scholarly journals Helicobacter hepaticus as disease driver in a novel CD40-mediated model of colitis

2020 ◽  
Author(s):  
Verena Friedrich ◽  
Ignasi Forne ◽  
Dana Matzek ◽  
Diana Ring ◽  
Bastian Popper ◽  
...  
Keyword(s):  
Specific Antigen ◽  
Disease Onset ◽  
Intestinal Bacteria ◽  
Th1 Cells ◽  
Bacterial Antigen ◽  
Helicobacter Hepaticus ◽  
Chaperonin Groel ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Colitis Model

ABSTRACTGut microbiota and the immune system are in constant exchange, which shapes both, host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40 – CD40L axis showed promising results as these molecules have been described to be deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals, which lack intestinal CD103+ dendritic cells (DCs) and therefore cannot induce regulatory T (iTreg) cells due to a constitutive CD40-signal in CD11c+ cells. These mice rapidly develop spontaneous fatal colitis with an increase of inflammatory IL-17+IFN-γ+ Th17/Th1 and IFN-γ+ Th1 cells. In the present study we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria and we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in absence of iTregs. When rederived to a different Hh-free SPF-microbiota, mice showed few signs of disease without fatalities, but upon recolonization of mice with Hh we found rapid disease onset and the generation of inflammatory Th17/Th1 and Th1 cells in the colon. Thus, the present work identifies a major bacterial antigen and highlights the impact of specific microorganisms on modulating the host immune response and its role on disease onset, progression and outcome in this colitis model.

A moderately elevated soy protein diet mitigates inflammatory changes in gut and in bone turnover during chronic TNBS-induced inflammatory bowel disease

2019 ◽  
Vol 44 (6) ◽  
pp. 595-605 ◽  
Author(s):  
Corinne E. Metzger ◽  
S. Anand Narayanan ◽  
David C. Zawieja ◽  
Susan A. Bloomfield
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bone Turnover ◽  
Soy Protein ◽  
Bowel Disease ◽  
Protein Diet ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
The Impact ◽  
Colitis Model

Inflammatory bowel disease is a condition that leads to gut pathologies such as abnormal lymphatic architecture, as well as to systemic comorbidities such as bone loss. Furthermore, current therapies are limited to low efficacy and incur side effects. Dietary interventions have been explored minimally, but may provide a treatment for improving gut outcomes and comorbidities. Indeed, plant-based soy protein has been shown to exert anti-inflammatory effects. Here, we tested the impact of a moderately elevated soy protein diet in a chronic, 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model on gut and bone inflammatory-mediated pathophysiological adaptations. Colitis was induced by intrarectal administration of TNBS. Gut histopathology was scored, and lymphatic structural changes and the local inflammatory state were assessed via immunofluorescence. In addition, the effects of gut inflammation on bone turnover and osteocyte proteins were determined via histomorphometry and immunohistochemistry, respectively. The moderately elevated soy protein diet produced improvements in both colonic and bone tissues. In TNBS animals given the soy protein intervention, colon histological scores were reduced and the abnormal lymphatic architecture resolved. There were also improvements in bone formation and reduced bone resorption. In addition, TNBS increased inflammatory cytokines such as tumor necrosis factor-α and receptor activator of nuclear factor κ-B ligand in the gut and bone, but this was resolved in both tissues with the dietary soy protein intervention. The moderately elevated soy protein diet mitigated gut and bone inflammation in a chronic, TNBS-induced colitis model, demonstrating the potential for soy protein as a potential anti-inflammatory dietary intervention for inflammatory bowel disease.

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

2005 ◽  
Vol 73 (2) ◽  
pp. 912-920 ◽  
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.

scholarly journals Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease

2022 ◽  
Author(s):  
James J Ashton ◽  
Konstantinos Boukas ◽  
Imogen S Stafford ◽  
Guo Cheng ◽  
Rachel Haggarty ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Signaling Pathway ◽  
Bowel Disease ◽  
Intestinal Bacteria ◽  
Genomic Variation ◽  
Gene Score ◽  
Diagnostic Endoscopy ◽  
Pediatric Inflammatory Bowel Disease ◽  
Inflammatory Bowel ◽  
The Impact

Abstract Background Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn’s disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription. Methods Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a “complex” score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription. Results Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (β = -0.702, P = 4.3 × 10-5) and increased NFKBIA (β = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (β = 0.8, P = 3.1475 × 10-8) and TXN (β = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (β = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (β = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients. Conclusions Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

The Impact of Alcohol in Inflammatory Bowel Diseases

2021 ◽  
Author(s):  
Bradley A White ◽  
Guilherme Piovezani Ramos ◽  
Sunanda Kane
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Intestinal Inflammation ◽  
Symptom Control ◽  
Disease Onset ◽  
Intestinal Barrier ◽  
Alcoholic Beverages ◽  
Mediated Effects ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
The Impact

Abstract Several environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD); however, the evidence for alcohol is sparse, as is its implications on disease activity and overall management. Here, we examine the available evidence for the effect of alcohol on IBD, including its association with the development of IBD, role in exacerbations, and potential medication interactions. Several mechanisms have been demonstrated to mediate the effects of ethanol in the gastrointestinal tract. Alcohol has been shown to alter the gut microbiome, disrupt intestinal barrier, and increase intestinal permeability, directly and indirectly promoting immune activation. Conversely, specific alcoholic beverages, notably red wine, may have anti-inflammatory properties capable of assisting in disease control and affecting disease monitoring. Nonetheless, most alcohol-mediated effects seem to facilitate intestinal inflammation and consequently impact disease onset, recurrence, and symptom control. Furthermore, alcohol use interferes with the metabolism of several medications leading to increased side effect profiles or even loss of effect. Notably, mesalamine, azathioprine, methotrexate, and biologic medications can all be affected by concomitant alcohol intake via a variety of mechanisms.

scholarly journals Oral iron exacerbates colitis and influences the intestinal microbiome

2018 ◽  
Author(s):  
Awad Mahalhal ◽  
Jonathan M. Williams ◽  
Sophie Johnson ◽  
Nicholas Ellaby ◽  
Carrie A. Duckworth ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Intestinal Bacteria ◽  
Oral Iron ◽  
Intestinal Microbiome ◽  
Dietary Iron ◽  
Faecal Calprotectin ◽  
Inflammatory Bowel ◽  
Ad Libitum ◽  
The Impact ◽  
Iron Replacement

AbstractInflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS.

scholarly journals Disease monitoring of biologic treatment in IBD: early impact and future implications of COVID-19 pandemic

2020 ◽  
pp. flgastro-2020-101563
Author(s):  
Stephanie Shields ◽  
Allan Dunlop ◽  
John Paul Seenan ◽  
Jonathan Macdonald
Keyword(s):  
Clinical Care ◽  
Chronic Illnesses ◽  
Therapeutic Drug ◽  
Disease Monitoring ◽  
Biologic Treatment ◽  
Faecal Calprotectin ◽  
Routine Clinical Care ◽  
Risk Of Disease ◽  
Inflammatory Bowel ◽  
The Impact

COVID-19 has dominated life in 2020 with, at the time of writing, over 4.9M global cases and >320 000 deaths. The impact has been most intensely felt in acute and critical care environments. However, with most UK elective work postponed, laboratory testing of faecal calprotectin halted due to potential risk of viral transmission and non-emergency endoscopies and surgeries cancelled, the secondary impact on chronic illnesses such as inflammatory bowel disease (IBD) is becoming apparent. Data from the Scottish Biologic Therapeutic Drug Monitoring (TDM) service shows a dramatic drop in TDM testing since the pandemic onset. April 2020 saw a 75.6% reduction in adalimumab testing and a 36.2% reduction in infliximab testing when compared with February 2020 data, a reduction coinciding with the widespread cancellation of outpatient and elective activity. It is feared that disruption to normal patterns of care and disease monitoring of biologic patients could increase the risk of disease flare and adverse clinical outcomes. Urgent changes in clinical practice have been instigated to mitigate the effects of the pandemic on routine clinical care. Further transformations are needed to maintain safe, effective, patient-centred IBD care in the future.

scholarly journals Factors Conditioning the Potential Effects TiO2 NPs Exposure on Human Microbiota: a Mini-Review

2021 ◽  
Author(s):  
Ewa Baranowska-Wójcik
Keyword(s):  
Titanium Dioxide Nanoparticles ◽  
Intestinal Barrier ◽  
Inorganic Nanoparticles ◽  
Potential Toxicity ◽  
Human Microbiota ◽  
Significant Interest ◽  
Inflammatory Bowel ◽  
Wide Group ◽  
The Impact ◽  
White Colour

AbstractThe recent years have seen a significant interest in the applications of nanotechnology in various facets of our lives. Due to their increasingly widespread use, human exposure to nanoparticles (NPs) is fast becoming unavoidable. Among the wide group of nanoparticles currently employed in industry, titanium dioxide nanoparticles, TiO2 NPs, are particularly popular. Due to its white colour, TiO2 is widely used as a whitening food additive (E 171). Yet, there have been few studies aimed at determining its direct impact on bacteria, while the available data suggest that TiO2 NPs may influence microbiota causing problems such as inflammatory bowel disease, obesity, or immunological disorders. Indeed, there are increasing concerns that its presence may lead to intestinal barrier impairment, including dysbiosis of intestinal microbiota. This article aims to present an overview of studies conducted to date with regard to the impact of TiO2 NPs on human microbiota as well as factors that can affect the same. Such information is necessary if we are to conclusively determine the potential toxicity of inorganic nanoparticles.

scholarly journals Multi-Omics Characterization of Inflammatory Bowel Disease-Induced Hyperplasia/Dysplasia in the Rag2−/−/Il10−/− Mouse Model

2020 ◽  
Vol 22 (1) ◽  
pp. 364
Author(s):  
Qiyuan Han ◽  
Thomas J. Y. Kono ◽  
Charles G. Knutson ◽  
Nicola M. Parry ◽  
Christopher L. Seiler ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Gastrointestinal Disease ◽  
Tumor Development ◽  
Proximal Colon ◽  
Helicobacter Hepaticus ◽  
Reduced Representation ◽  
Reduced Representation Bisulfite Sequencing ◽  
Inflammatory Bowel

Epigenetic dysregulation is hypothesized to play a role in the observed association between inflammatory bowel disease (IBD) and colon tumor development. In the present work, DNA methylome, hydroxymethylome, and transcriptome analyses were conducted in proximal colon tissues harvested from the Helicobacter hepaticus (H. hepaticus)-infected murine model of IBD. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (oxRRBS) analyses identified 1606 differentially methylated regions (DMR) and 3011 differentially hydroxymethylated regions (DhMR). These DMR/DhMR overlapped with genes that are associated with gastrointestinal disease, inflammatory disease, and cancer. RNA-seq revealed pronounced expression changes of a number of genes associated with inflammation and cancer. Several genes including Duox2, Tgm2, Cdhr5, and Hk2 exhibited changes in both DNA methylation/hydroxymethylation and gene expression levels. Overall, our results suggest that chronic inflammation triggers changes in methylation and hydroxymethylation patterns in the genome, altering the expression of key tumorigenesis genes and potentially contributing to the initiation of colorectal cancer.

scholarly journals Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paula Kappler ◽  
Michael A. Morgan ◽  
Philipp Ivanyi ◽  
Stefan J. Brunotte ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Biologically Active ◽  
Free Form ◽  
Total Testosterone ◽  
The Impact

AbstractTo date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.

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