scholarly journals A gene expression map of colon tissue in ulcerative colitis: new methods rewrite old stories

Biotarget ◽  
2020 ◽  
Vol 4 ◽  
pp. 2-2
Author(s):  
Panagiotis Skendros ◽  
Vasileios Papadopoulos ◽  
Konstantinos Ritis
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Colon Tissue ◽  
New Methods

scholarly journals P034 GB004, a novel gut-targeted prolyl hydroxylase inhibitor, induces HIF-1α target genes and is efficacious in mouse colitis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S148-S149
Author(s):  
K Taylor Meadows ◽  
M Kennedy ◽  
Z Naiman ◽  
M Sergeeva ◽  
B Paulson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Target Genes ◽  
Plasma Concentrations ◽  
Prolyl Hydroxylase ◽  
Target Engagement ◽  
Colon Tissue ◽  
Oral Dosing ◽  
Prolyl Hydroxylase Inhibitor ◽  
Compound Exposure

Abstract Background GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilises hypoxia inducible factor (HIF-α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-α stabilisation. GB004 is in clinical development for the treatment of ulcerative colitis. Methods Female wild-type C57BL/6 and immunodeficient B6.129S6-Rag2tm1FwaN12 ko/ko mice (Rag2) mice received either a single oral dose of GB004 or daily oral dosing for 7 days. Colitis was induced by administering 100 µg of anti-CD40 monoclonal antibody interperitoneally in Rag2 mice. GB004 oral dosing started on day 0 and continued once daily for 7 days. Body weight was measured daily. At termination, plasma was isolated for compound exposure and colons were excised, measured and weighed. Colon tissue was preserved in formalin for histology and 1 cm colon sections were snap-frozen for compound exposure and preserved with RNA for gene expression. Results A single oral administration or 7 days dosing of 10 mg/kg GB004 in healthy mice resulted in significantly higher exposure in the gastrointestinal tract (GI) (pylorus, duodenum, ileum and colon) than in plasma with colon to plasma ratio of ≥500. Target engagement in colon was demonstrated by induction of HIF-dependent genes (HIF1A), epithelial barrier genes (AKAP12, TFF3, NT5E) and anti-apoptotic genes (BNIP3). In colitis mice, GB004 plasma exposure was elevated compared with plasma concentrations in healthy mice, even so, GB004 exposure was still higher in the colon than plasma at a ratio of 90. Target engagement was demonstrated by an increase in NT5E, CLND1, BNIP3 and CA9 and a reduction in IL12B. In colitis mice, 1, 3 and 10 mg/kg GB004 demonstrated a dose-dependent reduction in colon inflammation and gland loss and 10 mg/kg GB004 showed a significant reduction in neutrophil score. Gene expression 4 h after the final GB004 dose demonstrated an increase in barrier genes AKAP12 and CLDN1 and a decrease in IL12B. Conclusion These studies demonstrate that oral GB004 has significantly higher exposure in the GI tract than in the plasma and induces HIF-1α-dependent genes in colon. In mouse colitis, GB004 has high colon exposure, induces target genes involved in barrier function and repair and demonstrates efficacy by reducing inflammation, gland loss and neutrophil inflammation. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, PK and PD both systemically and in colon (NCT03860896). Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

scholarly journals Effect of a Milk-Based Fruit Beverage Enriched with Plant Sterols and/or Galactooligosaccharides in a Murine Chronic Colitis Model

Foods ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 114 ◽  
Author(s):  
Gabriel López-García ◽  
Antonio Cilla ◽  
Reyes Barberá ◽  
Amparo Alegría ◽  
María Recio
Keyword(s):  
Ulcerative Colitis ◽  
Experimental Colitis ◽  
Plant Sterols ◽  
Mice Model ◽  
Colon Tissue ◽  
Clinical Model ◽  
Need To Evaluate ◽  
Anti Inflammatory ◽  
Enriched Milk ◽  
Inflammatory Effect

The potential anti-inflammatory effect of plant sterols (PS) enriched milk-based fruit beverages (PS, 1 g/100 mL) (MfB) with/without galactooligosaccharides (GOS, 2 g/100 mL) (MfB-G) in an experimental mice model of chronic ulcerative colitis was evaluated. Beverages were orally administered to mice every day by gavage to achieve PS and GOS doses of 35 and 90 mg/kg, respectively, and experimental colitis was induced by giving mice drinking water ad libitum containing 2% (w/v) dextran sulphate sodium (DSS) for 7 days, alternating with periods without DSS up to the end of the study (56 days). MfB beverage showed significant reduction of symptoms associated to ulcerative colitis and improved the colon shortening and mucosal colonic damage, but it was not able to reduce the increase of myeloperoxidase levels produced by DSS. MfB-G showed higher incidence of bloody feces and loss of stool consistency than MfB, as well as high levels of immune cells infiltration in colon tissue and myeloperoxidase. Therefore, PS-enriched milk-based fruit beverage could be an interesting healthy food to extend the remission periods of the diseases and the need to evaluate, in a pre-clinical model, the anti-inflammatory effect of the combination of bioactive compounds in the context of a whole food matrix.

scholarly journals Prebiotic Galactooligosaccharide Supplementation in Adults with Ulcerative Colitis: Exploring the Impact on Peripheral Blood Gene Expression, Gut Microbiota, and Clinical Symptoms

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3598
Author(s):  
Bridgette Wilson ◽  
Özge Eyice ◽  
Ioannis Koumoutsos ◽  
Miranda C. Lomer ◽  
Peter M. Irving ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Rating Scale ◽  
Activity Index ◽  
Fecal Calprotectin ◽  
Controlled Study ◽  
Gas Liquid Chromatography ◽  
Clinical Scores ◽  
Gastrointestinal Symptom Rating Scale ◽  
The Impact

Prebiotics may promote immune homeostasis and reduce sub-clinical inflammation in humans. This study investigated the effect of prebiotic galactooligosaccharide (GOS) supplementation in colonic inflammation. Seventeen patients with active ulcerative colitis (UC) consumed 2.8 g/d GOS for 6 weeks. At baseline and 6 weeks, gene expression (microarray), fecal calprotectin (ELISA), microbiota (16S rRNA), short-chain fatty acids (SCFAs; gas-liquid chromatography), and clinical outcomes (simple clinical colitis activity index (SCCAI), gastrointestinal symptom rating scale (GSRS), and Bristol stool form scale (BSFS)) were measured. Following prebiotics, clinical scores (SCCAI), fecal calprotectin, SCFAs, and pH were unchanged. Five genes were upregulated and two downregulated. Normal stool proportion (BSFS) increased (49% vs. 70%, p = 0.024), and the incidence (46% vs. 23%, p = 0.016) and severity (0.7 vs. 0.5, p = 0.048) of loose stool (GSRS), along with urgency (SCCAI) scores (1.0 vs. 0.5, p = 0.011), were reduced. In patients with a baseline SCCAI ≤2, prebiotics increased the relative abundance of Bifidobacterium from 1.65% (1.97) to 3.99% (5.37) (p = 0.046) and Christensenellaceae from 0.13% (0.33) to 0.31% (0.76) (p = 0.043). Prebiotics did not lower clinical scores or inflammation but normalized stools. Bifidobacterium and Christensenellaceae proportions only increased in patients with less active diseases, indicating that the prebiotic effect may depend on disease activity. A controlled study is required to validate these observations.

Effect of Huangqin Decoction on Improving the Mouse Model of Ulcerative Colitis by Inhibiting NF-κB p65 Signal Pathway

2021 ◽  
Vol 11 (7) ◽  
pp. 1394-1399
Author(s):  
Yinyu Wang ◽  
Chenxi Zheng ◽  
Ningning Cheng ◽  
Cong Sun
Keyword(s):  
Ulcerative Colitis ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Nuclear Factor ◽  
Histopathological Changes ◽  
Colon Tissue ◽  
Chinese Medicinal Herb ◽  
Western Blots ◽  
Natural Medicine ◽  
New Strategy

Natural medicine, such as traditional Chinese medicine, plays a role in treating ulcerative colitis (UC) because of its action on multiple targets. Here we have improved the effectiveness of a traditional Chinese medicinal herb, Huangqin decoction (HQD), on UC via the nuclear factor-κB (NF-κB) p65 signaling pathway in a mouse model. NF-κB is a crucial regulator of inflammation, cancer, and autoimmunity. It may be related to the initiation and development of UC. Histopathological changes in colon show that Huangqin Decoction can improve colon tissue environment In addition, the Western blots of the inflammatory cytokines related to the NF-κB p65 pathway suggest that HQD inhibits the development of UC by regulating the NF-κB p65 signaling pathway. These findings provide a basis for the clinical application of HQD and suggest a new strategy for treating UC in the future.

scholarly journals The Anti-inflammatory Immune Regulation Induced by Butyrate Is Impaired in Inflamed Intestinal Mucosa from Patients with Ulcerative Colitis

Inflammation ◽  
2019 ◽  
Vol 43 (2) ◽  
pp. 507-517 ◽  
Author(s):  
Maria K. Magnusson ◽  
Stefan Isaksson ◽  
Lena Öhman
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Principal Component ◽  
Short Chain Fatty Acids ◽  
Immune Profile ◽  
Mrna Gene ◽  
Discriminant Analyses ◽  
Anti Inflammatory ◽  
Mrna Gene Expression ◽  
Gut Microbiota Composition

Abstract Altered gut microbiota composition and reduced levels of short-chain fatty acids, such as butyrate, have been identified as key components of ulcerative colitis (UC). We aimed to determine and compare effects of butyrate on the intestinal immune profile of UC patients with active disease and non-inflamed controls. Biopsies were cultivated during 6 h with or without butyrate. Cytokines were measured in supernatants and mRNA gene expression was analyzed in biopsies using Qiagen RT2 Profiler PCR Arrays. The intestinal immune profile of cultured biopsies, as determined by mRNA gene expression and secreted cytokines, differed between inflamed UC samples and controls. Principal component analysis revealed that addition of butyrate differently regulated mRNA expression in inflamed biopsies from UC and non-inflamed biopsies from controls. Highly discriminant and predictive orthogonal partial least squares discriminant analyses identified 29 genes for UC (R2 = 0.94, Q2 = 0.86) and 23 genes for controls (R2 = 0.90, Q2 = 0.71) that were most regulated by butyrate. UC displayed more up-regulation of genes as compared with controls, and controls displayed the most prominent down-regulations. Ingenuity Pathway Analysis identified a down regulation of the Neuroinflammation Signaling pathway and predicted inhibition of the categories Inflammatory response, cellular movement, and cellular development as top diseases and functions, respectively, for controls but not for UC. In conclusion, butyrate has a different effect on gene regulation and more potently down-regulates gene expression of inflammatory pathways in non-inflamed controls than in inflamed tissue of UC patients. These discrepancies may at least partly explain why anticipated anti-inflammatory effects of local butyrate induction or supplementation are not always obtained.

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