Sclareol protected against intestinal barrier dysfunction ameliorating Crohn's disease-like colitis via Nrf2/NF-B/MLCK signalling.

BACKGROUND: Inflammation-induced intestinal barrier dysfunction is not only a pathological feature of Crohn's disease (CD) but also an important therapeutic target. Sclareol (SCL) is a nontoxic natural plant compound with anti-inflammatory effect, but its role in CD has not been established. METHODS: In vivo studies of mice with TNBS-induced colitis were carried out to evaluate the effects of SCL on CD-like colitis and intestinal barrier function. In vitro, a TNF-α-induced colonic organoid model was established to test the direct effect of SCL on inflammation-induced intestinal barrier injure and inflammatory response. The Nrf2/NF-κB/MLCK signalling was analysed to explore the mechanism of SCL. RESULTS: In vivo, SCL largely alleviated the colitis in TNBS mice, as evidenced by improvements in the weight loss, colitis symptoms, endoscopic score, macroscopic histological score, and histological inflammation score. Moreover, SCL significantly improved intestinal barrier dysfunction, manifested as reduced intestinal permeability and decreased intestinal bacterial translocation in TNBS mice. Importantly, SCL antagonised the intestinal mucosal inflammation while protecting tight junctions in TNBS mice. In vitro, SCL largely depressed pro-inflammatory cytokines levels and improved intestinal epithelial permeability in a TNF-α-induced colonic organoid model. In the context of CD, the protective effects of SCL against inflammation and intestinal barrier damage are at least partially results from the Nrf2 signalling activation and the NF-κB/MLCK signalling inhibition. CONCLUSIONS: SCL improved intestinal barrier dysfunction and alleviated CD-like colitis, possibly through modulation of Nrf2/NF-κB/MLCK signalling. In view of SCL's safety profile, there is hope that it will be useful in the clinic.

Correction: Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats.

Correction for 'Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats' by Yun-fei Bai et al., Food Funct., 2023, 14, 921-933, https://doi.org/10.1039/D2FO03031D.

Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats.

Hyperlipidemia is a global health risk factor, and its development is closely related to the absorption and metabolism of lipids in the intestine. In this study, the Auricularia auricula polysaccharide, the Tremella polysaccharide, and hawthorn flavonoids were mixed by equal weight (HDC), and then its effect on the intervention in the intestine and blood lipids of hyperlipidemic rats on a high-fat diet (HFD) was investigated. The results revealed that HDC significantly inhibited the development of hyperlipidemia and reduced lipid levels and fat accumulation. In addition, HDC improved the edema deformation of intestinal epithelial cells, impaired the intestinal barrier induced by HFD, and improved the antioxidant capacity of the intestine. HDC showed a significant synergistic effect. Analysis of the gut microbiota by 16s rRNA gene sequencing showed that HDC reduced the ratio of Bacteroidetes/Firmicutes and the relative abundance of actinomycetes. At the genus level, the relative abundance of Lactobacillus, Rumincococcaceae-UCG-14, and Muribaculaceae was increased and the relative abundance of Allobaculum, Corynebacterium-1, Blautia, and Turicibucter was decreased. Intestinal lipidomics showed that HDC reduced the levels of DGDG, LPE, PG, phSM, PIP2, SoG1, and SM in the intestine of HFD rats, although there were no significant differences in LPE, PG, and phSM. 42 HDC-acting lipid biomarkers were screened. In conclusion, these findings support the potential of HDC intervention to prevent hyperlipidemia by regulating gut microbiota and lipid absorption and metabolism in the intestine.

Pygopus2 ameliorates mesenteric adipocyte poor differentiation to alleviate Crohn's disease -like colitis via the Axin2/GSK3ß pathway.

OBJECTIVES: Crohn's disease (CD) mesenteric adipose tissue (MAT) inflammation affects enteritis through the interaction between the mesentery and intestine, and we previously found that poorly differentiated mesenteric adipocytes were related to its inflammatory features. Pygopus2 (Pygo2) is a key negative regulator of adipocyte differentiation. We aimed to determine whether Pygo2 participates in CD mesenteric lesions and whether Pygo2 knockdown would be beneficial in a CD model (Il-10-/- mice). METHODS: Pygo2 expression in MAT from control and CD patients and Il-10-/- mice was measured by immunohistochemistry. Lentiviral transfection was used to regulate Pygo2 expression in Il-10-/- mice, and the effects on mesenteric adipocyte differentiation, inflammation, and dysfunction during spontaneous colitis, as well as the possible mechanism, were investigated. RESULTS: Pygo2 expression was increased in MAT from CD patients and Il-10-/- mice, and its expression correlated with poor adipocyte differentiation and inflammation. Pygo2 knockdown significantly ameliorated colitis in Il-10-/- mice. Moreover, the downregulation of Pygo2 gene expression could promote adipocyte differentiation and inhibit adipocyte inflammation in vivo and in vitro, and the effects were at least partly mediated by the Axis inhibition protein 2 (Axin2)/glycogen synthase kinase 3 beta (GSK3ß) pathway. CONCLUSIONS: The increase in Pygo2 may be related to mesenteric adipocyte poor differentiation and inflammatory features of CD, and Pygo2 inhibition could alleviate CD-like colitis by improving mesenteric lesions by regulating the Axin2/GSK3ß pathway.

Aberrant Mesenteric Adipose Extracellular Matrix Remodelling is Involved in Adipocyte Dysfunction in Crohn's Disease: The Role of TLR-4-mediated Macrophages.

BACKGROUND AND AIMS: Hypertrophic mesenteric adipose tissue [htMAT] is involved in the disease progression of Crohn's disease [CD] through expressing proinflammatory adipokines from dysfunctional adipocytes by unknown mechanism. Adipocyte function is affected by dynamic adipose tissue extracellular matrix [ECM] remodelling that is mainly mediated by macrophages, and our study aimed to reveal whether aberrant ECM remodelling was present in CD-htMAT and its effects on adipocyte dysfunction, as well as the mechanism. METHODS: ECM remodelling was examined in MAT samples from CD patients and controls. Mice with dinitrobenzene sulphonic acid [DNBS]-induced colitis were used in vivo study, and lipopolysaccharide [LPS]-induced remodelling behaviour in macrophages was examined in vitro. Macrophages or TLR4 inhibition were used to analyse ECM remodelling mechanisms and their effects on adipocyte function. RESULTS: Aberrant ECM remodelling: was observed in CD-htMAT, which was characterised by a widened and deformed ECM structure accompanied by dysregulated matrix synthesis and degradation; served as a reservoir for inflammatory factors/cells dominated by macrophages; and was involved in adipocyte dysfunction. In addition, macrophages were the main source of ECM remodelling regulatory factors with activation of Toll-like receptor 4 [TLR4] in htMAT. In vivo, macrophage depletion or TLR4 inhibition largely attenuated mesenteric ECM remodelling while improving mesenteric adipocyte dysfunction during chronic enteritis. In vitro, antagonizing TLR4 significantly inhibited LPS-induced macrophage ECM remodelling behavior. CONCLUSIONS: The aberrant ECM remodelling in CD-htMAT contributed to mesenteric adipocyte dysfunction, which may be caused at least partly by TLR4-mediated macrophage remodelling behavior. Inhibiting ECM remodelling may be a potential therapeutic strategy for CD.