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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Probiotics and commensals reverse TNF-alpha- and IFN-gamma-induced dysfunction in human intestinal epithelial cells
Silvia Resta-Lenert1, Kim E Barrett
1Department of Medicine, University of California, San Diego, School of Medicine, San Diego, California, USA.
Background & Aims:
Commensal bacteria are crucial for the development of the mucosal immune system. Probiotics are commensals with special characteristics and may protect mucosal surfaces against pathogens. Pathogens cause significant phenotypic alterations in infected epithelial cells, and probiotics reverse these deleterious responses. We hypothesized that probiotics and/or commensals may also reverse epithelial damage produced by cytokines.
Methods:
Human intestinal epithelial cells were exposed basolaterally to interferon (IFN)-gamma (10(3) U/mL) or tumor necrosis factor (TNF)-alpha (10 ng/mL) for up to 48 hours and assessed for ion transport, transepithelial resistance (TER), and epithelial permeability in the presence or absence of probiotics (Streptococcus thermophilus [ST] and Lactobacillus acidophilus [LA]), or the commensal, Bacteroides thetaiotaomicron (BT).
Results:
Agonist-stimulated chloride secretion was inhibited by IFN-gamma, an effect prevented by ST/LA or BT. The ability of ST/LA or BT to restore Cl(-) secretion was blocked by inhibitors of p38 MAPK, ERK1, 2, and PI3K. The cystic fibrosis transmembrane conductance regulator (CFTR) and the NKCC1 cotransporter were down-regulated by IFN-gamma, and ST/LA pretreatment reversed this effect. Both TNF-alpha and IFN-gamma significantly reduced TER and increased epithelial permeability, effects prevented by ST/LA or BT. A Janus kinase (JAK) inhibitor synergistically potentiated effects of ST/LA or BT on TER and permeability, but p38, ERK1, 2, or PI3K inhibition did not. Finally, only probiotic-treated epithelial cells exposed to cytokines showed reduced activation of SOCS3 and STAT1,3.
Conclusions:
Deleterious effects of TNF-alpha and IFN-gamma on epithelial function are prevented by probiotic, and to a lesser extent, commensal pretreatment. These data extend the spectrum of effects of such bacteria on intestinal epithelial function and may justify their use in inflammatory disorders.
Insights
Probiotics and commensal bacteria protect intestinal epithelial cells from cytokine damage. These beneficial bacteria reverse harmful effects of tumor necrosis factor-alpha and interferon-gamma on gut barrier function.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Commensal bacteria are vital for mucosal immune system development.
- Probiotics, a subset of commensals, may shield mucosal surfaces from pathogens.
- Probiotics can reverse pathogen-induced epithelial cell damage.
Purpose of the Study:
- To investigate if probiotics and commensals can reverse epithelial damage induced by cytokines.
- To assess the impact of probiotics and commensals on cytokine-mediated alterations in intestinal epithelial cell function.
Main Methods:
- Human intestinal epithelial cells were treated with interferon-gamma (IFN-γ) or tumor necrosis factor-alpha (TNF-α).
- Cells were co-treated with probiotics (Streptococcus thermophilus [ST] and Lactobacillus acidophilus [LA]) or Bacteroides thetaiotaomicron (BT).
- Assessed outcomes included ion transport, transepithelial resistance (TER), and epithelial permeability.
Main Results:
- IFN-γ-induced inhibition of chloride secretion was prevented by ST/LA or BT.
- ST/LA or BT reversed TNF-α and IFN-γ-induced reductions in TER and increases in epithelial permeability.
- Probiotic pretreatment reduced cytokine-induced activation of SOCS3 and STAT1,3.
Conclusions:
- Probiotic and commensal pretreatment protect intestinal epithelial cells from deleterious cytokine effects.
- These findings support the use of probiotics in managing inflammatory gut disorders.
- The study expands understanding of beneficial bacteria's role in intestinal epithelial health.
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