Obacunone Protects Against Ulcerative Colitis in Mice by Modulating Gut Microbiota, Attenuating TLR4/NF-κB Signaling Cascades, and Improving Disrupted Epithelial Barriers.

Xiaoping Luo,Junyu Ren,Bei Yue,Yijing Ren,Zhilun Yu,Zhengtao Wang,Jing Zhang,Wei Dou

doi:10.3389/fmicb.2020.00497

Abstract

Obacunone, a natural limonoid compound abundantly distributed in citrus fruits, possesses various biological properties, such as antitumor, antioxidant, and antiviral activities. Recent studies suggested an anti-inflammatory activity of obacunone in vitro, but its efficacy on intestinal inflammation remains unknown. This study was designed to evaluate the effects and mechanisms of obacunone in ameliorating intestinal inflammation in a mouse model of ulcerative colitis (UC). We found that obacunone efficiently alleviated the severity of dextran sulfate sodium (DSS)-induced mouse UC by modulating the abnormal composition of the gut microbiota and attenuating the excessive activation of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling. The intestinal epithelial barrier was disrupted in DSS colitis mice, which was associated with activation of inflammatory signaling cascades. However, obacunone promoted the expression of tight junction proteins (TJP1 and occludin) and repressed the activation of inflammatory signaling cascades. In summary, our findings demonstrated that obacunone attenuated the symptoms of experimental UC in mice through modulation of the gut microbiota, attenuation of TLR4/NF-κB signaling cascades, and restoration of intestinal epithelial barrier integrity.

Highlights

Inflammatory bowel diseases (IBDs), consisting mainly of Crohn’s disease and ulcerative colitis (UC), are common, chronic, and relapsing inflammatory disorders of the digestive tract (Kaplan, 2015)
Our results revealed that dextran sulfate sodium (DSS) treatment disturbed gut microbiota homeostasis, and this gut microbiota imbalance could be reversed by obacunone treatment
The results showed that the mRNA levels of IL-1α, IL1β, IL-16, cyclooxygenase 2 (COX-2), and iNOS were markedly upregulated in LPS-stimulated macrophages; obacunone treatment attenuated the LPS-induced increase in the mRNA levels of these proinflammatory mediators (Figure 7E)

Summary

Introduction

Inflammatory bowel diseases (IBDs), consisting mainly of Crohn’s disease and ulcerative colitis (UC), are common, chronic, and relapsing inflammatory disorders of the digestive tract (Kaplan, 2015). The clinical features of UC include recurrent, chronic, and persistent inflammation in the gastrointestinal tract. The exact cause of UC remains unclear, accumulating evidence has Obacunone Protects Against IBD indicated that interaction between mucosal immunity and gut microbiota plays a key role in the pathogenesis of UC (Yue et al, 2019). Clinical studies have indicated that the composition of three major phyla of bacteria present in the gut microbiota of UC patients is disturbed, with a decrease in the proportion of Firmicutes and Bacteroidetes and an increase in that of Proteobacteria (Matsuoka and Kanai, 2015; MirsepasiLauridsen et al, 2019). Administration of antibacterial agents and probiotics in UC patients has suggested that the gut microbiota does play a role in the onset of UC (Sokol, 2014)

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Discussion

Conclusion