Unveiling the anti-inflammatory potential of 11ß,13-dihydrolactucin for application in inflammatory bowel disease management.

Management of inflammatory bowel disease (IBD) poses significant challenges, and there is a need for innovative therapeutic approaches. This study investigates the anti-inflammatory properties of the dietary sesquiterpene lactone (SL) 11ß,13-dihydrolactucin, which can be found in chicory, in three distinct complementary models of intestinal inflammation (two cell models and a zebrafish model), offering comprehensive insights into its potential application for IBD treatment alternatives. In a triple cell co-culture composed of Caco-2, HT29-MTX-E12, and Raji B, 11ß,13-dihydrolactucin demonstrated remarkable anti-inflammatory activity at several levels of the cellular inflammatory response. Notably, 11ß,13-dihydrolactucin prevented the activation of critical signalling pathways associated with inflammation, namely NF-κB and MAPK p38. This SL also decreased the release of the neutrophil-recruiting chemokine IL-8. Additionally, the compound reduced the gene expression of IL-6 and TNF-α, as well as the gene and protein expression of the inflammatory inducible enzymes iNOS and COX-2. In a myofibroblast-like human cell model, 11ß,13-dihydrolactucin decreased the release of the cytokine TNF-α and the COX-2-derived inflammation mediator PGE2. Finally, in a zebrafish model of gut inflammation, 11ß,13-dihydrolactucin effectively reduced neutrophil infiltration, further supporting its anti-inflammatory efficacy in a physiological context. Collectively, our findings highlight the promising anti-inflammatory potential of 11ß,13-dihydrolactucin across various facets of intestinal inflammation, providing a foundation for the consideration of chicory as a promising candidate for incorporation in food or nutraceutical products for the potential prevention of IBD.

A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBD) with chronic infiltration of immune cells in the gastrointestinal tract are common and largely incurable. The therapeutic targeting of IBD has been hampered by the complex causality of the disease, with environmental insults like cholesterol-enriched Western diets playing a critical role. To address this drug development challenge, we report an easy-to-handle dietary cholesterol-based in vivo assay that allows the screening of immune-modulatory therapeutics in transgenic zebrafish models. An improvement in the feeding strategy with high cholesterol diet (HCD) selectively induces a robust and consistent infiltration of myeloid cells in larvae intestines that is highly suitable for compound discovery efforts. Using transgenics with fluorescent reporter expression in neutrophils, we take advantage of the unique zebrafish larvae clarity to monitor an acute inflammatory response in a whole organism context with a fully functional innate immune system. The use of semi-automated image acquisition and processing combined with quantitative image analysis allows categorizing anti- or pro-inflammatory compounds based on a leukocytic inflammation index. Our HCD gut inflammation (HCD-GI) assay is simple, cost- and time-effective as well as highly physiological which makes it unique when compared to chemical-based zebrafish models of IBD. Besides, diet is a highly controlled, selective and targeted trigger of intestinal inflammation that avoids extra-intestinal outcomes and reduces the chances of chemical-induced toxicity during screenings. We show the validity of this assay for a screening platform by testing two dietary phenolic acids, namely gallic acid (GA; 3,4,5-trihydroxybenzoic acid) and ferulic acid (FA; 4-hydroxy-3-methoxycinnamic acid), with well described anti-inflammatory actions in animal models of IBD. Analysis of common IBD therapeutics (Prednisolone and Mesalamine) proved the fidelity of our IBD-like intestinal inflammation model. In conclusion, the HCD-GI assay can facilitate and accelerate drug discovery efforts on IBD, by identification of novel lead molecules with immune modulatory action on intestinal neutrophilic inflammation. This will serve as a jumping-off point for more profound analyses of drug mechanisms and pathways involved in early IBD immune responses.