P852 A metabolomics approach to discover biomarkers of chronic intestinal inflammation associated with gut microbiota dysbiosis in ulcerative colitis and Celiac Disease

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.

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Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism

Microbiome ◽

10.1186/s40168-021-01191-x ◽

2022 ◽

Vol 10 (1) ◽

Author(s):

Jae-Geun Lee ◽

Soohyun Lee ◽

Juhee Jeon ◽

Hyun Gi Kong ◽

Hyun-Ju Cho ◽

...

Keyword(s):

Sialic Acid ◽

Gut Microbiota ◽

High Performance ◽

Intestinal Inflammation ◽

Neutrophil Infiltration ◽

Amplicon Sequencing ◽

16S Rrna Amplicon Sequencing ◽

Chronic Intestinal Inflammation ◽

Gut Microbiota Dysbiosis

Abstract Background Host tp53 mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. Results We found that zebrafish tp53 mutant larvae exhibited elevated intestinal inflammation, by monitoring the NFκB activity in the mid-distal intestines of zebrafish larvae using an NFκB:EGFP transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis, Aeromonas spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in tp53 mutants. Importantly, the ex-germfree experiments supported the causality of the host tp53 mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. Conclusions These results demonstrate a crucial role for host tp53 in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a tp53 mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for tp53 mutation-induced dysbiosis, inflammation, and ultimately, related cancers.

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Downregulation of CPI-17 contributes to dysfunctional motility in chronic intestinal inflammation model mice and ulcerative colitis patients

Journal of Gastroenterology ◽

10.1007/s00535-008-2241-2 ◽

2008 ◽

Vol 43 (11) ◽

pp. 858-865 ◽

Cited By ~ 23

Author(s):

Takashi Ohama ◽

Masatoshi Hori ◽

Masahiko Fujisawa ◽

Masaharu Kiyosue ◽

Masaki Hashimoto ◽

...

Keyword(s):

Ulcerative Colitis ◽

Intestinal Inflammation ◽

Inflammation Model ◽

Chronic Intestinal Inflammation

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Desmethylbellidifolin Attenuates Dextran Sulfate Sodium-Induced Colitis: Impact on Intestinal Barrier, Intestinal Inflammation and Gut Microbiota

Planta Medica ◽

10.1055/a-1506-3476 ◽

2021 ◽

Author(s):

Jiaqi Wu ◽

Yuzheng Wu ◽

Yue Chen ◽

Mengyang Liu ◽

Haiyang Yu ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Inflammation ◽

Activity Index ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Function Evaluation ◽

Biological Drugs

AbstractUlcerative colitis has been recognized as a chronic inflammatory disease predominantly disturbing the colon and rectum. Clinically, the aminosalicylates, steroids, immunosuppressants, and biological drugs are generally used for the treatment of ulcerative colitis at different stages of disease progression. However, the therapeutic efficacy of these drugs does not satisfy the patients due to the frequent drug resistance. Herein, we reported the anti-ulcerative colitis activity of desmethylbellidifolin, a xanthone isolated from Gentianella acuta, in dextran sulfate sodium-induced colitis in mice. C57BL/6 mice were treated with 2% dextran sulfate sodium in drinking water to induce acute colitis. Desmethylbellidifolin or balsalazide sodium was orally administrated once a day. Biological samples were collected for immunohistological analysis, intestinal barrier function evaluation, cytokine measurement, and gut microbiota analysis. The results revealed that desmethylbellidifolin alleviated colon shortening and body weight loss in dextran sulfate sodium-induced mice. The disease activity index was also lowered by desmethylbellidifolin after 9 days of treatment. Furthermore, desmethylbellidifolin remarkably ameliorated colonic inflammation through suppressing the expression of interleukin-6 and tumor necrosis factor-α. The intestinal epithelial barrier was strengthened by desmethylbellidifolin through increasing levels of occludin, ZO-1, and claudins. In addition, desmethylbellidifolin modulated the gut dysbiosis induced by dextran sulfate sodium. These findings suggested that desmethylbellidifolin effectively improved experimental ulcerative colitis, at least partly, through maintaining intestinal barrier integrity, inhibiting proinflammatory cytokines, and modulating dysregulated gut microbiota.

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Susceptibility to Ulcerative Colitis and Genetic Polymorphisms of A251G SOD1 and C-262T CAT

Journal of Medical Biochemistry ◽

10.1515/jomb-2016-0002 ◽

2016 ◽

Vol 35 (3) ◽

pp. 333-336 ◽

Cited By ~ 5

Author(s):

Gadier El-Kheshen ◽

Maryam Moeini ◽

Mostafa Saadat

Keyword(s):

Ulcerative Colitis ◽

Statistical Analysis ◽

Genetic Polymorphisms ◽

Intestinal Inflammation ◽

Reactive Oxygen ◽

Protective Role ◽

Reactive Oxygen Metabolites ◽

Age And Gender ◽

And Gender ◽

Chronic Intestinal Inflammation

SummaryBackground: Reactive oxygen species can attack and damage almost every molecule found in living cells, including proteins, carbohydrates, lipids, and DNA. For this reason, their production is normally tightly controlled. Among the most important defenses against these radicals are the super oxide dismutase (SOD) enzymes and catalase (CAT). In creasing attention has been given to the role of reactive oxygen metabolites in the pathogenesis of ulcerative colitis (UC), which is defined as an idiopathic and chronic intestinal inflammation. Accordingly, we hypothesized a relation between genetic polymorphisms in the two antioxidant enzymes SOD1 A251G (rs2070424) and CAT C-262T (rs1001179) and the risk of UC.Methods: The present case-control study included 109 UC patients (46 males and 50 females) and 186 (67 males and 119 females) gender-matched healthy controls. Genotyping was done by the PCR-RFLP method.Results: After adjusting for age and gender, a significant association was observed between the AG+GG genotypes of SOD1 A251G polymorphism (vs. AA genotype) and risk of UC (OR=0.29, 95% CI: 0.10-0.86, P= 0.025) after adjusting for age and gender. Our statistical analysis revealed that the CAT C-262T polymorphism did not associate with the risk of UC before and/or after adjusting for age and gender.Conclusions: Based on the present statistical analysis, the G allele of the SOD1 A251G polymorphism decreases the risk of UC, thus it might be assumed that the G allele has a protective role.

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Protective effect and mechanism of Monascus-fermented red yeast rice against colitis caused by Salmonella enterica serotype Typhimurium ATCC 14028

Food & Function ◽

10.1039/d0fo01017k ◽

2020 ◽

Vol 11 (7) ◽

pp. 6363-6375

Author(s):

Ya-ping Huang ◽

Ping Li ◽

Ting Du ◽

Xin-jun Du ◽

Shuo Wang

Keyword(s):

Gut Microbiota ◽

Protective Effect ◽

Salmonella Enterica ◽

Intestinal Inflammation ◽

Underlying Mechanism ◽

Red Yeast Rice ◽

Red Yeast ◽

Gut Microbiota Dysbiosis

The effect of red yeast rice on Salmonella enterica-induced intestinal inflammation and gut microbiota dysbiosis in mice as well as the underlying mechanism.

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Study on the mechanism of Indigo naturalis and its two main compounds (indigo and indirubin) in the treatment of ulcerative colitis based on TLR4/MyD88/NF-κB pathway and intestinal microorganisms

10.21203/rs.3.rs-31454/v1 ◽

2020 ◽

Author(s):

Qi-yue Yang ◽

Ya-nan He ◽

Le-le Ma ◽

Run-chun Xu ◽

Nan Li ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Activity Index ◽

Disease Activity Index ◽

Pathological Section ◽

Inflammatory Cytokine Production ◽

Tnf Α ◽

Indigo Naturalis ◽

Inflammation Cytokines

Abstract Background: Indigo naturalis is a natural dye extracted from plants and has a good anti-inflammatory effect. Clinical studies have shown that it can improve ulcerative colitis (UC), but the active constituents and the mechanism are unclear. Methods: The anti-UC activity of Indigo naturalis and its two main compounds (indigo and indirubin) were investigated in dextran sulfate sodium (DSS)-induced UC mice. Indigo naturalis, indigo and indirubin were administrated to DSS-induced UC rats by oral gavage for 1 weeks. The anti-UC effect was evaluated by pathological section, inflammatory cytokine production, western blotting, and gut microbiota analysis via 16S rRNA sequencing. Results: Indigo naturalis, indigo and indirubin can improve the UC induced by DSS. Their effect intensity is Indigo naturalis > indirubin > indigo based on disease activity index, body weight, colon length and pathological section. Indigo naturalis, indigo and indirubin also decrease the expression of NF-κB，TLR4 and MYD88 proteins, thus reducing the level of related inflammation cytokines (IL-1β, IL-6 and TNF-α) both in serum and tissue. In addition, Indigo naturalis and indigo improved symptoms of gut microbial disturbance, and decreased Firmicutes/Bacteroidetes ratio and the significantly increased probiotics such as Lactobacillus. Indirubin has little effect on the regulation of gut microbial. Conclusions: Indigo naturalis could attenuate the DSS-induced UC in mice, by means of ameliorating intestinal inflammation, improving intestinal mucosa, and regulating the disturbed gut microbiota. Indigo and indirubin could also attenuate the DSS-induced UC in mice, but their comprehensive effect is not as good as Indigo naturalis.

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Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation

Science Translational Medicine ◽

10.1126/scitranslmed.aba0624 ◽

2020 ◽

Vol 12 (566) ◽

pp. eaba0624 ◽

Cited By ~ 3

Author(s):

Bruno Lamas ◽

Leticia Hernandez-Galan ◽

Heather J. Galipeau ◽

Marco Constante ◽

Alexandra Clarizio ◽

...

Keyword(s):

Celiac Disease ◽

Gut Microbiota ◽

Aryl Hydrocarbon Receptor ◽

Intestinal Inflammation ◽

Susceptibility Gene ◽

Rrna Gene ◽

Microbiota Composition ◽

Aryl Hydrocarbon ◽

Pathway Activation ◽

Gut Microbiota Composition

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene. NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with Lactobacillus reuteri that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16S rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers. In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer L. reuteri, or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten. We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals. Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation. These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.

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High-Fat Diet Promotes DSS-Induced Ulcerative Colitis by Downregulated FXR Expression through the TGFB Pathway

BioMed Research International ◽

10.1155/2020/3516128 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Di Zhao ◽

Chenwen Cai ◽

Qiyi Chen ◽

Shuang Jin ◽

Bo Yang ◽

...

Keyword(s):

Ulcerative Colitis ◽

High Fat Diet ◽

Target Genes ◽

Intestinal Inflammation ◽

Farnesoid X Receptor ◽

Mucosal Barrier ◽

High Fat ◽

Colon Rectal Cancer ◽

Chronic Intestinal Inflammation

Ulcerative colitis is one of the IBD which cause a chronic intestinal inflammation and dysfunctional of the mucosal barrier. For now, the incident of UC was steadily increased all over the world. It has become a novel independent risk factor of several severe diseases especially colon-rectal cancer. However, the etiology of UC was still obscure. Previous studies show that high-fat diet contributed to the pathogenesis of immune system dysregulation, and farnesoid X receptor (FXR) was also implicated in the pathogenesis of various inflammatory symptoms. Yet, their inner roles in the pathogenesis of UC have not been mentioned. In this study, we aim to investigate the role of FXR in UC. High-fat diet (HFD) promotes the progression of DSS-induced UC, shows an increasing secretion of bile acid in serum, and leads to a downregulation of FXR target genes (FXRα, Shp, and lbabp). Adding FXR agonist FexD rescues the phenotype induced by high-fat diet, whereas TGFBRI inhibitor SB431542 abrogates the restoration by FexD in DSS-induced UC mice. To further verify the relationship between the FXR and TGFB signaling pathway, we made a UC-HFD model in the Caco2 cell line. Results shows the same conclusion that FXR mitigate UC inflammation through a TGFB-dependent pathway. These results expand the role of FXR in ulcerative colitis and suggest that FXR activation may be considered a therapeutic strategy for UC.

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