The effects of food additives on gut mucosa have been an area of growing concern and research, given their pervasive use in processed foods and potential implications for gut health and colorectal cancer. Food additives encompass a wide range of substances, including emulsifiers, artificial sweeteners, preservatives, colorants and thickeners. The interaction between these additives, gut microbiota, and the mucosal lining can lead to inflammatory responses and alterations in gut homeostasis, potentially contributing to colorectal cancer.
Effects of food additives on gut mucosal integrity
Emulsifiers
Emulsifiers, such as carboxymethylcellulose (CMC) and polysorbate-80, are used to improve the texture and shelf-life of processed foods. Studies have shown that these additives can disrupt the mucosal barrier mainly with two mechanisms. A) By decreasing mucus thickness: emulsifiers can degrade the mucus layer that protects the epithelial lining, making it more susceptible to pathogenic invasion; B) inducing epithelial permeability by disruption of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1), that compromises the epithelial barrier, leading to increased intestinal permeability or “leaky gut”. Chassaing et al. (2015) demonstrated that dietary emulsifiers induce low-grade inflammation and metabolic syndrome in mice by altering the gut microbiota and increasing intestinal permeability.
Additives such as emulsifiers and preservatives can activate NF-κB, a transcription factor that promotes the expression of pro-inflammatory genes. Some food additives can also activate Toll-like receptors (TLRs) like TLR-4 on the epithelial surface, triggering an immune response that results in chronic inflammation. The integrity of tight junctions, leading to increased epithelial permeability, is the result of chenges in gene expression. Syntetic acyl-glicerol derivatives and polysorbate-80 may activate intracellular protein kinase C-alpha and -beta, like some tumor promoters (e.g. phorbol-myristate; PMA). As a result, this can increase reactive oxygen species (ROS) production, leading to oxidative damage of the mucosal lining. This allows pathogens and toxins to translocate across the epithelium, which can trigger an immune response.
Artificial Sweeteners
Sweeteners like aspartame, sucralose and saccharin have been implicated in modifying the gut microbiome and promoting pro-inflammatory conditions. Artificial sweeteners can compromise the gut mucosal barrier by modulating tight junction proteins: studies indicate that artificial sweeteners may affect the expression and function of proteins such as occludin and claudin, which are critical for maintaining the tight junctions between epithelial cells. For example, Palmnäs et al. (2014) demonstrated that the artificial sweetener sucralose affects the expression of gut tight junction proteins, contributing to increased intestinal permeability in rodent models. Though not fully elucidated, certain sweeteners like saccharin can engage toll-like receptor 4 (TLR4), initiating downstream signaling that results in inflammation and immune activation mediated by NF-kB trasncription factor: the result is the production of inflammatory cytokines like TNF-alpha and IL-6.
These additives can alter gut microbiota composition: studies show that artificial sweeteners can promote dysbiosis, an imbalance in the microbial community. Suez et al. (2014) found that non-caloric artificial sweeteners induce glucose intolerance by altering the gut microbiota in both mice and humans. Artificial sweeteners may interfere with the secretion of glucagon-like peptide-1 (GLP-1), a hormone involved in insulin regulation and satiety. This interference is mediated by the gut’s enteroendocrine cells, which interact with microbial products. Moreover, lab researches has demonstrated that saccharin and sucralose can decrease beneficial bacterial species like Lactobacillus while promoting the growth of potentially pathogenic Enterobacteria. Palmnäs et al. (2014) suggested that sucralose consumption in rodent models altered gut microbiota composition, reducing the production of shiort-chain fatty acids (SCFAs; propionate, butyrate and others) primarily produced by the fermentation of dietary fibers,that play a crucial role in maintaining gut barrier integrity and regulating immune responses.
The role of gut microbiota
The gut microbiota plays a crucial role in modulating the effects of food additives. Some of them indeed may shift the metabolic activity of the microbiota, producing harmful byproducts like lipopolysaccharides (LPS) that promote inflammation. The balance between beneficial and pathogenic microbes is altered, resulting in a pro-inflammatory environment due to the onset of dysbiosis. As a consequence, some food additives reduce the production SCFAs. Cani et al. (2008) showed that high-fat diets supplemented with emulsifiers led to a decrease in Akkermansia muciniphila, a bacterium associated with healthy mucus production and gut barrier integrity. The shift towards a dysbiotic microbiota can result in the production of carcinogenic compounds like secondary bile acids and nitrosamines.
Secondary bile acids are (mostly deoxycholic, ursocholic and lithocholic acids may ahve toxc effect on gut mucosa: high concentrations of deoxycholate can disrupt the integrity of the epithelial barrier by affecting the expression of tight junction proteins, leading to increased gut permeability. These acids also may stimulate the production of reactive oxygen species (ROS), enhancing the cellular damage and the onset of DNA strand breaks. These phenomena are the cause of potentially oncogenic mutations. Nitrosamines derived from the nitrogenous metabolites of Gram-negative bacteria may concur to the carcinogenic effects on gut mucosa. O’Keefe et al. (2016) highlighted the relationship between microbial activity, inflammation, and colorectal cancer, showing how dysbiosis can contribute to carcinogenesis
Implications for colorectal cancer
The chronic inflammation induced by certain food additives may contribute to the initiation and progression of colorectal cancer through several mechanisms. Persistent activation of NF-κB and other inflammatory pathways can lead to DNA damage, promoting tumorigenesis. Additionally, as mentioned earlier, emulsifier activate PKC isoforms that enhance mucosal inflammation and proliferative responses. PKC-alpha nd -beta converge on the mitogenic protein kinases (ERK-1 and -2) by activating the upstream kinase c-Raf. Chronic and sustained ERK activation is observed in cancer cells. It is to remark that emulsifier are not carcinogens per sé; though, they may behave like tumor promoters. Chronic exposure to pro-inflammatory signals and oxidative stress can lead to epigenetic modifications that promote tumor growth (e.g. DNA demethylation and histone acetylation). Garrett et al. (2009) highlighted the link between chronic inflammation and colorectal cancer, emphasizing how inflammation-driven cytokine signaling can promote tumorigenic processes.
Potential protective strategies
To mitigate the negative effects of food additives, several strategies can be considered. A diet rich in natural, unprocessed foods can reduce exposure to industrial additives. Choosing the right foods, may help as well: polyphenols and other anti-inflammatory dietary components may help counteract the pro-inflammatory effects of food additives. One may choose to focus on foods rich in apigenin, chrisin and luteolin (celery, tarragon, oranges, apples, green tea, honey, propolis, fennel, peppers, lettuce and spinachs). Rich sources of polyphenols are also berries (especially in antocyanins, quercitin and their glycosides). These substances are actively metabolized by Lactobacilli, Bifidobacteria, Ruminococcus, Akkermansua, Prevotella, Streptococci and other benefical strains. Chromones, chalcones and phenolic acids derived from bacterial fermentation are provided with chemopreventive effects on tissues due to their antioxidant (ROS quenchers) and antinflammatory properties. In addition, due to the restored dialogue between bacteri and local immunity, these substances help immune cells to stay alert against any sign of “primed” cells committed to carcinogenesis. Lastly, supplementation with prebiotics and probiotics can restore a healthy microbiota composition and strengthen mucosal barriers. The constant intalke of yogurt, kefir, kombucha and other fermented foods help the gut to stay balanced and, as a consequence, our health as well.
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