Correlation between cyclical epithelial barrier dysfunction and bacterial translocation in the relapses of intestinal inflammation

Porras, Mónica; Martín, María Teresa; Yang, Ping‐Chang; Jury, Jennifer; Perdue, Mary H.; Vergara, P.

doi:10.1097/01.mib.0000231571.88806.62

Cited by 67 publications

(55 citation statements)

References 46 publications

(86 reference statements)

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“…In patients suffering from UC, MUC2 protein levels are significantly decreased during active phases of the disease, resulting in a thinner protective mucus layer (Hinoda et al, 1998;Tytgat et al, 1996). In animal models of chronic intestinal inflammatory conditions that cycle between active and quiescent phases, paracellular permeability remains increased regardless of the inflammatory state, whereas transcellular permeability is only increased during active inflammation (Porras et al, 2006). Similar observations have been made in humans, where patients with quiescent CD have significantly increased intestinal permeability when compared to controls (Wyatt et al, 1993).…”

Section: Anatomy and Function Of The Physical Barriersupporting

confidence: 70%

The Roles of Interleukin-17 and T Helper 17 Cells in Intestinal Barrier Function

Trusevych¹,

Mortimer²,

Chadee³

2012

Inflammatory Bowel Disease - Advances in Pathogenesis and Management

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Section: Anatomy and Function Of The Physical Barriersupporting

confidence: 70%

The Roles of Interleukin-17 and T Helper 17 Cells in Intestinal Barrier Function

Trusevych¹,

Mortimer²,

Chadee³

2012

Inflammatory Bowel Disease - Advances in Pathogenesis and Management

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“…Other mechanisms, such as attenuation of critical host defense functions or local surface abnormalities, could also be involved. Irrespective of the relative contributions of these mechanisms, our data suggest the concept that an intact epithelial barrier in the intestinal tract is important not only for preventing systemic access of luminal microbes (47), as evidenced by increased splenic bacterial numbers in IL-6-deficient mice with extensive colon ulceration, but also for curtailing the luminal presence of systemically available nutrients that can promote growth of subsets of luminal microbes.…”

Section: Discussionmentioning

confidence: 90%

IL-6-Dependent Mucosal Protection Prevents Establishment of a Microbial Niche for Attaching/Effacing Lesion-Forming Enteric Bacterial Pathogens

Dann

Spehlmann

Hammond

et al. 2008

The Journal of Immunology

159

142

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Enteric infections with attaching/effacing lesion-inducing bacterial pathogens are a worldwide health problem. A murine infection model with one such pathogen, Citrobacter rodentium, was used to elucidate the importance of the pleiotropic immune regulator, IL-6, in the pathogenesis of infection. IL-6 was strongly induced in colonic epithelial cells and macrophages upon C. rodentium infection and was required for effective host defense, because mice lacking IL-6 failed to control bacterial numbers 2–3 wk after infection and exhibited increased mortality. IL-6 was not needed for mounting effective T and B cell responses to the pathogens, nor was it important for induction of IFN-γ or TNF-α, cytokines involved in host defense against the bacteria, or the antibacterial effector, NO. Instead, IL-6 played a key role in mucosal protection, since its absence was associated with marked infection-induced apoptosis in the colonic epithelium and subsequent ulcerations. Cell culture studies confirmed that IL-6 protected colon epithelial cells directly against inducible apoptosis, which was accompanied by increased expression of an array of genes encoding antiapoptotic proteins, including Bcl-xL, Mcl-1, cIAP-2, and Bcl-3. Ulcerations appeared to be pathogenetically important, because bacteria localized preferentially to those regions, and chemically induced colonic ulcerations promoted bacterial colonization. Furthermore, blood components likely present in ulcer exudates, particularly alanine, asparagine, and glycine, promoted bacterial growth. Thus, IL-6 is an important regulator of host defense against C. rodentium by protecting the mucosa against ulcerations which can act as a microbial niche for the bacteria.

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“…Rats with high levels of proinflammatory markers (active phase) show intestinal hypomotility associated with bacterial translocation. By contrast, animals with lower levels of proinflammatory markers (inactive phase) have intestinal hypermotility and absence of bacterial translocation (Porras et al, 2006a). It is interesting that these opposite patterns are associated with a dysregulated expression of NOS isoenzymes; a sustained down-regulation of nNOS exists through the inflammatory state (in both active and inactive phases), with iNOS up-regulation occurring only during the active phase (Porras et al, 2006b).…”

mentioning

confidence: 94%

The Nitric Oxide Donor LA-419 [S-(6-Nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate] Prevents Intestinal Dysmotility, Bacterial Translocation, and Inflammation in a Rat Model of Enteritis

Porras

Martín

Teran³

et al. 2007

J Pharmacol Exp Ther

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Indomethacin induces a chronic model of inflammatory bowel disease (IBD) characterized by spontaneous relapses of inflammation, bacterial translocation, and long-lasting motor disturbances derived from cyclical up-regulated inducible nitricoxide synthase (iNOS) and sustained down-regulated neuronal NOS (nNOS). The aims of this study were to evaluate whether LA-419 [S-(6-nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate], a NO-donor drug, could re-establish the normal expression of NOS and, hence, prevent the development of intestinal dysmotility, bacterial translocation, and relapses of inflammation associated to this model. Enteritis was induced in rats by administration of indomethacin with and without treatment with a novel NO-donor: LA-419 (0.5 mg/ml in the drinking water). Inflammatory reaction was evaluated by measuring blood leukocytes, serum tumor necrosis factor, and tissue myeloperoxidase. Intestinal motor activity was evaluated using strain-gauges. Ileal expression of iNOS and nNOS mRNA was determined by reverse transcription-polymerase chain reaction. Bacterial translocation was evaluated in cultures from mesenteric lymph nodes. The indomethacin-induced acute inflammatory reaction was associated with a rise in blood leukocytes and tumor necrosis factor. In the chronic stage, blood leukocyte monitoring allowed the selection of animals in active and inactive phases. Active phase was associated with iNOS up-regulation, high myeloperoxidase levels, hypomotility, and bacterial translocation. In contrast, inactive phase was associated with hypermotility and absence of bacterial translocation. LA-419 treatment restored nitric-oxide synthase isoenzyme expression and prevented the oscillation of both inflammatory and motor parameters that could be cyclically observed in inflamed rats. LA-419 also prevented intestinal dysmotility, bacterial translocation, and relapses of intestinal inflammation. LA-419 might be a novel therapeutic approach to prevent acute inflammatory relapses in patients with IBD.

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Correlation between cyclical epithelial barrier dysfunction and bacterial translocation in the relapses of intestinal inflammation

Cited by 67 publications

References 46 publications

The Roles of Interleukin-17 and T Helper 17 Cells in Intestinal Barrier Function

The Roles of Interleukin-17 and T Helper 17 Cells in Intestinal Barrier Function

IL-6-Dependent Mucosal Protection Prevents Establishment of a Microbial Niche for Attaching/Effacing Lesion-Forming Enteric Bacterial Pathogens

The Nitric Oxide Donor LA-419 [S-(6-Nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate] Prevents Intestinal Dysmotility, Bacterial Translocation, and Inflammation in a Rat Model of Enteritis

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