scholarly journals Antibiotic Treatment Alters the Colonic Mucus Layer and Predisposes the Host to ExacerbatedCitrobacter rodentium-Induced Colitis

2011 ◽  
Vol 79 (4) ◽  
pp. 1536-1545 ◽  
Author(s):  
M. Wlodarska ◽  
B. Willing ◽  
K. M. Keeney ◽  
A. Menendez ◽  
K. S. Bergstrom ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Mucosal Barrier ◽  
Intestinal Immunity ◽  
Mucus Layer ◽  
Microbial Composition ◽  
Bacterial Stimulation ◽  
Increased Susceptibility ◽  
Stimulation Of

ABSTRACTAntibiotics are often used in the clinic to treat bacterial infections, but the effects of these drugs on microbiota composition and on intestinal immunity are poorly understood.Citrobacter rodentiumwas used as a model enteric pathogen to investigate the effect of microbial perturbation on intestinal barriers and susceptibility to colitis. Streptomycin and metronidazole were used to induce alterations in the composition of the microbiota prior to infection withC. rodentium. Metronidazole pretreatment increased susceptibility toC. rodentium-induced colitis over that of untreated and streptomycin-pretreated mice, 6 days postinfection. Both antibiotic treatments altered microbial composition, without affecting total numbers, but metronidazole treatment resulted in a more dramatic change, including a reduced population ofPorphyromonadaceaeand increased numbers of lactobacilli. Disruption of the microbiota with metronidazole, but not streptomycin treatment, resulted in an increased inflammatory tone of the intestine characterized by increased bacterial stimulation of the epithelium, altered goblet cell function, and thinning of the inner mucus layer, suggesting a weakened mucosal barrier. This reduction in mucus thickness correlates with increased attachment ofC. rodentiumto the intestinal epithelium, contributing to the exacerbated severity ofC. rodentium-induced colitis in metronidazole-pretreated mice. These results suggest that antibiotic perturbation of the microbiota can disrupt intestinal homeostasis and the integrity of intestinal defenses, which protect against invading pathogens and intestinal inflammation.

scholarly journals Modulation of gut mucosal biofilms

2005 ◽  
Vol 93 (S1) ◽  
pp. S35-S40 ◽  
Author(s):  
Brigitta Kleessen ◽  
Michael Blaut
Keyword(s):  
Colonic Mucosa ◽  
Mucosal Barrier ◽  
Mucus Layer ◽  
Faecal Flora ◽  
New Approach ◽  
Serovar Typhimurium ◽  
Health Promoting ◽  
Gut Mucosal Barrier ◽  
Induced Changes ◽  
Stimulation Of

Non-digestible inulin-type fructans, such as oligofructose and high-molecular-weight inulin, have been shown to have the ability to alter the intestinal microbiota composition in such a way that members of the microbial community, generally considered as health-promoting, are stimulated. Bifidobacteria and lactobacilli are the most frequently targeted organisms. Less information exists on effects of inulin-type fructans on the composition, metabolism and healthrelated significance of bacteria at or near the mucosa surface or in the mucus layer forming mucosa-associated biofilms. Using rats inoculated with a human faecal flora as an experimental model we have found that inulin-type fructans in the diet modulated the gut microbiota by stimulation of mucosa-associated bifidobacteria as well as by partial reduction of pathogenicSalmonella enterica subsp. entericaserovar Typhimurium and thereby benefit health. In addition to changes in mucosal biofilms, inulin-type fructans also induced changes in the colonic mucosa stimulating proliferation in the crypts, increasing the release of mucins, and altering the profile of mucin components in the goblet cells and epithelial mucus layer. These results indicate that inulin-type fructans may stabilise the gut mucosal barrier. Dietary supplementation with these prebiotics could offer a new approach to supporting the barrier function of the mucosa.

Macrophage Motility Dysfunction in a Patient with Recurrent Infections.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3835-3835
Author(s):  
Paul T. Jubinsky ◽  
Mary Short ◽  
Anthony Ashton ◽  
Diane Cox ◽  
Fiona Pixley
Keyword(s):  
Peripheral Blood ◽  
Bacterial Infections ◽  
Cell Function ◽  
Time Lapse ◽  
Early Age ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Susceptibility To Infection ◽  
Normal Individuals ◽  
Increased Susceptibility

Abstract Three members of a family with normal parents had a common constellation of findings that included absent corpus callosum and recurrent bacterial infections. The older male and female siblings both died from infection at an early age. The patient’s CBC was significant for elevated numbers of monocytes that were large and vacuolated. Her T- and B-cell function was normal. These preliminary findings suggested a defect in innate immunity. Evaluation of the patient’s peripheral blood monocytes by flow cytometry showed normal size and maturity. Phagocytosis and activation of peripheral blood derived macrophages by cytokines were also similar to controls. In contrast, the patient’s cultured macrophages were significantly more spread than those from normal individuals and contained a disordered actin cytoskeleton when cultured on fibronectin. The ability of the macrophage to transmigrate across an endothelial cell barrier was impaired. However examination by time-lapse videomicroscopy showed that the mutant macrophages had increased protrusional activity and movement. This is the first report describing a genetic macrophage motility disorder that results in an increased susceptibility to infection.

scholarly journals Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

2018 ◽  
Vol 10 (464) ◽  
pp. eaao4755 ◽  
Author(s):  
Nicholas A. Scott ◽  
Anna Andrusaite ◽  
Peter Andersen ◽  
Melissa Lawson ◽  
Cristina Alcon-Giner ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
Cell Function ◽  
Antibiotic Use ◽  
Antibiotic Administration ◽  
Intestinal Immunity ◽  
T Helper 1 ◽  
Trichuris Muris ◽  
Cell Immunity ◽  
Increased Susceptibility

Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (TH1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring TH17 and TH2 responses for clearance (bacterialCitrobacter rodentiumand helminthTrichuris murisinfections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell–mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.

scholarly journals Immunological design of commensal communities to treat intestinal infection and inflammation

2021 ◽  
Vol 17 (1) ◽  
pp. e1009191
Author(s):  
Rebecca L. Brown ◽  
Max L. Y. Larkinson ◽  
Thomas B. Clarke
Keyword(s):  
Intracellular Signaling ◽  
Intestinal Inflammation ◽  
Secondary Response ◽  
Mucosal Barrier ◽  
Intestinal Immunity ◽  
Antibiotic Resistant ◽  
Commensal Species ◽  
Mucosal Barrier Function ◽  
Infection And Inflammation ◽  
Tlr4 Activation

The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-κB signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-κB signaling. Thus, by profiling the immunological impact of major human commensal species our work paves the way for rational microbiota reengineering to protect against antibiotic resistant infections and to treat intestinal inflammation.

scholarly journals Oxyresveratrol Ameliorates Dextran Sulfate Sodium-Induced Colitis in Rats by Suppressing Inflammation

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2630
Author(s):  
Jiah Yeom ◽  
Seongho Ma ◽  
Jeong-Keun Kim ◽  
Young-Hee Lim
Keyword(s):  
Inflammatory Cytokine ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Intestinal Inflammation ◽  
Mucus Layer ◽  
Beneficial Effects ◽  
Intestinal Mucus ◽  
Anti Inflammatory ◽  
Apoptotic Effects ◽  
Intestinal Mucus Layer

Colitis causes destruction of the intestinal mucus layer and increases intestinal inflammation. The use of antioxidants and anti-inflammatory agents derived from natural sources has been recently highlighted as a new approach for the treatment of colitis. Oxyresveratrol (OXY) is an antioxidant known to have various beneficial effects on human health, such as anti-inflammatory, antibacterial activity, and antiviral activity. The aim of this study was to investigate the therapeutic effect of OXY in rats with dextran sulfate sodium (DSS)-induced acute colitis. OXY ameliorated DSS-induced colitis and repaired damaged intestinal mucosa. OXY downregulated the expression of pro-inflammatory cytokine genes (TNF-α, IL-6, and IL-1β) and chemokine gene MCP-1, while promoting the production of anti-inflammatory cytokine IL-10. OXY treatment also suppressed inflammation via inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in the colon, as well as the activity of myeloperoxidase (MPO). OXY exhibited anti-apoptotic effects, shifting the Bax/Bcl-2 balance. In conclusion, OXY might improve DSS-induced colitis by restoring the intestinal mucus layer and reducing inflammation within the intestine.

LOSS OF GLUTATHIONE PEROXIDASE 1 ATTENUATES COLITIS AND IS CRITICAL IN ACTIVATING EPITHELIAL REGENERATIVE RESPONSES

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S27-S27
Author(s):  
Jared Hendren ◽  
Koral Kasnyik ◽  
Christopher Williams ◽  
Sarah Short
Keyword(s):  
Stem Cell ◽  
Glutathione Peroxidase ◽  
Target Genes ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Cellular Metabolism ◽  
Intestinal Injury ◽  
Gene Set Enrichment Analysis ◽  
Intestinal Cell ◽  
Glutathione Peroxidase 1

Abstract Many selenium-containing “selenoproteins” function as antioxidants, and work by our lab and others has demonstrated that selenoproteins often protect against intestinal inflammatory diseases, including colitis. Glutathione peroxidase 1 (GPx1) is a ubiquitous, mitochondrial and cytosolic selenoprotein which catalyzes the reduction of hydrogen peroxide by glutathione. Previously, we determined that despite its antioxidant role, loss of GPx1 greatly reduced disease severity in the dextran sodium sulfate (DSS) colitis model. Furthermore, GPx1 loss increased baseline intestinal cell proliferation, enhanced enteroid plating efficiency, and induced expression of stem cell-associated genes, such as Lgr5. Next, we aimed to determine the mechanism by which GPx1 modifies response to DSS. We observed that GPx1 is increased in colonic tissues from DSS-treated mice as compared to nontreated controls, suggesting that GPx1 may functionally contribute to intestinal injury responses. While GPx1 is expressed in both intestinal epithelial and immune cells, in situ hybridization to visualize Gpx1 identified epithelial cells as the most highly expressing cell type, with the greatest Gpx1 upregulation observed in wound-adjacent and regenerative crypts. Next, we investigated whether GPx1 loss affects stem cell function after injury. Here, we determined that both proliferation (p<0.01) and Lgr5 expression (p<0.05) were increased in the crypts of Gpx1-/- DSS-treated mice in comparison to WT controls. Similarly, organoids established from ulcerative colitis tissue displayed increased growth rates (p<0.01), expression of stem cell and Wnt target genes such as AXIN2 (p<0.0001) and LGR5 (p<0.01), and proliferation (p<0.05) following GPX1 knockdown. Together, these results indicate that GPx1 has an epithelial-cell autonomous role, and that its loss activates stem cell and proliferative responses which may both protect from intestinal injury and promote healing. Interestingly, recent research has highlighted the role of cellular metabolism in maintaining intestinal stem cell function, and GPx1 has previously been implicated in these processes. RNA-sequencing from DSS-treated mice and gene set enrichment analysis identified a positive association with oxidative phosphorylation-associated genes in Gpx1-/- mice (NES: 1.78; FDR q-val: 0.01), suggesting altered metabolism which may favor stem cell function. Further analysis of cellular metabolism using GPX1 knockdown colorectal cancer cells observed higher basal respiration (p<0.0001) and ATP generation (p<0.0001). Together, these results suggest that unlike other intestinal selenoproteins studied to date, loss of GPx1 augments stem cell injury responses to protect against intestinal inflammation, likely via augmenting epithelial regenerative responses.

scholarly journals A Japanese traditional medicine Hochuekkito promotes negative conversion of vancomycin-resistant Enterococci

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Junko Kohno ◽  
Tsuyoshi Kawamura ◽  
Akiko Kikuchi ◽  
Tetsuya Akaishi ◽  
Shin Takayama ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Tertiary Care ◽  
Albumin Level ◽  
Kampo Medicine ◽  
Care Hospital ◽  
Intestinal Immunity ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Japanese Traditional Medicine ◽  
Negative Conversion

AbstractVancomycin-resistant enterococci (VRE) are prominent causes of nosocomial infections. Japanese traditional (Kampo) medicine promotes intestinal immunity and protects against bacterial infections. We assessed potential differences in the clinical course of VRE-positive patients, based on their characteristics and treatment with Kampo medicines. This retrospective observational study collected data from VRE-positive patients from August 2018 to July 2019 at a tertiary-care hospital in Japan. The data of 122 consecutive VRE-positive inpatients were analyzed. Sixty-nine patients were treated with probiotics, among whom, 18 were further treated with Kampo medicines. Twenty-six of the 122 patients subsequently died. In univariate analyses, subsequent VRE negative conversion significantly reduced the mortality of VRE-detected patients (p = .0003). Administration of probiotics (p = .0065) and Kampo medicines with probiotics (p = .0002), especially of the Kampo medicine hochuekkito (p = .0014), and a higher serum albumin level positively contributed to the subsequent VRE negative conversion. Multivariate analyses demonstrated that Kampo medicines and body mass index contributed to VRE negative conversion. Hochuekkito shortened the time needed for VRE negative conversion (p = 0.0485). Administration of Kampo medicines, especially of hochuekkito, in addition to probiotics in VRE patients may promote VRE negative conversion.

Effects of l-leucine, its 2-keto acid metabolite and its nonmetabolized analogue on rat tumoral islet cell function

1988 ◽  
Vol 1 (1) ◽  
pp. 69-76 ◽  
Author(s):  
V. Leclercq-Meyer ◽  
J. Marchand ◽  
A. Sener ◽  
F. Blachier ◽  
W. J. Malaisse
Keyword(s):  
Insulin Release ◽  
Cell Function ◽  
Islet Cells ◽  
Adenine Nucleotides ◽  
Secretory Response ◽  
Acid Metabolite ◽  
Dual Effect ◽  
Islet Cell Function ◽  
Insulinoma Cells ◽  
Stimulation Of

ABSTRACT l-Leucine and 2-ketoisocaproate stimulated insulin release from perifused rat tumoral islet cells (RINm5F line). The secretory response coincided with an increase in the intracellular ATP/ADP ratio, a stimulation of 45Ca outflow from cells perifused in the presence of extracellular Ca2+, and an increase in 32P efflux from cells prelabelled with radioactive orthophosphate. In contrast to d-glucose, however, l-leucine or 2-ketoisocaproate failed to decrease 86Rb outflow, to inhibit 45Ca outflow from cells perifused in the absence of Ca2+ and to enhance the labelling of inositol-containing phospholipids in cells exposed to myo-[2-3H]inositol. These findings suggest that d-glucose, l-leucine and 2-ketoisocaproate exert dissimilar effects on the subcellular distribution of adenine nucleotides and/or 86Rb. The nonmetabolized analogue of l-leucine, 2-aminobicyclo-[2.2.1]heptane-2-carboxylic acid (BCH), also caused an initial stimulation of insulin release and 32P efflux, but this was soon followed by a severe and irreversible inhibition of insulin output, associated with a permanent enhancement of 86Rb outflow. The dual ionic and secretory response to BCH is interpreted in the light of its dual effect on the catabolism of endogenous amino and fatty acids, and raises the view that BCH could be used to interfere with the function of insulinoma cells.

scholarly journals Nutritional Therapy Strategies in Pediatric Crohn’s Disease

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 212
Author(s):  
Charlotte M. Verburgt ◽  
Mohammed Ghiboub ◽  
Marc A. Benninga ◽  
Wouter J. de Jonge ◽  
Johan E. Van Limbergen
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Enteral Nutrition ◽  
Intestinal Inflammation ◽  
Management Strategies ◽  
Nutritional Therapy ◽  
Nutritional Deficiencies ◽  
Intestinal Immunity ◽  
Exclusive Enteral Nutrition ◽  
Therapy Strategies

The increase in incidences of pediatric Crohn’s Disease (CD) worldwide has been strongly linked with dietary shifts towards a Westernized diet, ultimately leading to altered gut microbiota and disturbance in intestinal immunity and the metabolome. Multiple clinical studies in children with CD have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission with an excellent safety profile. However, EEN is poorly tolerated, limiting its compliance and clinical application. This has spiked an interest in the development of alternative and better-tolerated nutritional therapy strategies. Several nutritional therapies have now been designed not only to treat the nutritional deficiencies seen in children with active CD but also to correct dysbiosis and reduce intestinal inflammation. In this review, we report the most recent insights regarding nutritional strategies in children with active CD: EEN, partial enteral nutrition (PEN), Crohn’s disease exclusion diet (CDED), and CD treatment-with-eating diet (CD-TREAT). We describe their setup, efficacy, safety, and (dis)advantages as well as some of their potential mechanisms of action and perspectives. A better understanding of different nutritional therapeutic options and their mechanisms will yield better and safer management strategies for children with CD and may address the barriers and limitations of current strategies in children.

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