Analysis of Gene Expression in Ceca of Helicobacter hepaticus-Infected A/JCr Mice before and after Development of Typhlitis

ABSTRACT The inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. The causes of these diseases remain unknown; however, prevailing theories suggest that chronic intestinal inflammation results from a dysregulated immune response to ubiquitous bacterial antigens. While a substantial body of data has been amassed describing the role of the adaptive immune system in perpetuating and sustaining inflammation, very little is known about the early signals, prior to the development of inflammation, that initiate and direct the abnormal immune response. To this end, we characterized the gene expression profile of A/JCr mice with Helicobacter hepaticus-induced typhlitis at month 1 of infection, prior to the onset of histologic disease, and month 3 of infection, after chronic inflammation is fully established. Analysis of the gene expression in ceca of H. hepaticus infected mice revealed 25 up-regulated and 3 down-regulated genes in the month-1 postinoculation group and 31 up-regulated and 2 down-regulated genes in the month-3 postinoculation group. Among these was a subset of immune-related genes, including interferon-inducible protein 10, monokine induced by gamma interferon, macrophage-induced protein 1 alpha, and serum amyloid A1. Semiquantitative real-time reverse transcriptase PCR confirmed the increased expression levels of these genes, as well as elevated expression of gamma interferon. To our knowledge, this is the first report profiling cecal gene expression in H. hepaticus-infected A/JCr mice. The findings of altered gene expression prior to the development of any features of pathology and the ensuing chronic disease course make this an attractive model for studying early host response to microbe-induced inflammatory bowel disease.

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Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22052645 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2645

Author(s):

Dinh Nam Tran ◽

Seon Myeong Go ◽

Seon-Mi Park ◽

Eui-Man Jung ◽

Eui-Bae Jeung

Keyword(s):

Immune Response ◽

Cellular Proliferation ◽

Intestinal Inflammation ◽

Critical Role ◽

Experimental Colitis ◽

Innate Immune ◽

Inflammatory Conditions ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

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Role of the Helicobacter hepaticus Flagellar Sigma Factor FliA in Gene Regulation and Murine Colonization

Journal of Bacteriology ◽

10.1128/jb.00626-08 ◽

2008 ◽

Vol 190 (19) ◽

pp. 6398-6408 ◽

Cited By ~ 15

Author(s):

Torsten Sterzenbach ◽

Lucie Bartonickova ◽

Wiebke Behrens ◽

Birgit Brenneke ◽

Jessika Schulze ◽

...

Keyword(s):

Gene Regulation ◽

Sigma Factor ◽

Intestinal Inflammation ◽

Gall Stone ◽

Helicobacter Hepaticus ◽

Intestinal Colonization ◽

Wild Type ◽

Chronic Intestinal Inflammation ◽

Flagellar Genes

ABSTRACT The enterohepatic Helicobacter species Helicobacter hepaticus colonizes the murine intestinal and hepatobiliary tract and is associated with chronic intestinal inflammation, gall stone formation, hepatitis, and hepatocellular carcinoma. Thus far, the role of H. hepaticus motility and flagella in intestinal colonization is unknown. In other, closely related bacteria, late flagellar genes are mainly regulated by the sigma factor FliA (σ28). We investigated the function of the H. hepaticus FliA in gene regulation, flagellar biosynthesis, motility, and murine colonization. Competitive microarray analysis of the wild type versus an isogenic fliA mutant revealed that 11 genes were significantly more highly expressed in wild-type bacteria and 2 genes were significantly more highly expressed in the fliA mutant. Most of these were flagellar genes, but four novel FliA-regulated genes of unknown function were identified. H. hepaticus possesses two identical copies of the gene encoding the FliA-dependent major flagellin subunit FlaA (open reading frames HH1364 and HH1653). We characterized the phenotypes of mutants in which fliA or one or both copies of the flaA gene were knocked out. flaA_1 flaA_2 double mutants and fliA mutants did not synthesize detectable amounts of FlaA and possessed severely truncated flagella. Also, both mutants were nonmotile and unable to colonize mice. Mutants with either flaA gene knocked out produced flagella morphologically similar to those of wild-type bacteria and expressed FlaA and FlaB. flaA_1 mutants which had flagella but displayed reduced motility did not colonize mice, indicating that motility is required for intestinal colonization by H. hepaticus and that the presence of flagella alone is not sufficient.

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Anthocyanins and intestinal barrier function: a review

Journal of Food Bioactives ◽

10.31665/jfb.2019.5175 ◽

2019 ◽

Vol 5 ◽

pp. 18-30 ◽

Cited By ~ 4

Author(s):

Jonathan C. Valdez ◽

Bradley W. Bolling

Keyword(s):

Barrier Function ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Berry Anthocyanins ◽

Chronic Intestinal Inflammation

Chronic intestinal inflammation, occurring in inflammatory bowel diseases (IBD), is associated with compromised intestinal barrier function. Inflammatory cytokines disrupt tight junctions and increase paracellular permeability of luminal antigens. Thus, chronic intestinal barrier dysfunction hinders the resolution of inflammation. Dietary approaches may help mitigate intestinal barrier dysfunction and chronic inflammation. A growing body of work in rodent models of colitis has demonstrated that berry consumption inhibits chronic intestinal inflammation. Berries are a rich dietary source of polyphenolic compounds, particularly anthocyanins. However, berry anthocyanins have limited bioavailability and are extensively metabolized by the gut microbiota and host tissue. This review summarizes the literature regarding the beneficial functions of anthocyanin-rich berries in treating and preventing IBD. Here, we will establish the role of barrier function in the pathogenesis of IBD and how dietary anthocyanins and their known microbial catabolites modulate intestinal barrier function.

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A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

10.1101/2021.10.27.466206 ◽

2021 ◽

Author(s):

Alberto Gomez-Carballa ◽

Irene Rivero-Calle ◽

Jacobo Pardo-Seco ◽

Jose Gomez-Rial ◽

Carmen Rivero-Velasco ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Local Level ◽

Antiviral Response ◽

Innate Immune ◽

Nasal Epithelium ◽

Severe Illness ◽

Immune Gene ◽

Innate Antiviral Response ◽

Immune Related Genes

Background: COVID-19 symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences. Methods and findings: We carried out a multi-tissue (nasal, buccal and blood; n = 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. We then used a differential expression approach and pathways analysis to detect tissue specific immune severity signals in COVID-19 patients. Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were shown in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis. Conclusions: We found severity-related signatures in patient tissues mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.

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Immunological Regulation of Intestinal Fibrosis in Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab251 ◽

2021 ◽

Author(s):

Giorgos Bamias ◽

Theresa T Pizarro ◽

Fabio Cominelli

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Large Scale ◽

Intestinal Inflammation ◽

Temporal Association ◽

Stricture Formation ◽

Intestinal Fibrosis ◽

Matrix Deposition ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation

Abstract Intestinal fibrosis is a late-stage phenotype of inflammatory bowel disease (IBD), which underlies most of the long-term complications and surgical interventions in patients, particularly those with Crohn’s disease. Despite these issues, antifibrotic therapies are still scarce, mainly due to the current lack of understanding concerning the pathogenetic mechanisms that mediate fibrogenesis in patients with chronic intestinal inflammation. In the current review, we summarize recent evidence regarding the cellular and molecular factors of innate and adaptive immunity that are considered critical for the initiation and amplification of extracellular matrix deposition and stricture formation. We focus on the role of cytokines by dissecting the pro- vs antifibrotic components of the immune response, while taking into consideration their temporal association to the progressive stages of the natural history of IBD. We critically present evidence from animal models of intestinal fibrosis and analyze inflammation-fibrosis interactions that occur under such experimental scenarios. In addition, we comment on recent findings from large-scale, single-cell profiling of fibrosis-relevant populations in IBD patients. Based on such evidence, we propose future potential targets for antifibrotic therapies to treat patients with IBD.

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Potential of Plant-sourced Phenols for Inflammatory Bowel Disease

Current Medicinal Chemistry ◽

10.2174/0929867324666171009100900 ◽

2019 ◽

Vol 25 (38) ◽

pp. 5191-5217 ◽

Cited By ~ 4

Author(s):

Hai-tao Xiao ◽

Bo Wen ◽

Xiang-chun Shen ◽

Zhao-xiang Bian

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Term Treatment ◽

Term Therapy ◽

Inflammatory Status ◽

Long Term Treatment ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation

Inflammatory bowel disease (IBD) is an uncontrolled chronic inflammatory intestinal disorder, which requires medications for long-term therapy. Facing the challenges of severe side effects and drug resistance of conventional medications, to develop the strategies meet the stringent safety and effectiveness in the long-term treatment are urgent in the clinics. In this regard, a growing body of evidence confirms plant-sourced phenols, such as flavonoids, catechins, stilbenes, coumarins, quinones, lignans, phenylethanoids, cannabinoid phenols, tannins, phenolic acids and hydroxyphenols, exert potent protective benefits with fewer undesirable effects in conditions of acute or chronic intestinal inflammation through improvement of colonic oxidative and pro-inflammatory status, preservation of the epithelial barrier function and modulation of gut microbiota. In this review, the great potential of plant-sourced phenols and their action mechanisms for the treatment or prevention of IBD in recent research are summarized, which may help further development of new preventive/adjuvant regimens for IBD.

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Dietary Emulsifiers Directly Impact Adherent-Invasive E. coli Gene Expression to Drive Chronic Intestinal Inflammation

Cell Reports ◽

10.1016/j.celrep.2020.108229 ◽

2020 ◽

Vol 33 (1) ◽

pp. 108229

Author(s):

Emilie Viennois ◽

Alexis Bretin ◽

Philip E. Dubé ◽

Alexander C. Maue ◽

Charlène J.G. Dauriat ◽

...

Keyword(s):

Gene Expression ◽

Intestinal Inflammation ◽

E Coli ◽

Chronic Intestinal Inflammation

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An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer

Journal of Experimental Medicine ◽

10.1084/jem.20101330 ◽

2010 ◽

Vol 207 (8) ◽

pp. 1573-1577 ◽

Cited By ~ 94

Author(s):

Mark Asquith ◽

Fiona Powrie

Keyword(s):

Intestinal Inflammation ◽

Innate Immune ◽

Intestinal Epithelial ◽

Intestinal Homeostasis ◽

Functional Roles ◽

Innate Immune Signaling ◽

Distinct Disease ◽

Inflammatory Bowel ◽

Immune Sensing ◽

Chronic Intestinal Inflammation

Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses to the intestinal microbiota, and by chronic intestinal inflammation. Several recent studies demonstrate the importance of innate microbial recognition by immune and nonimmune cells in the gut. Paradoxically, either diminished or exacerbated innate immune signaling may trigger the breakdown of intestinal homeostasis, leading to IBD and colitis-associated cancer (CAC). This dichotomy may reflect divergent functional roles for immune sensing in intestinal epithelial cells and leukocytes, which may vary with distinct disease mechanisms.

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Regulation of Mucosal Immune Responses – The Missing Link in IBD?

Canadian Journal of Gastroenterology ◽

10.1155/1996/426087 ◽

1996 ◽

Vol 10 (2) ◽

pp. 105-109

Author(s):

Charles O Elson ◽

Robert P Mccabe ◽

Kenneth W Beagley ◽

Almaz Sharmanov ◽

Steven L Brandwein ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Intestinal Inflammation ◽

Bacterial Flora ◽

Cell Subset ◽

Experimental Models ◽

Bacterial Antigens ◽

Mucosal Immune Responses ◽

Chronic Intestinal Inflammation

Although the etiology of inflammatory bowel disease (IBD) remains unknown, a major working hypothesis is that it represents a dysregulated immune response to common enteric bacterial antigens. Until recently there has been a relative dearth of experimental models to study this hypothesis. However, exciting developments in experimental models of colitis, including spontaneous, transgenic and knockout mice, now allow this and other hypotheses to be tested. The regulation of mucosal immune responses is not well understood in the normal animal, much less in those with chronic intestinal inflammation. Clearly the CD4 Th1 and Th2 pathways are important in the host response to microbial pathogens, and recent data indicate that the intestinal mucosa seems to be a site of preferential Th2 responses toward exogenous antigens. Deletion of certain cytokine genes involved in maintaining this Th1/Th2 balance (interleukin [IL]-2, IL-10) resulted in colitis, although deletion of others (IL-4, interferon-gamma) that are also involved did not. Whether these cytokine gene deletions cause a dysregulation of the mucosal immune response has yet to be shown. However, the importance of regulation can be demonstrated in a model in which a normal CD4+T cell subset (CD45Rbhigh) is transferred into syngeneic severe combined immunodeficiency syndrome recipients. This results in a striking colitis over the ensuing weeks with chronic diarrhea and wasting of the animals. If the reciprocal CD4+subset (CD45Rblow) is co-transferred or if whole CD4+T cells are transferred no colitis ensues. Therefore, T cells capable of causing colitis are present in normal animals but are prevented from doing so by immunoregulatory mechanisms. The antigens that drive the colitis in several of these models (IL-2 knockout mouse, human leukocyte antigen B27/β2M transgenic rat) appear to be those of the normal enteric bacterial flora because germ-free animals do not get the disease. Spontaneously colitic C3H/HeJBir mice also show prominent reactivity to enteric bacterial antigens. There are major differences among inbred mouse strains in susceptibility to colitis. The genes involved are not yet identified, but newly available technologies should allow that. In summary, these new models provide an experimental foundation to one of the major hypotheses on the cause of IBD, and will allow dissection of the genetic, environmental and immune components contributing to chronic colitis.

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