title: Analysis of the protective effect of Flavonoids in IBD using Nanotechnology
Creators: name: Li, Mingrui
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2025
Subjects: subject: Flavonoid, Nanoparticles, Monocrotaline, IBD, PLGA, pH-sensitive polymer

description: Over the past few years, the incidence rate of inflammatory bowel disease (IBD) has significantly risen all over the world. Most of the patients with IBD suffer from severe symptoms and complications, of which ulcerative colitis (UC) individuals run a high risk of developing colorectal cancer. Being an autoimmune disease, recent studies have shown that the pathogenesis of IBD is related to environmental factors, gut microbiota, excess immunity, and genetic susceptibility. Nevertheless, the precise cause of IBD remains ambiguous. Up to date, there is no known cure for IBD, and traditional medications have troublesome side-effects. For these reasons, some phytochemicals with more tolerance and less adverse effects capture the interest of medical scientists. In our previous animal experiments, we found that Flavo-Natin, a flavonoid combo mainly consisting of apigenin and epigallocatechin-3-gallate (EGCG), was able to significantly mitigate the levels of inflammation in acute experimental colitis models (oxazolone-mediated). Furthermore, the protective effects of Flavo-Natin in chronic experimental colitis models induced by oxazolone were confirmed. Meanwhile, it was observed that MPO activity and the levels of proinflammatory cytokines in colonic tissue obviously decreased. In contrast, the levels of anti-inflammatory cytokines dramatically increased. However, it was observed that flavonoids exhibited a significant protective effect against colitis only when administered in large doses. In vitro studies, incubating Caco-2 cell monolayers with different varieties of flavonoids, it was found that quercetin, naringenin, and EGCG increased transepithelial electrical resistance (TEER), indicating the protective effect of some flavonoids on the intestinal epithelial barrier function. Over 6000 plants in nature can produce pyrrolizidine alkaloids (PAs), which mainly exist in plant seeds. When seeds contaminate tea or herb, PAs can enter the body and generate toxic effects. Flavonoid dietary supplements on the market are often sold in the form of a mixture of various herbal powders, which are easily contaminated by PAs. In order to eliminate potential interference factors in vivo studies, we investigated the enterotoxicity of monocrotaline (MCT) considered as a representative PA. Through oral administration of MCT, we found that enterotoxicity occurred in mice exposed to long-term MCT, mainly affecting upper small intestine. In contrast, changes of the structure in lower small intestine and colon are slight. In addition, MCT did not exacerbate colitis induced by oxazolone. Currently, the use of flavonoids in IBD is still unsatisfactory due to poor absorption, rapid metabolism, and other reasons, resulting in low bioactivity in vivo. Previous studies conducted in our institute have observed that budesonide loaded nanoparticles (NPs) with pH-sensitive coating greatly improved anti-inflammation activity in experimental models of IBD. Based on these findings, we hypothesized that the bioavailability and bioactivity of flavonoids also can be increased through nanotechnology. Therefore, we fabricated flavonoids loaded NPs encapsulated by polymers (PLGA and Eudragit S100), including apigenin, EGCG, quercetin and naringenin. In vitro study, we found that apigenin and quercetin NPs were able to traverse intestinal epithelial barrier formed by Caco-2 cells, contrastingly, free apigenin and quercetin were unable to penetrate Caco-2 cell monolayer. In vivo study, the anti-inflammatory activities of flavonoid NPs were significantly enhanced in acute oxazolone-induced colitis models, when compared to free flavonoids. Collectively, our studies demonstrated that flavonoids exert a protective role in oxazolone-induced colitis mouse models. Meanwhile, we found that polymeric nanocarrier can greatly improve the bioactivity of flavonoids in IBD treatment. Our research has also revealed MCT can induce enterotoxicity, which mainly occurs in upper small intestine.