scholarly journals A36 THE ROLE OF MICROBIAL INDOLE METABOLITES IN CONTROLLING INFLAMMATORY RESPONSES AND HEALING IN RESPONSE TO DSS-INDUCED COLITIS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 43-44
Author(s):  
K Nieves ◽  
K L Flannigan ◽  
L Alston ◽  
C Thomson ◽  
K McCoy ◽  
...  
Keyword(s):  
Immune Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Pregnane X Receptor ◽  
Lipocalin 2 ◽  
Mortality And Morbidity ◽  
Microbial Metabolite ◽  
Specific Pathogen ◽  
Mucosal Homeostasis ◽  
Xenobiotic Receptor

Abstract Background Failure to resolve inflammation is often associate with the complications of Crohn’s Disease (CD). The pregnane X receptor (PXR), a xenobiotic receptor, is recognized for its role in suppressing inflammation and has recently been shown to influence fibrogenesis in the liver. In the intestine, PXR-signaling can be influenced by the microbial tryptophan metabolite indole-3- propionic acid (IPA), which can modulate intestinal inflammation, in turn influencing fibrogenesis, resolution and healing. This suggests that the gut microbiota could modulate mucosal homeostasis and resolution of inflammation via microbial metabolites Aims To understand and characterize the interplay between microbial complexity and the regulation of host inflammatory and healing responses, specifically focusing on the PXR and its microbial metabolite ligand IPA. Methods Intestinal inflammation was induced using DSS (1%, 1.5%, 2% and 3.5%) for 5 days followed by healing for 25 days in C57Bl/6 stably derived moderately diverse mouse microbiota 2 (sDMDMm2) colonized gnotobiotic and C57Bl/6 specific pathogen free (SPF) mice. Inflammation, architectural changes and fibrosis were assessed using Haemotoxylin and Eosin and Masson-Trichrome histological stains. Weight was recorded daily for the first 10 days and every other day after for 25 days, for a total of 30 days. Fecal lipocalin was quantified in samples collected throughout the study to assess inflammation. Innate immune cell influx was measured by flow cytometry, and the microbiota assessed via 16S rRNA sequencing. Results The gnotobiotic sDMDMm2 mice were exquisitely sensitive to DSS-induced colitis, exhibiting significantly increased mortality and morbidity at 2% and 3.5% w/v DSS compared to the SPF group. To elicit the same degree of disease to assess recovery, sDMDMm2 mice were exposed to 1.5% DSS and SPF mice to 3.5% DSS. Following 25 days recovery, sDMDMm2 colonized mice showed increased levels of fecal lipocalin 2, as compared to the SPF mice. DSS-treated sDMDMm2 mice supplemented with IPA during their recovery presented lower levels of fecal lipocalin, similar to colitic SPF mice. IPA supplemented sDMDMm2 mice also exhibited greater overall survival, with no significant differences in neutrophil count compared to mice given H20 during recovery. Conclusions A model system with a less complex microbiota (sDMDMm2) has a higher susceptibility to acute inflammation and a diminished capacity to resolve said inflammation. Addition of the microbial metabolite IPA normalized the recovery of the sDMDMm2 colonized mice, to a response indistinguishable from SPF mice, while also increasing survival. These data highlight the importance of microbial complexity in the regulation of intestinal mucosal homeostasis. Funding Agencies CAG, CCC, CIHR

scholarly journals Intestinal Transcriptome Analysis Reveals Soy Derivative-Linked Changes in Atlantic Salmon

2020 ◽  
Vol 11 ◽  
Author(s):  
Viswanath Kiron ◽  
Youngjin Park ◽  
Prabhugouda Siriyappagouder ◽  
Dalia Dahle ◽  
Ghana K. Vasanth ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Head Kidney ◽  
Intestinal Morphology ◽  
Control Fish ◽  
Farmed Fish ◽  
Distal Intestine ◽  
Cell Counts

Intestinal inflammation in farmed fish is a non-infectious disease that deserves attention because it is a major issue linked to carnivorous fishes. The current norm is to formulate feeds based on plant-derived substances, and the ingredients that have antinutritional factors are known to cause intestinal inflammation in fishes such as Atlantic salmon. Hence, we studied inflammatory responses in the distal intestine of Atlantic salmon that received a feed rich in soybean derivatives, employing histology, transcriptomic and flow cytometry techniques. The fish fed on soy products had altered intestinal morphology as well as upregulated inflammation-associated genes and aberrated ion transport-linked genes. The enriched pathways for the upregulated genes were among others taurine and hypotaurine metabolism, drug metabolism—cytochrome P450 and steroid biosynthesis. The enriched gene ontology terms belonged to transmembrane transporter- and channel-activities. Furthermore, soybean products altered the immune cell counts; lymphocyte-like cell populations were significantly higher in the whole blood of fish fed soy products than those of control fish. Interestingly, the transcriptome of the head kidney did not reveal any differential gene expression, unlike the observations in the distal intestine. The present study demonstrated that soybean derivatives could evoke marked changes in intestinal transport mechanisms and metabolic pathways, and these responses are likely to have a significant impact on the intestine of Atlantic salmon. Hence, soybean-induced enteritis in Atlantic salmon is an ideal model to investigate the inflammatory responses at the cellular and molecular levels.

scholarly journals Emerging roles of metabolites of ω3 and ω6 essential fatty acids in the control of intestinal inflammation

2019 ◽  
Vol 31 (9) ◽  
pp. 569-577 ◽  
Author(s):  
Takahiro Nagatake ◽  
Jun Kunisawa
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Essential Fatty Acids ◽  
Octadecenoic Acid ◽  
Eicosatetraenoic Acid ◽  
Intestinal Epithelial ◽  
New Era ◽  
Biologic Effects ◽  
Mucosal Homeostasis ◽  
Nutritional Immunology

AbstractThe gastrointestinal tract is continuously exposed to the external environment, which contains numerous non-self antigens, including food materials and commensal micro-organisms. For the maintenance of mucosal homeostasis, the intestinal epithelial layer and mucosal immune system simultaneously provide the first line of defense against pathogens and are tightly regulated to prevent their induction of inflammatory responses to non-pathogenic antigens. Defects in mucosal homeostasis lead to the development of inflammatory and associated intestinal diseases, such as Crohn’s disease, ulcerative colitis, food allergy and colorectal cancer. The recent discovery of novel dietary ω3 and ω6 lipid-derived metabolites—such as resolvin, protectin, maresin, 17,18-epoxy-eicosatetraenoic acid and microbe-dependent 10-hydroxy-cis-12-octadecenoic acid—and their potent biologic effects on the regulation of inflammation have initiated a new era of nutritional immunology. In this review, we update our understanding of the role of lipid metabolites in intestinal inflammation.

scholarly journals Alleviation of Intestinal Inflammation by Dietary Pomegranate Extract Supplementation in Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1145-1145
Author(s):  
Jieping Yang ◽  
Patrizia Germano ◽  
Suwan Oh ◽  
Sijia Wang ◽  
Jing Wang ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Rna Extraction ◽  
Bioinformatic Analysis ◽  
Bioactive Metabolites ◽  
Lipocalin 2 ◽  
Knock Out ◽  
Funding Sources ◽  
Dss Colitis ◽  
Inflammatory Parameters

Abstract Objectives Inflammatory bowel disease (IBD) results from a complex interaction among host, microbial and environmental factors. Among these, diet has emerged as an important and actionable modifier of IBD activity. Pomegranate major bioactive metabolites, ellagic acid and urolithins, have been shown to improve symptoms of IBD in chemically induced mouse models of colitis. Here, we aim to test the hypothesis that dietary pomegranate extract (PomX) supplementation will reduce the development of colitis in IL-10 knock out (IL-10−/−) mice, which spontaneously develop chronic colitis after birth. Methods 4 week old male IL-10−/− mice were randomly assigned to a high fat high sucrose (HFHS) diet, or to a HFHS diet supplemented with 0.25% PomX for 8 weeks. At the end of the experiment, the mice were euthanized and intestinal tissues were isolated and frozen for RNA extraction, or fixed for histologic analysis. Plasma samples were collected and processed for lipocalin 2 assay. Results Histomorphological analysis of colonic tissues revealed lower histological scores in HFHS-PomX fed mice, 3.9 ± 1.0 vs. 2.6 ± 0.5 in HFHS fed mice (n = 8, P = 0.02). In addition, signs of rectal prolapse were observed in 62.5% of IL-10−/− mice in the HFHS group vs. 12.5% in the HFHS/PomX group (P = 0.04). RNAseq and bioinformatic analysis, obtained from the colonic tissues (n = 4 mice/each group), showed in PomX treated mice a downregulation of 483 genes and an upregulation of 263 genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome analyses showed that PomX downregulated genes which are mainly associated with immune inflammatory responses, defenses, and neutrophil degranulation, including IL1α, IL6 and TNFα pro-inflammatory cytokines. Spleen weights were lower in HFHS-PomX treated mice as compared to HFHS fed control mice (P = 0.04). In addition, PomX treated mice showed a trend of higher body weights (∼13%) and lower lipocalin 2 plasma levels (∼46%) as compared to HFHS fed mice. Conclusions Our data demonstrated that PomX supplementation decreased colitis symptoms and lowered the inflammatory parameters of colitis in HFHS fed IL10−/− mice. These data support the anti-inflammatory effects of dietary PomX supplementation that were previously observed in the DSS colitis murine model. Funding Sources This project was supported by UCLA Center for Human Nutrition.

20 ELUCIDATING THE ROLE OF FUSOBACTERIUM NUCLEATUM IN INTESTINAL INFLAMMATION

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S29-S29
Author(s):  
Melinda Engevik ◽  
Heather Danhof ◽  
Robert Britton ◽  
James Versalovic
Keyword(s):  
Immune Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Bacterial Species ◽  
Fusobacterium Nucleatum ◽  
Outer Membrane Vesicles ◽  
Patient Treatment ◽  
Mucus Layer

Abstract Background While the direct cause of inflammatory bowel disease (IBD) is unknown, the gut microbiota is speculated to play a key role. The complexity of the microbiome has made it difficult to pinpoint whether bacterial species are specifically associated with IBD exacerbations; although select microbes have emerged as compelling candidates. Several groups have identified increased abundance in Fusobacterium in IBD patients. Fusobacterium nucleatum drives inflammation in the oral cavity, but few studies have examined the potential for F. nucleatum to promote intestinal inflammation. We hypothesize that F. nucleatum secretes Outer Membrane Vesicles (OMVs) that activate epithelial Toll-like receptor 4 (TLR4) to drive inflammation. Methods & Results Given the prevalence of F. nucleatum in IBD specimens, we sought to determine if this pathobiont could promote pro-inflammatory responses in human epithelial cultures. Using fluorescently tagged F. nucleatum, we demonstrate that F. nucleatum subspecies polymorphum adheres to the mucus layer of human colonic HT29-MTX cells. Application of F. nucleatum metabolites to HT29-MTX cells resulted in upregulation of pro-inflammatory cytokines IL-8 and TNF by qPCR and ELISA. Purified OMVs from F. nucleatum alone were able to stimulate IL-8 and TNF production. This demonstrates the robust response of colonic epithelial cells to F. nucleatum. Additionally, we used human jejunum and colon enteroid monolayers treated with F. nucleatum metabolites in an anti-oxidant free enteroid media and found that F. nucleatum secreted products promoted TNF secretion by ELISA. Using the Luminex Magpix Platform we further queried the enteroid system to assess which pathways were activated. Enteroid monolayers treated with F. nucleatum metabolites exhibited increased phosphorylated ERK and CREB, downstream effectors of TLRs. We next sought to address whether F. nucleatum alone could elicit pro-inflammatory responses in a mouse model. Mice harboring a human microbiota, or humanized mice, were treated for 5 days with a cocktail of antibiotics and treated with F. nucleatum (108 CFU) by oral gavage; a regimen designed to mimic IBD patient treatment. Compared to control mice that received antibiotics and PBS vehicle control, mice treated with F. nucleatum exhibited disruption of the colonic architecture, with increased immune infiltrate and depleted mucus layer, resulting in a closer proximity of luminal contents to the epithelium. Analysis of mucosal gene expression revealed increased levels of epithelial TNF and KC (mouse homolog of IL-8), in addition to immune cell derived IL-6 in F. nucleatum-treated mice compared for controls. Conclusions These data provide evidence that F. nucleatum is capable of driving a pro-inflammatory signaling cascade in vitro and in vivo and F. nucleatum may represent a specific target for drug therapy.

scholarly journals BAFF Blockade Attenuates Inflammatory Responses and Intestinal Barrier Dysfunction in a Murine Endotoxemia Model

2020 ◽  
Vol 11 ◽  
Author(s):  
Runze Quan ◽  
Chaoyue Chen ◽  
Wei Yan ◽  
Ying Zhang ◽  
Xi Zhao ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Survival Rates ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction ◽  
Protein Levels ◽  
Lps Challenge ◽  
Endotoxemia Model

B cell-activating factor (BAFF) production is increased in septic patients. However, the specific role of BAFF in sepsis remains unknown. This study was designed to investigate the expression and function of BAFF in an experimental endotoxemia model and to identify the potential mechanisms. We established an endotoxemia mouse (6–8 weeks, 20–22 g) model by administering 30 mg/kg lipopolysaccharide (LPS). BAFF levels in the circulating system and organ tissues were measured 4 and 8 h after LPS injection. Survival rates in the endotoxemia mice were monitored for 72 h after BAFF blockade. The effects of BAFF blockade on systemic and local inflammation, organ injuries, and intestinal barrier function were also evaluated 4 h after LPS treatment. BAFF production was systemically and locally elevated after LPS challenge. BAFF blockade improved the survival rate, systemic inflammation, and multi-organ injuries. Moreover, BAFF blockade attenuated both intestinal inflammation and impaired intestinal permeability. BAFF blockade upregulated ZO-1 and occludin protein levels via the NF-κB/MLCK/MLC signaling pathway. These results suggested that BAFF blockade protects against lethal endotoxemia at least partially by alleviating inflammation, multi-organ injuries, and improving intestinal barrier function and provides a novel focus for further research on sepsis and experimental evidence for clinical therapy.

scholarly journals Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

2021 ◽  
Vol 22 (11) ◽  
pp. 6141
Author(s):  
Teodora Larisa Timis ◽  
Ioan Alexandru Florian ◽  
Sergiu Susman ◽  
Ioan Stefan Florian
Keyword(s):  
Immune Cells ◽  
Arteriovenous Malformations ◽  
Intracranial Aneurysms ◽  
Immune Cell ◽  
Vascular Malformations ◽  
Cerebral Injury ◽  
Future Research ◽  
Mortality And Morbidity ◽  
The Central Nervous System ◽  
The Brain

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.

scholarly journals A Missing Link: Engagements of Dendritic Cells in the Pathogenesis of SARS-CoV-2 Infections

2021 ◽  
Vol 22 (3) ◽  
pp. 1118
Author(s):  
Abdulaziz Alamri ◽  
Derek Fisk ◽  
Deepak Upreti ◽  
Sam K. P. Kung
Keyword(s):  
Dendritic Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Viral Disease ◽  
Cell Recruitment ◽  
Cross Presentation ◽  
Cell Immunity ◽  
Immune Cell Recruitment

Dendritic cells (DC) connect the innate and adaptive arms of the immune system and carry out numerous roles that are significant in the context of viral disease. Their functions include the control of inflammatory responses, the promotion of tolerance, cross-presentation, immune cell recruitment and the production of antiviral cytokines. Based primarily on the available literature that characterizes the behaviour of many DC subsets during Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), we speculated possible mechanisms through which DC could contribute to COVID-19 immune responses, such as dissemination of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to lymph nodes, mounting dysfunctional inteferon responses and T cell immunity in patients. We highlighted gaps of knowledge in our understanding of DC in COVID-19 pathogenesis and discussed current pre-clinical development of therapies for COVID-19.

scholarly journals A Salmonella Virulence Factor Activates the NOD1/NOD2 Signaling Pathway

mBio ◽  
2011 ◽  
Vol 2 (6) ◽  
Author(s):  
A. Marijke Keestra ◽  
Maria G. Winter ◽  
Daisy Klein-Douwel ◽  
Mariana N. Xavier ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Type Iii Secretion ◽  
Salmonella Enterica ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Content Type ◽  
Type Iii

ABSTRACTThe invasion-associated type III secretion system (T3SS-1) ofSalmonella entericaserotype Typhimurium (S. Typhimurium) activates the transcription factor NF-κB in tissue culture cells and induces inflammatory responses in animal models through unknown mechanisms. Here we show that bacterial delivery or ectopic expression of SipA, a T3SS-1-translocated protein, led to the activation of the NOD1/NOD2 signaling pathway and consequent RIP2-mediated induction of NF-κB-dependent inflammatory responses. SipA-mediated activation of NOD1/NOD2 signaling was independent of bacterial invasionin vitrobut required an intact T3SS-1. In the mouse colitis model, SipA triggered mucosal inflammation in wild-type mice but not in NOD1/NOD2-deficient mice. These findings implicate SipA-driven activation of the NOD1/NOD2 signaling pathway as a mechanism by which the T3SS-1 induces inflammatory responsesin vitroandin vivo.IMPORTANCESalmonella entericaserotype Typhimurium (S. Typhimurium) deploys a type III secretion system (T3SS-1) to induce intestinal inflammation and benefits from the ensuing host response, which enhances growth of the pathogen in the intestinal lumen. However, the mechanisms by which the T3SS-1 triggers inflammatory responses have not been resolved. Here we show that the T3SS-1 effector protein SipA induces NF-κB activation and intestinal inflammation by activating the NOD1/NOD2 signaling pathway. These data suggest that the T3SS-1 escalates innate responses through a SipA-mediated activation of pattern recognition receptors in the host cell cytosol.

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