Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment

Compromised epithelial barrier function and tight junction alterations are hallmarks of a number of gastrointestinal disorders, including inflammatory bowel disease (IBD). Increased levels of IL-18 have been observed in mucosal samples from Crohn's disease and ulcerative colitis patients. Remarkably, several reports have demonstrated that immunological or genetic blockage of IL-18 ameliorates the severity of colitis in multiple in vivo models of IBD. Nevertheless, the effects of IL-18 on intestinal epithelial barrier function remain unclear. We hypothesized that IL-18 could disrupt intestinal epithelial barrier structure and function, thus contributing to tissue damage in the context of IBD. The aims of the present study were to determine the effects of IL-18 on epithelial barrier structure and function and to characterize the mechanisms involved in these modulatory properties. Human colonic epithelial Caco-2 monolayers were coincubated with IL-18 for 24 h and processed for immunocytochemistry, immunoblotting, quantitative PCR, and permeability measurements (transepithelial resistance, FITC-dextran fluxes, and bacterial translocation). Our findings indicate that IL-18 selectively disrupts tight junctional occludin, without affecting the distribution pattern of claudin-4, claudin-5, zonula occludens-1, or E-cadherin. This effect coincided with a significant increase in myosin light chain kinase (MLCK) protein levels and activity. Pharmacological inhibition of MLCK and NF-κB prevented IL-18-induced loss of occludin. Although too subtle to alter paracellular permeability, these fine changes correlated with an MLCK-dependent increase in neutrophil transepithelial migration. In conclusion, our data suggest that IL-18 may potentiate inflammation in the context of IBD by facilitating neutrophil transepithelial migration via MLCK-dependent disruption of tight junctional occludin.

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Transepidermal water loss: the signal for recovery of barrier structure and function.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)38361-9 ◽

1989 ◽

Vol 30 (3) ◽

pp. 323-333 ◽

Cited By ~ 4

Author(s):

G Grubauer ◽

P M Elias ◽

K R Feingold

Keyword(s):

Water Loss ◽

Transepidermal Water Loss ◽

Structure And Function ◽

Barrier Structure ◽

And Function

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Antrum Mucosal Protein-18 Peptide Targets Tight Junctions to Protect and Heal Barrier Structure and Function in Models of Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1097/mib.0000000000000499 ◽

2015 ◽

pp. 1 ◽

Cited By ~ 2

Author(s):

Peili Chen ◽

Danika Bakke ◽

Lauren Kolodziej ◽

James Lodolce ◽

Christopher R. Weber ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Tight Junctions ◽

Bowel Disease ◽

Structure And Function ◽

Barrier Structure ◽

Inflammatory Bowel ◽

Mucosal Protein ◽

And Function

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Sub-Inhibitory Clindamycin and Azithromycin reduce S. aureus Exoprotein Induced Toxicity, Inflammation, Barrier Disruption and Invasion

Journal of Clinical Medicine ◽

10.3390/jcm8101617 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1617 ◽

Cited By ~ 2

Author(s):

Hu ◽

Ramezanpour ◽

Hayes ◽

Liu ◽

Psaltis ◽

...

Keyword(s):

Structure And Function ◽

Mucosal Barrier ◽

Enzyme Linked Immunosorbent Assay ◽

Protein Synthesis Inhibitor ◽

Barrier Structure ◽

Synthesis Inhibitor ◽

Barrier Disruption ◽

Human Nasal Epithelial Cells ◽

Invasive Capacity ◽

And Function

Background: Chronic rhinosinusitis (CRS) is defined as a chronic inflammation of the nose and paranasal sinus mucosa associated with relapsing infections—particularly with S. aureus. Long-term treatments with protein synthesis inhibitor antibiotics have been proposed to reduce inflammation in the context chronic severe inflammatory airway pathologies, including CRS. This study assessed the effect of subinhibitory clindamycin and azithromycin on S. aureus exoprotein induced inflammation, toxicity and invasiveness. Methods: S. aureus ATCC51650 and two clinical isolates grown in planktonic and biofilm form were treated with subinhibitory clindamycin and azithromycin. Exoproteins were collected and applied to primary human nasal epithelial cells (HNECs) in monolayers and at air-liquid interface. This was followed by lactate dehydrogenase (LDH), enzyme-linked immunosorbent assay (ELISA), Transepithelial Electrical Resistance (TEER) and paracellular permeability assays to assess the effect on cell toxicity, inflammatory cytokine production and mucosal barrier structure and function, respectively. The effect of these treatments was tested as well on the S. aureus invasiveness of HNECs. Results: Subinhibitory clindamycin reduced S. aureus exoprotein production in planktonic and biofilm form, thereby blocking exoprotein-induced toxicity, reversing its detrimental effects on mucosal barrier structure and function and modulating its inflammatory properties. Sub-inhibitory azithromycin had similar effects—albeit to a lesser extent. Furthermore, clindamycin—but not azithromycin—treated S. aureus lost its invasive capacity of HNECs. Conclusion: Subinhibitory clindamycin and azithromycin reduce S. aureus exoprotein production, thereby modulating the inflammatory cascade by reducing exoprotein-induced toxicity, inflammation, mucosal barrier disruption and invasiveness.

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