scholarly journals Oxygen battle in the gut: Hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine

2020 ◽  
Vol 295 (30) ◽  
pp. 10493-10505 ◽  
Author(s):  
Rashi Singhal ◽  
Yatrik M. Shah
Keyword(s):  
Barrier Function ◽  
Inflammatory Responses ◽  
Intestinal Barrier ◽  
Nutrient Absorption ◽  
Intestinal Barrier Function ◽  
Adaptation To Hypoxia ◽  
Hypoxia Inducible Factors ◽  
Epithelial Barrier Function ◽  
Hypoxic Conditions ◽  
Progression Of Disease

The gastrointestinal tract is a highly proliferative and regenerative tissue. The intestine also harbors a large and diverse microbial population collectively called the gut microbiome (microbiota). The microbiome–intestine cross-talk includes a dynamic exchange of gaseous signaling mediators generated by bacterial and intestinal metabolisms. Moreover, the microbiome initiates and maintains the hypoxic environment of the intestine that is critical for nutrient absorption, intestinal barrier function, and innate and adaptive immune responses in the mucosal cells of the intestine. The response to hypoxia is mediated by hypoxia-inducible factors (HIFs). In hypoxic conditions, the HIF activation regulates the expression of a cohort of genes that promote adaptation to hypoxia. Physiologically, HIF-dependent genes contribute to the aforementioned maintenance of epithelial barrier function, nutrient absorption, and immune regulation. However, chronic HIF activation exacerbates disease conditions, leading to intestinal injury, inflammation, and colorectal cancer. In this review, we aim to outline the major roles of physiological and pathological hypoxic conditions in the maintenance of intestinal homeostasis and in the onset and progression of disease with a major focus on understanding the complex pathophysiology of the intestine

scholarly journals BAFF Blockade Attenuates Inflammatory Responses and Intestinal Barrier Dysfunction in a Murine Endotoxemia Model

2020 ◽  
Vol 11 ◽  
Author(s):  
Runze Quan ◽  
Chaoyue Chen ◽  
Wei Yan ◽  
Ying Zhang ◽  
Xi Zhao ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Survival Rates ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction ◽  
Protein Levels ◽  
Lps Challenge ◽  
Endotoxemia Model

B cell-activating factor (BAFF) production is increased in septic patients. However, the specific role of BAFF in sepsis remains unknown. This study was designed to investigate the expression and function of BAFF in an experimental endotoxemia model and to identify the potential mechanisms. We established an endotoxemia mouse (6–8 weeks, 20–22 g) model by administering 30 mg/kg lipopolysaccharide (LPS). BAFF levels in the circulating system and organ tissues were measured 4 and 8 h after LPS injection. Survival rates in the endotoxemia mice were monitored for 72 h after BAFF blockade. The effects of BAFF blockade on systemic and local inflammation, organ injuries, and intestinal barrier function were also evaluated 4 h after LPS treatment. BAFF production was systemically and locally elevated after LPS challenge. BAFF blockade improved the survival rate, systemic inflammation, and multi-organ injuries. Moreover, BAFF blockade attenuated both intestinal inflammation and impaired intestinal permeability. BAFF blockade upregulated ZO-1 and occludin protein levels via the NF-κB/MLCK/MLC signaling pathway. These results suggested that BAFF blockade protects against lethal endotoxemia at least partially by alleviating inflammation, multi-organ injuries, and improving intestinal barrier function and provides a novel focus for further research on sepsis and experimental evidence for clinical therapy.

scholarly journals Lubiprostone Induces Claudin-1 and Protects Intestinal Barrier Function

Pharmacology ◽  
2019 ◽  
Vol 105 (1-2) ◽  
pp. 102-108 ◽  
Author(s):  
Norio Nishii ◽  
Tadayuki Oshima ◽  
Min Li ◽  
Hirotsugu Eda ◽  
Kumiko Nakamura ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Fluorescein Isothiocyanate ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Dependent Manner ◽  
Epithelial Permeability ◽  
Epithelial Barrier Function ◽  
Dose Dependent

Introduction: Lubiprostone, a chloride channel activator, is said to reduce epithelial permeability. However, whether lubiprostone has a direct effect on the epithelial barrier function and how it modulates the intestinal barrier function remain unknown. Therefore, the effects of lubiprostone on intestinal barrier function were evaluated in vitro. Methods: Caco-2 cells were used to assess the intestinal barrier function. To examine the expression of claudins, immunoblotting was performed with specific antibodies. The effects of lubiprostone on cytokines (IFNγ, IL-6, and IL-1β) and aspirin-induced epithelial barrier disruption were assessed by transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) labeled-dextran permeability. Results: IFNγ, IL-6, IL-1β, and aspirin significantly decreased TEER and increased epithelial permeability. Lubiprostone significantly improved the IFNγ-induced decrease in TEER in a dose-dependent manner. Lubiprostone significantly reduced the IFNγ-induced increase in FITC labeled-dextran permeability. The changes induced by IL-6, IL-1β, and aspirin were not affected by lubiprostone. The expression of claudin-1, but not claudin-3, claudin-4, occludin, and ZO-1 was significantly increased by lubiprostone. Conclusion: Lubiprostone significantly improved the IFNγ-induced decrease in TEER and increase in FITC labeled-dextran permeability. Lubiprostone increased the expression of claudin-1, and this increase may be related to the effect of lubiprostone on the epithelial barrier function.

scholarly journals 3343 Identification of host-microbial interaction networks that mediate intestinal epithelial barrier function in necrotizing enterocolitis

2019 ◽  
Vol 3 (s1) ◽  
pp. 13-13
Author(s):  
David R Hill ◽  
Roberto Cieza ◽  
Veda K. Yadagiri ◽  
Phillip Tarr ◽  
Jason R. Spence ◽  
...  
Keyword(s):  
Barrier Function ◽  
Bacterial Colonization ◽  
Intestinal Barrier ◽  
Microbial Interactions ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Epithelial Barrier Function ◽  
Novel Approach ◽  
Species Specific

OBJECTIVES/SPECIFIC AIMS: The central goal of this proposal is to characterize the mechanisms that mediate success or failure of immature intestinal barrier in necrotizing enterocilitis. METHODS/STUDY POPULATION: To do this, I will utilize stem cell derived human intestinal organoids (HIOs), an innovative model of the immature intestine, and a cohort of bacterial isolates collected from premature infants who developed NEC to interrogate the cause-effect relationship of these strains on maintenance of the intestinal barrier. I hypothesize that the epithelial response to bacterial colonization is strain-dependent and results in differences in inflammatory signaling that shape epithelial barrier function in the immature intestine. RESULTS/ANTICIPATED RESULTS: Preliminary data shows that colonization of HIOs with different bacteria leads to species-specific changes in barrier function, and some species selectively damage the epithelial barrier while others enhance epithelial barrier function. I have identified key inflammatory signals that serve as central drivers of intestinal barrier function. DISCUSSION/SIGNIFICANCE OF IMPACT: Characterization of this process is expected to substantially advance scientific understanding of early events in NEC pathogenesis and lead to new opportunities for targeted therapeutic intervention to accelerate barrier maturation or prevent hyperinflammatory reactivity in the neonatal intestine. The research proposed in this application represents an entirely novel approach to studying host-microbial interactions in the immature. Conceptually, this novel translational approach will help to define the pivotal role of colonizing bacteria in initiating epithelial inflammation in NEC patients.

scholarly journals Macleaya cordataExtract Decreased Diarrhea Score and Enhanced Intestinal Barrier Function in Growing Piglets

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Gang Liu ◽  
Guiping Guan ◽  
Jun Fang ◽  
Yordan Martínez ◽  
Shuai Chen ◽  
...  
Keyword(s):  
Barrier Function ◽  
Inflammatory Responses ◽  
Practical Interest ◽  
Intestinal Barrier ◽  
Basal Diet ◽  
Growing Pigs ◽  
Intestinal Barrier Function ◽  
Control Group ◽  
Supplement Group ◽  
Macleaya Cordata

Macleaya cordataextract is of great scientific and practical interest to researchers, due to its antimicrobial and anti-inflammatory responses within experimental animals. This study was designed to determine the diarrhea score and innate immunity of growing piglets after they had receivedMacleaya cordataextract supplements. A total of 240 growing pigs were randomly assigned to one of three dietary treatments, with 8 replicates per treatment and 10 piglets per replicate. All pigs received a basal diet containing similar amounts of nutrients. The three treatments were a control (no additive), an antibiotic (200 mg/kg colistin), and theMacleaya cordataextract supplement group (40 mg/kgMacleaya cordataextract). The diarrhea score was calculated after D 28. The jejunal samples were obtained from five piglets selected randomly from each treatment on D 28. In comparison with the control group, the dietaryMacleaya cordataextract and colistin group demonstrated a substantially decreased diarrhea score. The introduction ofMacleaya cordataextract supplements to the diet significantly increased volumes of ZO-1 and claudin-1, particularly in comparison with the pigs in the control group (P<0.05). The findings indicate thatMacleaya cordataextract does enhance intestinal barrier function in growing piglets and that it could be used as a viable substitute for antibiotics.

scholarly journals JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function

2013 ◽  
Vol 24 (18) ◽  
pp. 2849-2860 ◽  
Author(s):  
Ana C. Monteiro ◽  
Ronen Sumagin ◽  
Carl R. Rankin ◽  
Giovanna Leoni ◽  
Michael J. Mina ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Paracellular Permeability ◽  
Small Gtpase ◽  
Intestinal Barrier Function ◽  
Epithelial Permeability ◽  
Functional Link ◽  
Epithelial Barrier Function ◽  
And Control ◽  
Interfering Rna

Intestinal barrier function is regulated by epithelial tight junctions (TJs), structures that control paracellular permeability. Junctional adhesion molecule-A (JAM-A) is a TJ-associated protein that regulates barrier; however, mechanisms linking JAM-A to epithelial permeability are poorly understood. Here we report that JAM-A associates directly with ZO-2 and indirectly with afadin, and this complex, along with PDZ-GEF1, activates the small GTPase Rap2c. Supporting a functional link, small interfering RNA–mediated down-regulation of the foregoing regulatory proteins results in enhanced permeability similar to that observed after JAM-A loss. JAM-A–deficient mice and cultured epithelial cells demonstrate enhanced paracellular permeability to large molecules, revealing a potential role of JAM-A in controlling perijunctional actin cytoskeleton in addition to its previously reported role in regulating claudin proteins and small-molecule permeability. Further experiments suggest that JAM-A does not regulate actin turnover but modulates activity of RhoA and phosphorylation of nonmuscle myosin, both implicated in actomyosin contraction. These results suggest that JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.

scholarly journals PG-mediated closure of paracellular pathway and not restitution is the primary determinant of barrier recovery in acutely injured porcine ileum

2003 ◽  
Vol 285 (5) ◽  
pp. G967-G979 ◽  
Author(s):  
Jody L. Gookin ◽  
Joseph A. Galanko ◽  
Anthony T. Blikslager ◽  
Robert A. Argenzio
Keyword(s):  
Epithelial Cells ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Acute Injury ◽  
Intestinal Barrier Function ◽  
Ileal Mucosa ◽  
Epithelial Barrier Function ◽  
Ussing Chambers ◽  
Relative Contribution ◽  
Primary Determinant

Small bowel epithelium is at the frontline of intestinal barrier function. Restitution is considered to be the major determinant of epithelial repair, because function recovers in parallel with restitution after acute injury. As such, studies of intact mucosa have largely been replaced by migration assays of cultured epithelia. These latter studies fail to account for the simultaneous roles played by villous contraction and paracellular permeability in recovery of barrier function. NSAIDs result in increased intestinal permeability and disease exacerbation in patients with inflammatory bowel disease (IBD). Thus we examined the reparative attributes of endogenous PGs after injury of ileal mucosa by deoxycholate (6 mM) in Ussing chambers. Recovery of transepithelial electrical resistance (TER) from 20-40 Ω·cm2 was abolished by indomethacin (Indo), whereas restitution of 40-100% of the villous surface was unaffected despite concurrent arrest of villous contraction. In the presence of PG, resident crypt and migrating epithelial cells were tightly apposed. In tissues treated with Indo, crypt epithelial cells had dilated intercellular spaces that were accentuated in the migrating epithelium. TER was fully rescued from the effects of Indo by osmotic-driven collapse of the paracellular space, and PG-mediated recovery was significantly impaired by blockade of Cl- secretion. These studies are the first to clearly distinguish the relative contribution of paracellular resistance vs. restitution to acute recovery of epithelial barrier function. Restitution was ineffective in the absence of PG-mediated paracellular space closure. Failure of PG-mediated repair mechanisms may underlie barrier failure resulting from NSAID use in patients with underlying enteropathy.

scholarly journals Epithelial PBLD attenuates intestinal inflammatory response and improves intestinal barrier function by inhibiting NF-κB signaling

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Shengbo Chen ◽  
Hongbin Liu ◽  
Zhijun Li ◽  
Jingyi Tang ◽  
Bing Huang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Barrier Function ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Trinitrobenzene Sulfonic Acid ◽  
Intestinal Epithelial ◽  
Colonic Tissue ◽  
Tnf Α

AbstractIntestinal barrier function defects and dysregulation of intestinal immune responses are two key contributory factors in the pathogenesis of ulcerative colitis (UC). Phenazine biosynthesis-like domain-containing protein (PBLD) was recently identified as a tumor suppressor in gastric cancer, hepatocellular carcinoma, and breast cancer; however, its role in UC remains unclear. Therefore, we analyzed colonic tissue samples from patients with UC and constructed specific intestinal epithelial PBLD-deficient (PBLDIEC−/−) mice to investigate the role of this protein in UC pathogenesis. We found that epithelial PBLD was decreased in patients with UC and was correlated with levels of tight junction (TJ) and inflammatory proteins. PBLDIEC−/− mice were more susceptible to dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis compared with wild-type (WT) mice. In DSS-induced colitis, PBLDIEC−/− mice had impaired intestinal barrier function and greater immune cell infiltration in colonic tissue than WT mice. Furthermore, TJ proteins were markedly reduced in PBLDIEC−/− mice compared with WT mice with colitis. Nuclear factor (NF)-κB activation was markedly elevated and resulted in higher expression levels of downstream effectors (C–C motif chemokine ligand 20, interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in colonic epithelial cells isolated from PBLDIEC−/− mice than WT mice with colitis. PBLD overexpression in intestinal epithelial cells (IECs) consistently inhibited TNF-α/interferon-γ-induced intestinal barrier disruption and TNF-α-induced inflammatory responses via the suppression of NF-κB. In addition, IKK inhibition (IKK-16) rescued excessive inflammatory responses induced by TNF-α in PBLD knockdown FHC cells. Co-immunoprecipitation assays showed that PBLD may interact with IKKα and IKKβ, thus inhibiting NF-κB signaling, decreasing inflammatory mediator production, attenuating colonic inflammation, and improving intestinal barrier function. Modulating PBLD expression may provide a novel approach for treatment in patients with UC.

Probiotic bacteria and intestinal epithelial barrier function

2010 ◽  
Vol 298 (6) ◽  
pp. G807-G819 ◽  
Author(s):  
Christina L. Ohland ◽  
Wallace K. MacNaughton
Keyword(s):  
Barrier Function ◽  
Defense Mechanisms ◽  
Intestinal Barrier ◽  
Single Layer ◽  
Secretory Iga ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Irritable Bowel ◽  
The Many

The intestinal tract is a diverse microenvironment where more than 500 species of bacteria thrive. A single layer of epithelium is all that separates these commensal microorganisms and pathogens from the underlying immune cells, and thus epithelial barrier function is a key component in the arsenal of defense mechanisms required to prevent infection and inflammation. The epithelial barrier consists of a dense mucous layer containing secretory IgA and antimicrobial peptides as well as dynamic junctional complexes that regulate permeability between cells. Probiotics are live microorganisms that confer benefit to the host and that have been suggested to ameliorate or prevent diseases including antibiotic-associated diarrhea, irritable bowel syndrome, and inflammatory bowel disease. Probiotics likely function through enhancement of barrier function, immunomodulation, and competitive adherence to the mucus and epithelium. This review summarizes the evidence about effects of the many available probiotics with an emphasis on intestinal barrier function and the mechanisms affected by probiotics.

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