in Microbiota

Abstract

Sucralose is a calorie-free high-intensity artificial sweetener that is widely used in thousands of foods and beverages all over the world. Although it was initially regarded as a safe, inert food additive, its adverse effect on gut microbiota and health has drawn more and more attention as evidence accumulates. Studies by us and others revealed that sucralose exacerbated gut damage and inflammation in animal models for inflammatory bowel disease (IBD), including those for both ulcerative colitis, and Crohn's disease. Our study demonstrated that sucralose greatly aggravated dextran sulfate sodium (DSS)-induced colitis along with causing changes in gut microbiota, the gut barrier and impaired inactivation of digestive proteases mediated by deconjugated bilirubin. It is welldocumented that IBD greatly increases the risk of colorectal cancer (CRC), the globally third-most-common cancer, which, like IBD, has a high rate in the developed countries. Azoxymethane (AOM)/DSS has been the most commonly used animal model for CRC. In this study, we further explored the effect of sucralose on tumorigenesis and the possible mechanism involved using the AOM/DSS mouse model. First, 1.5 mg/ml sucralose was included in the drinking water for 6 weeks to reach a relatively stable phase of impact on gut microbiota. Then, 10 mg/kg AOM was administered through intraperitoneal injection. Seven days later, 2.5% DSS was put in the drinking water for 5 days, followed by 2 weeks without DSS. The 5 days of DSS was then repeated, and the mice were sacrificed 6 weeks after AOM injection. The results showed that sucralose caused significant increases in the number and size of AOM/DSS-induced colorectal tumors along with changes in other parameters such as body and spleen weight, pathological scores, mortality, fecal β-glucuronidase and digestive proteases, gut barrier molecules, gut microbiota, inflammatory cytokines and pathways (TNFα, IL-1β, IL-6, IL-10, and TLR4/Myd88/NF-κB signaling), and STAT3/VEGF tumor-associated signaling pathway molecules. These results suggest that sucralose may increase tumorigenesis along with dysbiosis of gut microbiota, impaired inactivation of digestive protease, damage to the gut barrier, and exacerbated inflammation.

Analysis of Caloric and Noncaloric Sweeteners Present in Dairy Products Aimed at the School Market and Their Possible Effects on Health

“…Regarding sucralose, though it is considered harmless and without the genotoxic potential to produce genetic damage or cancer in humans, a study mentioned that because of the conditions that this sweetener causes on the intestine (the inactivation of digestive proteases, the microbiota, and the intestinal barrier), it can promote the development of colorectal cancer [ 80 ].…”

Artificial Sweeteners: History and New Concepts on Inflammation

“…Other sucralose-containing commercial products, such as Sweetal (sucralose + sorbitol), significantly elevated liver enzyme levels (ALT, AST) and kidney function enzymes (urea, creatinine) in Balb/c albino mice after 18 weeks (administered 5 h/day in drinking water; 5.2 mg/ml sucralose) (2). Similar in vivo pro-inflammatory effects [hepatic mediators (5), severity of chemically-induced colitis (6, 57)] following pure sucralose supplementation have also been reported (5,6,57).…”

“…While the Food and Drug Administration (FDA) deems AS to be safe, there is evidence that AS influence inflammation pathways (1)(2)(3)(4)(5)(6)(7). Owing to the potent sweetening effect of most AS and bitterness/lingering aftertaste, most commercial products contain a commercial proprietary blend of two or more AS, as well as ingredients to make AS more palatable.…”

“…Preclinical animal studies indicate that some AS studied contribute to the development or worsening of gastrointestinal inflammation (1)(2)(3)(4)(5)(6)(7), while some are reported as having an anti-inflammatory effect (12). Findings are, however, controversial because of potential conflicts of interest, as AS manufacturers often sponsor professional organizations to author the studies.…”

A Crosstalk between Diet, Microbiome and microRNA in Epigenetic Regulation of Colorectal Cancer

“…One of them is sucralose, which is used in wide variety of foods and beverages all over the world. Despite the fact that sucralose have been considered healthy, independent studies have shown that sucralose promotes gut damage, inflammation and colitis-associated CRC in murine models along with dysbiosis of gut microbiota [ 36 ].…”