Galanin receptor 3 attenuates inflammation and influences the gut microbiota in an experimental murine colitis model

AbstractThe regulatory (neuro)peptide galanin and its three receptors (GAL1–3R) are involved in immunity and inflammation. Galanin alleviated inflammatory bowel disease (IBD) in rats. However, studies on the galanin receptors involved are lacking. We aimed to determine galanin receptor expression in IBD patients and to evaluate if GAL2R and GAL3R contribute to murine colitis. Immunohistochemical analysis revealed that granulocytes in colon specimens of IBD patients (Crohn’s disease and ulcerative colitis) expressed GAL2R and GAL3R but not GAL1R. After colitis induction with 2% dextran sulfate sodium (DSS) for 7 days, mice lacking GAL3R (GAL3R-KO) lost more body weight, exhibited more severe colonic inflammation and aggravated histologic damage, with increased infiltration of neutrophils compared to wild-type animals. Loss of GAL3R resulted in higher local and systemic inflammatory cytokine/chemokine levels. Remarkably, colitis-associated changes to the intestinal microbiota, as assessed by quantitative culture-independent techniques, were most pronounced in GAL3R-KO mice, characterized by elevated numbers of enterobacteria and bifidobacteria. In contrast, GAL2R deletion did not influence the course of colitis. In conclusion, granulocyte GAL2R and GAL3R expression is related to IBD activity in humans, and DSS-induced colitis in mice is strongly affected by GAL3R loss. Consequently, GAL3R poses a novel therapeutic target for IBD.

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Protective Effect ofLaminaria japonicawith Probiotics on Murine Colitis

Mediators of Inflammation ◽

10.1155/2014/417814 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Seok-Jae Ko ◽

Youngmin Bu ◽

Jinhyun Bae ◽

Yu-mi Bang ◽

Jinsung Kim ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Laminaria Japonica ◽

Therapeutic Effects ◽

Inflammatory Disorder ◽

Simultaneous Administration ◽

Edible Seaweed ◽

Murine Colitis ◽

Histological Score ◽

Inflammatory Bowel ◽

Colitis Model

Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disorder of the gastrointestinal tract. Most IBD treatments are unsatisfactory; therefore, various dietary supplements have emerged as promising interventions.Laminaria japonica(LJ) is an edible seaweed used to regulate digestive symptoms. Probiotics have been reported to improve digestive problems and their simultaneous administration with seaweeds has been shown to produce synergistic therapeutic effects. Here, we investigated the effect of LJ combination with probiotics on dextran sodium sulfate-induced colitis model in mice. Aqueous LJ extracts (LJE) at doses from 100 to 300 mg/kg and probiotics at a dose of 300 mg/kg were orally administered for 7 days. Body weight, colon length, histological score, macroscopic damage, and the levels of cytokines IFN-γ, IL-1β, IL-6, IL-10, IL-12 (P40), IL-12 (P70), IL-17, and TNF-αwere assessed. LJE alone caused a significant improvement of colitis signs such as colon length, histological score, and IL-1βand IL-6 production. LJE and probiotics demonstrated a synergistic effect by the histological score and levels of IL-1β, IL-6, and IL-12 (P40) but not IFN-γ, IL-10, and IL-12 (P70). In conclusion, LJE was effective in inducing protection against colitis in mice and acted synergistically with probiotics.

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Molecular and Microbial Signatures Predictive of Prebiotic Action of Neoagarotetraose in a Dextran Sulfate Sodium-Induced Murine Colitis Model

Microorganisms ◽

10.3390/microorganisms8070995 ◽

2020 ◽

Vol 8 (7) ◽

pp. 995

Author(s):

Fang Liu ◽

Jianan Liu ◽

Thomas T.Y. Wang ◽

Zhen Liu ◽

Changhu Xue ◽

...

Keyword(s):

Gut Microbiome ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Inflammation ◽

16S Rrna Gene Sequencing ◽

Rrna Gene ◽

Murine Colitis ◽

Bioactive Properties ◽

Rrna Gene Sequencing ◽

Colitis Model

Neoagarotetraose (NT), a hydrolytic product of agar by β-agarase, is known to possess bioactive properties. However, the mechanisms via which NT alleviates intestinal inflammation remain unknown. In this study, a dextran sulfate sodium (DSS)-induced murine model was developed to evaluate the effect of NT on gut microbiome and microbial metabolism using 16S rRNA gene sequencing and untargeted metabolomics. Our data demonstrate that NT ingestion improved gut integrity and inflammation scores. NT reversed the abundance of Proteobacteria from an elevated level induced by DSS and significantly increased the abundance of Verrucomicrobia. Further, NT significantly increased the abundance of Akkermansia and Lactobacillus and concomitantly decreased that of Sutterella, which were among the important features identified by random forests analysis contributing to classification accuracy for NT supplementation. A microbial signature consisting of Adlercreutzia (denominator) and Turicibacter (numerator) predicted the NT supplementation status. Moreover, NT significantly modulated multiple gut metabolites, particularly those related to histidine, polyamine and tocopherol metabolism. Together, our findings provided novel insights into the mechanisms by which NT modulated the gut microbiome and metabolome and should facilitate the development of NT as a potent prebiotic for colitis management.

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The ameliorative effect of a Lactobacillus strain with good adhesion ability against dextran sulfate sodium-induced murine colitis

Food & Function ◽

10.1039/c8fo01453a ◽

2019 ◽

Vol 10 (1) ◽

pp. 397-409 ◽

Cited By ~ 9

Author(s):

Guangqiang Wang ◽

Yingnan Liu ◽

Zhi Lu ◽

Yiting Yang ◽

Yongjun Xia ◽

...

Keyword(s):

Ulcerative Colitis ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Good Adhesion ◽

Disease Symptoms ◽

Murine Colitis ◽

Adhesion Ability ◽

Ameliorative Effect ◽

Excellent Adhesion ◽

Colitis Model

The objective of this study was to effectively screen out a Lactobacillus strain with excellent adhesion ability and ameliorative effect on the disease symptoms of a murine ulcerative colitis model.

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Novel Histone Deacetylase 6 Inhibitor CKD-506 Inhibits NF-κB Signaling in Intestinal Epithelial Cells and Macrophages and Ameliorates Acute and Chronic Murine Colitis

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz317 ◽

2020 ◽

Vol 26 (6) ◽

pp. 852-862 ◽

Cited By ~ 5

Author(s):

Jung Won Lee ◽

Soung-Min Lee ◽

Jaeyoung Chun ◽

Jong Pil Im ◽

Su-Kil Seo ◽

...

Keyword(s):

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Histone Deacetylase 6 ◽

Chronic Colitis ◽

Acute Colitis ◽

Murine Colitis ◽

Tnf Α ◽

Inflammatory Bowel ◽

Iκbα Phosphorylation ◽

Colitis Model

Abstract Background Selective blocking of HDAC6 has become a promising strategy in treating inflammatory bowel disease. CKD-506 is a novel isoform-selective inhibitor of histone deacetylase 6. The present study was performed to evaluate the effect of CKD-506 on the NF-κB signaling pathway in intestinal epithelial cells (IECs) and macrophages and on murine models of acute and chronic colitis. Methods RAW264RAW264.7 murine macrophages and COLO 205 human IECs were pretreated with CKD-506 and then stimulated with lipopolysaccharides (LPS). Cytokine expression of TNF-α, interleukin (IL)-6, IL-8, and IL-10 was measured by ELISA. The effect of CKD-506 on NF-κB signaling was evaluated by Western blotting of IκBα phosphorylation/degradation and electrophoretic mobility shift assay. In vivo studies were performed using a dextran sulfate sodium (DSS)–induced acute colitis model, a chronic colitis model in IL-10 knockout mice, and an adoptive transfer model. Colitis was quantified by the disease activity index, colon length, and histopathologic evaluation. Results CKD-506 suppressed the expression of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α in IECs and macrophages. CKD-506 strongly inhibited IκBα phosphorylation/degradation and the DNA-binding activity of NF-κB. Oral administration of CKD-506 attenuated DSS-induced acute colitis and chronic colitis in IL-10-/- and adoptive transfer models. CKD-506 ameliorated weight loss, disease activity, and histopathologic score in colitis mice and downregulated IκBα phosphorylation and pro-inflammatory cytokine production significantly. Conclusions CKD-506 blocked NF-κB signaling in IECs and macrophages and ameliorated experimental acute and chronic murine colitis models, which suggests that CKD-506 is a promising candidate for inflammatory bowel disease treatment as a small molecular medicine.

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Probiotic Lactobacillus spp. Diminish Helicobacter hepaticus-Induced Inflammatory Bowel Disease in Interleukin-10-Deficient Mice

Infection and Immunity ◽

10.1128/iai.73.2.912-920.2005 ◽

2005 ◽

Vol 73 (2) ◽

pp. 912-920 ◽

Cited By ~ 99

Author(s):

Jeremy A. Peña ◽

Arlin B. Rogers ◽

Zhongming Ge ◽

Vivian Ng ◽

Sandra Y. Li ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Real Time ◽

Bowel Disease ◽

Interleukin 10 ◽

Helicobacter Hepaticus ◽

Murine Colitis ◽

Tnf Α ◽

Inflammatory Bowel ◽

Deficient Mice ◽

Colitis Model

ABSTRACT Clinical and experimental evidence has demonstrated the potential role of probiotics in the prevention or treatment of inflammatory bowel disease. Probiotic clones with direct immunomodulatory activity may have anti-inflammatory effects in the intestine. We investigated the roles of tumor necrosis factor alpha (TNF-α)-inhibitory Lactobacillus clones with a pathogen-induced murine colitis model. Murine-derived probiotic lactobacilli were selected in vitro for their ability to inhibit TNF-α secretion by Helicobacter hepaticus-stimulated macrophages. Interleukin-10 (IL-10)-deficient mice were treated with probiotic Lactobacillus reuteri in combination with Lactobacillus paracasei and then challenged with H. hepaticus. Ten weeks postinoculation, the severity of typhlocolitis was assessed by histologic examination of the cecocolic region. Intestinal proinflammatory cytokine responses were evaluated by real-time quantitative reverse transcriptase PCR and immunoassays, and the quantities of intestinal H. hepaticus were evaluated by real-time PCR. Intestinal colonization by TNF-α-inhibitory lactobacilli reduced intestinal inflammation in H. hepaticus-challenged IL-10-deficient mice despite similar quantities of H. hepaticus in cocolonized animals. Proinflammatory colonic cytokine (TNF-α and IL-12) levels were lowered in Lactobacillus-treated animals. In this H. hepaticus-challenged IL-10-deficient murine colitis model, lactobacilli demonstrated probiotic effects by direct modulation of mucosal inflammatory responses.

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Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

International Journal of Cell Biology ◽

10.1155/2015/745237 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Sean P. Kessler ◽

Dana R. Obery ◽

Carol de la Motte

Keyword(s):

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Experimental Colitis ◽

Hyaluronan Synthase ◽

Wild Type ◽

Colon Tissue ◽

Dss Colitis ◽

Chemically Induced ◽

Inflammatory Bowel ◽

Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

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A refined and translationally relevant model of chronic DSS colitis in BALB/c mice

Laboratory Animals ◽

10.1177/0023677217742681 ◽

2017 ◽

Vol 52 (3) ◽

pp. 240-252 ◽

Cited By ~ 9

Author(s):

Maximilian Hoffmann ◽

Ulla Schwertassek ◽

Aleksandra Seydel ◽

Klaus Weber ◽

Werner Falk ◽

...

Keyword(s):

Dextran Sulfate ◽

Significant Loss ◽

Refined Model ◽

Relevant Model ◽

Dss Colitis ◽

Clinical Scores ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Colitis Model ◽

Pro Inflammatory Cytokines

Inflammatory bowel diseases (IBD) are chronic relapsing disorders of the gastrointestinal tract. Several mouse models for IBD are available, but the acute dextran sulfate sodium (DSS)-induced colitis model is mostly used for preclinical studies. However, this model lacks chronicity and often leads to significant loss of mice. The aim of this study was to establish a refined and translationally relevant model of DSS chronic colitis in BALB/c mice. In the first part, we compared several standard therapeutic (ST) treatments for IBD in the acute DSS colitis model to identify the optimal treatment control for a DSS colitis model as compared to literature data. In the second part, we tested the two most effective ST treatments in a refined model of chronic DSS colitis. Cyclosporine A (CsA) and 6-thioguanine (6-TG) caused considerable reduction of clinical scores in acute DSS colitis. The clinical outcome was confirmed by the results for colon length and by histopathological evaluation. Moreover, CsA and 6-TG considerably reduced mRNA expression of several pro-inflammatory cytokines in spleen and colon. Both compounds also showed a substantial therapeutic effect in the refined model of chronic DSS colitis with regard to clinical scores and histopathology as well as the expression of inflammatory markers. The refined model of chronic DSS colitis reflects important features of IBD and is well suited to test potential IBD therapeutics.

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