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Ursolic Acid Regulates Intestinal Microbiota and Inflammatory Cell Infiltration to Prevent Ulcerative Colitis.

ABSTRACT: Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disorder in the colon and rectum leading to low life-quality and high societal costs. Ursolic acid (UA) is a natural product with pharmacological and biological activities. The studies are aimed at investigating the protective and treatment effects of UA against the dextran sulfate sodium- (DSS-) induced UC mouse model and its underlying mechanism. UA was orally administered at different time points before and after the DSS-induced model. Mice body weight, colon length, and histological analysis were used to evaluate colon tissue damage and therapeutic evaluation. Intestinal transcriptome and microbe 16 s sequencing was used to analyze the mechanisms of UA in the prevention and treatment of UC. The early prevention effect of UA could effectively delay mouse weight loss and colon length shorten. UA alleviated UC inflammation and lowered serum and colon IL-6 levels. Three classical inflammatory pathways: MAPKs, IL-6/STAT3, and PI3K were downregulated by UA treatment. The proportion of macrophages and neutrophils in inflammatory cell infiltration was reduced in UA treatment groups. UA could significantly reduce the richness of intestinal flora to avoid the inflammatory response due to the destruction of the intestinal epithelial barrier. The function of UA against UC was through reducing intestinal flora abundance and regulating inflammatory and fatty acid metabolism signaling pathways to affect immune cell infiltration and cytokine expression.

SUBMITTER: Sheng Q

PROVIDER: S-EPMC8111854 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo explore the composition of the intestinal microbiota in ulcerative colitis (UC) patients and to identify differences in the microbiota between patients with active disease and those in remission.MethodsBetween September 2020 and June 2021, we enrolled into our study, and collected stool samples from, patients with active UC or in remission and healthy control subjects. The diagnosis of UC was based on clinical, endoscopic, radiological, and histological findings. The composition of the intestinal microbiota was determined by sequencing of the 16S rRNA V3-V4 region and by bioinformatic methods. The functional composition of the intestinal microbiota was predicted using PICRUSt 2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) software.ResultsWe found that the intestinal flora was significantly less rich and diverse in UC patients than in healthy control subjects. Beta diversity analysis revealed notable differences in the intestinal flora compositions among the three groups, but there was no statistical difference in alpha diversity between UC patients with active disease and those in remission. At the phylum level, the relative abundances of Proteobacteria and Patescibacteria were significantly higher, and the relative abundances of Desulfobacterota and Verrucomicrobiota were lower, in UC patients with active disease than in the healthy control group. Higher levels of potential pathogens and lower levels of butyrate-producing bacteria were also detected in UC patients with active disease. Linear discriminant analysis Effect Size (LefSe) revealed that 71 bacterial taxa could serve as biomarkers, with 26 biomarkers at the genus level. In addition, network analysis showed that there was a positive correlation between Roseburia and Lachnospira. Functional predictions indicated that gene functions involving the metabolism of some substances, such as methane, lipopolysaccharide, geraniol, and ansamycins, were significantly different among the three groups.ConclusionThe richness and diversity of the intestinal microbiota differed significantly among the three groups. Richness describes the state of being rich in number of intestinal bacteria, whereas diversity is the number of different species of intestinal bacteria. Different bacterial taxa could be used as biomarkers, expanding our understanding of the relationship between the intestinal microbiota microenvironment and UC in the future.

Project description:BackgroundUlcerative colitis (UC) is a relapsing nontransmural inflammatory disease that is restricted to the colon and is characterized by flare-ups of bloody diarrhea. In this study, we aimed to investigate intestinal bacterial diversity in healthy controls and patients with UC with and without active disease, from Ghana and Denmark.MethodsThe study included 18 UC patients (9 with active and 9 with inactive disease) and 18 healthy controls from Ghana. In addition 16 UC patients from Denmark (8 UC with active and 8 UC with inactive disease) and 19 healthy controls from Denmark. Microbiota diversity analysis relied on sequencing of ribosomal small subunit genes. Purified genomic DNA was submitted to PCR using a primer set targeting prokaryotes and eukaryotes. The purified DNA was sequenced on the Illumina MiSeq system in a 2 × 250 bp set up (Illumina, San Diego, CA, USA). Blinded analysis of the taxonomy table was performed using BioNumerics-7.5 (Applied Maths NV, Sint-Martens-Latem, Belgium).ResultsWhen analyzing the taxonomy data for prokaryotes, cluster and principal component analysis shows Danish healthy controls clustered together, but separate from healthy controls from Ghana, which also clustered together. The Shannon diversity index (SDI) for prokaryotes shows significant differences between Danish healthy controls and patients in comparison with the corresponding groups from Ghana (p = 0.0056). Significant increased abundance of Escherichia coli was detected in healthy controls from Ghana in comparison with healthy controls from Denmark. The SDI of the prokaryotes ranges between 0 and 3.1 in the Ghana study groups, while in the Danish study groups it ranges between 1.4 and 3.2, the difference is however not significant (p = 0.138). Our data show a significant increased abundance of eukaryotes species in the healthy control group from Ghana and Denmark in comparison with patient groups from Ghana and Denmark.ConclusionOverall, healthy controls and patients with UC from Denmark have increased diversity of prokaryotes. Healthy controls from Denmark and Ghana have increased abundance of eukaryotes in comparison with UC patient groups from Denmark and Ghana.

Project description:Nuciferine, a major aporphine alkaloid obtained from the leaves of Nelumbo nucifera, exhibits anti-cancer and anti-inflammatory properties; however, its protective effects against inflammatory bowel diseases (IBD) has never been explored. In this study, an ulcerative colitis (UC) model was established in BALb/c mice by the continuous administration of 5% dextran sulfate sodium (DSS) in drinking water for 1 week. From day 8 to day 14, the DSS-treated mice were divided into a high-dose and a low-dose nuciferine treatment group and were intraperitoneally injected with the corresponding dose of the drug. Body weight loss, disease activity index (DAI), and colon length were measured. Histological changes were observed using hematoxylin and eosin staining. T lymphocyte proliferation was assessed by MTT assay. The ratio of CD3+, CD4+, CD8+, Th1, Th2, Th17, and Treg cells were estimated by flow cytometry. Finally, 16S rRNA sequencing was performed to compare the composition and relative abundance of the gut microbiota among the different treatment groups. The results showed that nuciferine treatment led to a significant improvement in symptoms, such as histological injury and colon shortening in mice with DSS-induced UC. Nuciferine treatment improved the Th1/Th2 and Treg/Th17 balance in the DSS-induced IBD model, as well as the composition of the intestinal microflora. At the phylum level, compared with the control group, the abundance of Firmicutes and Actinobacteriota was decreased in the model group, whereas that of Bacteroidetes increased. Meanwhile, at the genus level, compared with the control group, the numbers of the genera Lachnospiraceae_Clostridium, Bilophila and Halomonas reduced in the model group, while those of Bacteroides, Parabacteroides, and Paraprevotella increased. Notably, nuciferine administration reversed this DSS-induced gut dysbiosis. These results indicated that nuciferine modulates gut microbiota homeostasis and immune function in mice with DSS-induced UC.

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Ursolic Acid Regulates Intestinal Microbiota and Inflammatory Cell Infiltration to Prevent Ulcerative Colitis.

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