Disruption of sulphated glycosaminoglycans in intestinal inflammation

Murch, Simon; MacDonald, T T; Walker-Smith, J A; Lionetti, Paolo; Levin, Michael; Klein, Nigel

doi:10.1016/0140-6736(93)90485-y

Cited by 172 publications

(106 citation statements)

References 27 publications

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“…Therefore, our findings may also have implications for intestinal inflammation or sepsis. In fact, intestinal biopsies from patients with inflammatory bowel diseases reveal the very same loss of HS specifically from the basolateral surface of the epithelial cells (39). The prospect of heparin treatment strongly warrants further investigations in this field.…”

Section: Discussionmentioning

confidence: 97%

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

Bode

Murch

Freeze

2006

Journal of Biological Chemistry

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Protein-losing enteropathy (PLE), the loss of plasma proteins through the intestine, is a symptom in ostensibly unrelated diseases. Emerging commonalities indicate that genetic insufficiencies predispose for PLE and environmental insults, e.g. viral infections and inflammation, trigger PLE onset. The specific loss of heparan sulfate (HS) from the basolateral surface of intestinal epithelial cells only during episodes of PLE suggests a possible mechanistic link. In the first tissue culture model of PLE using a monolayer of intestinal epithelial HT29 cells, we proved that HS loss directly causes protein leakage and amplifies the effects of the proinflammatory cytokine tumor necrosis factor ␣ (TNF␣). Here, we extend our in vitro model to assess the individual and combined effects of HS loss, interferon ␥ (IFN␥), TNF␣, and increased pressure, and find that HS plays a central role in the patho-mechanisms underlying PLE. Increased pressure, mimicking venous hypertension seen in postFontan PLE patients, substantially increased protein leakage, but HS loss, IFN␥, or TNF␣ alone had only minor effects. However, IFN␥ up-regulated TNFR1 expression and amplified TNF␣-induced protein leakage. IFN␥ and TNF␣ compromised the integrity of the HT29 monolayer and made it more susceptible to increased pressure. HS loss itself compromises the integrity of the monolayer, amplifying the effects of pressure, but also amplifies the effects of both cytokines. In the absence of HS a combination of increased pressure, IFN␥, and TNF␣ caused maximum protein leakage. Soluble heparin fully compensated for HS loss, providing a reasonable explanation for patient favorable response to heparin therapy.

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Section: Discussionmentioning

confidence: 97%

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

Bode

Murch

Freeze

2006

Journal of Biological Chemistry

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“…19 Histochemical studies have shown a reduction in mucosal sulphated proteoglycans, including those on endothelium, in ulcerative colitis. 20 Heparin might have the potential to replace this de®cit by adhering to the endothelium, 21 thus restoring the normal negative charge of the endothelium to repel the negativelycharged neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Treatment of corticosteroid‐resistant ulcerative colitis with heparin —a report of 16 cases

Evans

Wong

Morris

et al. 1997

Aliment Pharmacol Ther

135

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Background:Heparin, a group of sulphated glycosaminoglycans, in addition to its anticoagulant activity, has a wide range of potentially anti‐inflammatory effects. These include inhibition of neutrophil elastase and inactivation of chemokines. Previous reports of fortuitous improvement in ulcerative colitis patients treated with heparin for prophylaxis of venous thrombosis, prompted us to perform a pilot study in patients with corticosteroid‐resistant ulcerative colitis.Methods:Sixteen hospitalized patients in relapse from ulcerative colitis and unresponsive to high‐dose corticosteroid therapy were treated with intravenous standard heparin (subcutaneous in two patients), the dose was adjusted to provide standard anticoagulant activity. Five patients continued with subcutaneous injections on discharge, with a gradual reduction in the frequency of doses.Results:Within 1 week of starting heparin, 12/16 patients had shown a considerable reduction in stool frequency. After 2 weeks of heparin therapy median stool frequency had improved from 8.0/day (range 6.3–10.0) pre‐treatment to 3.5/day (2.5–5.25) (P=0.008), and by 4 weeks 12/16 achieved clinical remission. Four patients required elective colectomy. Three patients were treated with heparin on a second occasion during a relapse, two failed to respond and required subsequent colectomy. Nine remain well. No serious complications were seen due to the anticoagulant activity, apart from bruising at subcutaneous injection sites.Conclusion:The response to heparin in patients with ulcerative colitis resistant to standard therapy is encouraging and supports the previous uncontrolled evidence for a therapeutic effect. A controlled trial of heparin in ulcerative colitis is clearly indicated.

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“…Mucins and glycosaminoglycans (GAGs) are classes of glycoproteins associated with the epithelia of the GI tract and help to maintain its integrity and regulate its permeability. Prior work has observed that sulfated GAGs are depleted and disrupted in inflammatory bowel disease [61], and mucolytic bacteria appear to proliferate to particularly high levels in the intestines of patients with ulcerative colitis or Crohn's disease [62]. Other studies have also found that gut flora, such as the commensal B. thetaiotaomicron, metabolize these glycans, and that this metabolism contributes to their ability to colonize the gut [63] [64].…”

Section: Accurate Metagenome Annotation Clarifies Community Functionamentioning

confidence: 99%

Automated and accurate estimation of gene family abundance from shotgun metagenomes

Nayfach

Bradley

Wyman

et al. 2015

Preprint

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Shotgun metagenomic DNA sequencing is a widely applicable tool for characterizing the functions that are encoded by microbial communities. Several bioinformatic tools can be used to functionally annotate metagenomes, allowing researchers to draw inferences about the functional potential of the community and to identify putative functional biomarkers. However, little is known about how decisions made during annotation affect the reliability of the results. Here, we use statistical simulations to rigorously assess how to optimize annotation accuracy and speed, given parameters of the input data like read length and library size. We identify best practices in metagenome annotation and use them to guide the development of the Shotgun Metagenome Annotation Pipeline (ShotMAP). ShotMAP is an analytically flexible, end-to-end annotation pipeline that can be implemented either on a local computer or a cloud compute cluster. We use ShotMAP to assess how different annotation databases impact the interpretation of how marine metagenome and metatranscriptome functional capacity changes across seasons. We also apply ShotMAP to data obtained from a clinical microbiome investigation of inflammatory bowel disease. This analysis finds that gut microbiota collected from Crohn's disease patients are functionally distinct from gut microbiota collected from either ulcerative colitis patients or healthy controls, with differential abundance of metabolic pathways related to host-microbiome interactions that may serve as putative biomarkers of disease. Author SummaryMicrobial communities perform a wide variety of functions, from marine photosynthesis to aiding digestion in the human gut. Shotgun "metagenomic" sequencing can be used to sample millions of short DNA sequences from such communities directly, without needing to first culture its constituents in the laboratory. Using these data, researchers can survey which functions are encoded by mapping these short sequences to known protein families and pathways. Several tools for this annotation already exist. But, annotation is a multi-step process that includes identification of genes in a metagenome and determination of the type of protein each gene encodes. We currently know little about how different choices of parameters during annotation influences the final results. In this work, we systematically test how several key decisions affect the accuracy and speed of annotation, and based on these results, develop new software for annotation, which we named ShotMAP. We then use ShotMAP to functionally characterize marine communities and gut communities in a clinical cohort of inflammatory bowel disease. We find several functions are differentially represented in the gut microbiome of Crohn's disease patients, which could be candidates for biomarkers and could also offer insight into the pathophysiology of Crohn's. ShotMAP is freely available (https://github.com/sharpton/shotmap).

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Disruption of sulphated glycosaminoglycans in intestinal inflammation

Cited by 172 publications

References 27 publications

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

Treatment of corticosteroid‐resistant ulcerative colitis with heparin —a report of 16 cases

Automated and accurate estimation of gene family abundance from shotgun metagenomes

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