Circadian Disruption Alters Gut Barrier Integrity via a ß-catenin-MMP-related Pathway

Abstract We evaluated the mechanistic link between circadian rhythms and gut barrier permeability. Mice were subjected to either constant 24-hour light (LL) or 12-hour light/dark cycles (LD). Mice housed in LL experienced a significant increase in gut barrier permeability that was associated with dysregulated ß-catenin expression and altered expression of tight junction (TJ) proteins. Silencing of ß-catenin resulted in disruption of barrier function in SW480 cells, with ß-catenin appearing to an upstream regulator of Bmal1 and Clock. In addition, ß-catenin silencing downregulated ZO-1 and occludin TJ proteins with only limited or no changes at their mRNA levels, suggesting post transcriptional regulation. Indeed, silencing of ß-catenin significantly upregulated expression of matrix metallopeptidase (MMP)-2 and MMP-9, and blocking MMP-2/9 activity attenuated epithelial disruption induced by ß-catenin silencing. These results indicate the regulatory role of circadian disruption on gut barrier integrity and the associations between TJ proteins and circadian rhythms, while demonstrating the regulatory role of ß-catenin in this process.

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Regulatory role of glucocorticoids and glucocorticoid receptor mRNA levels on tyrosine hydroxylase gene expression in the locus coeruleus during repeated immobilization stress

Brain Research ◽

10.1016/s0006-8993(02)02647-1 ◽

2002 ◽

Vol 943 (2) ◽

pp. 216-223 ◽

Cited By ~ 61

Author(s):

Shinya Makino ◽

Mark A Smith ◽

Philip W Gold

Keyword(s):

Gene Expression ◽

Tyrosine Hydroxylase ◽

Glucocorticoid Receptor ◽

Locus Coeruleus ◽

Immobilization Stress ◽

Regulatory Role ◽

Mrna Levels ◽

Receptor Mrna ◽

Glucocorticoid Receptor Mrna

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A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00475.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. E1276-E1282 ◽

Cited By ~ 24

Author(s):

Long Cheng ◽

Xiao Han ◽

Yuguang Shi

Keyword(s):

Diabetic Retinopathy ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Regulatory Role ◽

Mrna Levels ◽

Diabetic Mice ◽

Acyltransferase Activity ◽

Onset Of Diabetes ◽

Anti Inflammatory

Platelet-activating factor (PAF) and lysophosphatidylcholine (LPC) are potent inflammatory lipids. Elevated levels of PAF and LPC are associated with the onset of diabetic retinopathy and neurodegeneration. However, the molecular mechanisms underlying such defects remain elusive. LPCAT1 is a newly reported lysophospholipid acyltransferase implicated in the anti-inflammatory response by its role in conversion of LPC to PC. Intriguingly, the LPCAT1 enzyme also catalyzes the synthesis of PAF from lyso-PAF with use of acetyl-CoA as a substrate. The present studies investigated regulatory roles of LPCAT1 in the synthesis of inflammatory lipids during the onset of diabetes. Our work shows that LPCAT1 plays an important role in the inactivation of PAF by catalyzing the synthesis of alkyl-PC, an inactivated form of PAF with use of acyl-CoA and lyso-PAF as substrates. In support of a role of LPCAT1 in anti-inflammatory responses in diabetic retinopathy, LPCAT1 is most abundantly expressed in the retina. Moreover, LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain tissues in response to the onset of diabetes in Ins2 Akita and db/db mice, mouse models of type 1 and type 2 diabetes, respectively. Conversely, treatment of db/db mice with rosiglitazone, an antidiabetes compound, significantly upregulated LPCAT1 mRNA levels concurrently with increased acyltransferase activity in the retina and brain. Collectively, these findings identified a novel regulatory role of LPCAT1 in catalyzing the inactivation of inflammatory lipids in the retina of diabetic mice.

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Altered expression of miRNAs and mRNAs reveals the potential regulatory role of miRNAs in the developmental process of early weaned goats

PLoS ONE ◽

10.1371/journal.pone.0220907 ◽

2019 ◽

Vol 14 (8) ◽

pp. e0220907 ◽

Cited By ~ 5

Author(s):

Rongrong Liao ◽

Yuhua Lv ◽

Lihui Zhu ◽

Yuexia Lin

Keyword(s):

Developmental Process ◽

Regulatory Role ◽

Altered Expression ◽

Potential Regulatory Role

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Microbiome Composition and Circadian Rhythm Disruption Alters Epithelial Barrier Integrity

Columbia Undergraduate Science Journal ◽

10.52214/cusj.v15i1.7408 ◽

2021 ◽

Vol 15 ◽

pp. 6-15

Author(s):

Elisha Pinker ◽

Timur Tuganbaev

Keyword(s):

Circadian Rhythms ◽

Gut Microbiome ◽

Epithelial Barrier ◽

Ecological Communities ◽

Intestinal Epithelial ◽

Barrier Permeability ◽

Barrier Integrity ◽

Microbiome Composition ◽

Wide Range ◽

Community Impacts

The intestine is home to one of the most complex ecological communities, termed the human gut microbiome. The gut microbiome modulates a wide range of human diseases from diabetes to neurological disorders to cancer. Separating the host and the gut microbiome is the epithelial barrier. The intestinal epithelium serves as an adaptive interaction hub between the host and microbiome that plays an important role in deciding the outcome of host-microbiome interactions. Regulation of epithelial barrier permeability to ions, nutrients and microbiome metabolites is known to be a tightly controlled process on the host side. However, whether the microbiome community also affects epithelial permeability remains unclear. Here, we show that alterations in microbiota composition by treatment with antibiotics selectively targeting specific members of the microbiome community impacts the permeability of the intestine. Additionally, modulating the microbiome through other methods such as altering diet composition shows changes in permeability of the epithelial barrier. As daily feeding rhythm entrains diurnal fluctuations in microbiome, we have set out to measure epithelial barrier permeability throw out the clock. We have discovered that the permeability of the intestinal epithelial barrier exhibits circadian rhythms in mice. Disruption of these rhythms, through jet-lag or genetic deficiencies in circadian machinery, consequently alters epithelial barrier integrity. Together, these findings provide evidence that disruptions in circadian rhythms as well as alterations in microbiome composition have direct consequences in intestinal permeability, and that microbiome might serve as a tool in regulating epithelium permeability.

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Nature-Identical Compounds and Organic Acids Ameliorate and Prevent the Damages Induced by an Inflammatory Challenge in Caco-2 Cell Culture

Molecules ◽

10.3390/molecules25184296 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4296

Author(s):

Andrea Toschi ◽

Barbara Rossi ◽

Benedetta Tugnoli ◽

Andrea Piva ◽

Ester Grilli

Keyword(s):

Organic Acids ◽

Intestinal Barrier ◽

Biological Properties ◽

Epithelial Cell Line ◽

Mrna Levels ◽

Intestinal Epithelial ◽

Negative Effects ◽

Gut Barrier ◽

Pro Inflammatory Cytokines

Bioactive compounds, such as organic acids (OA) and nature-identical compounds (NIC), can exert a role in the protection of intestinal mucosa functionality due to their biological properties. The aim of this study was to understand the role of 2 OA (citric and sorbic acid) and 2 NIC (thymol and vanillin), alone or combined in a blend (OA + NIC), on intestinal barrier functionality, either during homeostatic condition or during an inflammatory challenge performed with pro-inflammatory cytokines and lipopolysaccharides (LPS). The study was performed on the human epithelial cell line Caco-2, a well-known model of the intestinal epithelial barrier. The results showed how OA and NIC alone can improve transepithelial electrical resistance (TEER) and mRNA levels of tight junction (TJ) components, but OA + NIC showed stronger efficacy compared to the single molecules. When an inflammatory challenge occurred, OA + NIC blend was able both to ameliorate, and prevent, damage caused by the pro-inflammatory stimulus, reducing or preventing the drop in TEER and improving the TJ mRNA expression. The data support the role of OA + NIC in modulating gut barrier functionality and reducing the negative effects of inflammation in intestinal epithelial cells, thereby supporting the gut barrier functionality.

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Bridge the Gap – The Efficacy of β-Carotene in Immune Sensing of LPS and Intestinal Barrier Integrity in Colon Epithelial Cells

Current Developments in Nutrition ◽

10.1093/cdn/nzab034_005 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 71-71

Author(s):

Junrui Cheng ◽

Emilio Balbuena ◽

Baxter Miller ◽

Abdulkerim Eroglu

Keyword(s):

Epithelial Cells ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Low Grade ◽

Mrna Levels ◽

Limited Information ◽

Barrier Dysfunction ◽

Barrier Integrity ◽

Β Carotene

Abstract Objectives Gastrointestinal (GI) disorders are causing significant global health care burden. Lipopolysaccharide (LPS), a structural component of Gram-negative bacteria, induces low-grade inflammation and disturbs GI homeostasis. While the anti-inflammatory function of β-Carotene (BC), a provitamin A carotenoid, has been explored in multiple systems, a limited information exists on the roles of BC in modulating LPS-induced inflammation in colonocytes. Therefore, we aimed to mechanistically investigate the role of BC in LPS-induced colonic inflammation and intestinal barrier dysfunction. Methods Human colon epithelial cells (HT-29) were primed with interferon-γ at 50 ng/mL for 12 hours, then treated with 1 µg/mL LPS and BC at 1, 10, 100 nM, and 1, 10 µM for 15 hours. Inflammatory cytokines were quantified with an ELISA assay. The fold change in mRNA levels was determined by qPCR. Changes in proteins of interest were evaluated using both Western blot and immunocytochemistry (ICC) assays. Results LPS-stimulated production of IL-6 and TNFα levels was inhibited by BC treatment at 10 nM – 1 μM; IL-1β in whole cell lysates and supernatant IL-6 levels were decreased by BC treatment at all dosages. LPS-induced elevation of C-reactive protein and cyclooxygenase-1 mRNA was reversed with 1 μM and 10 μM BC treatment. Claudin-1 and occludin are major tight junction proteins that contribute to maintaining colonic barrier integrity. Intriguingly, BC at 10 nM – 1 μM significantly enhanced claudin-1 and occludin mRNA and protein levels. The up-regulation of claudin-1 was also validated in the ICC assay. A further exploration of the underlying mechanisms showed that BC inhibited the LPS-activated TLR4-NF-κB p65 pathway to alleviate inflammation in the cells. CD14, a membrane protein expressed on the surfaces of epithelial cells, could restore the impaired intestinal barrier function. In this study, an increased CD14 protein level was found in BC-treated cells, which was correlated with the improved claudin-1 and occludin levels, indicating that BC may promote colonic barrier integrity via up-regulating CD14. Conclusions BC plays a role in modulating LPS-induced TLR4 signaling pathway and enhancing gut barrier integrity. These novel findings will shed light on the role of BC in alleviating endotoxin-induced GI disorders. Funding Sources USDA.

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High-fat diet intake modulates maternal intestinal adaptations to pregnancy, and results in placental hypoxia and impaired fetal gut development

10.1101/436816 ◽

2018 ◽

Cited By ~ 1

Author(s):

Wajiha Gohir ◽

Katherine M. Kennedy ◽

Jessica G. Wallace ◽

Michelle Saoi ◽

Christian J. Bellissimo ◽

...

Keyword(s):

Gut Microbiota ◽

Health Research ◽

High Fat Diet ◽

Intestinal Inflammation ◽

Mrna Levels ◽

Gut Development ◽

High Fat ◽

Gut Barrier ◽

Barrier Integrity ◽

Diet Intake

Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. In this study we investigated how high-fat diet intake impacts the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation, and fetal intestinal development at E18.5. High-fat diet (HFD) was associated with decreased relative abundancesof SCFA producing genera during pregnancy. These diet-induced shifts paralleled decreased maternal intestinal mRNA levels of SCFA receptor Gpr41, modestly decreased cecal butyrate, and altered mRNA levels of inflammatory cytokines and immune cell markers in the maternal intestine. Maternal HFD resulted inimpaired gut barrier integrity, with corresponding increases in circulating maternal levels of LPS and TNF.Placentafromhigh-fat fed damsdemonstrated blood vessel immatu-rityand hypoxia, decreased freecarnitine, acylcarnitine derivatives, TMAO, as well as altered mRNA levels of inflammation, autophagy and ER stress markers. HFD exposed fetuses had increased activation of NF-κB and inhibition of the unfolded protein response in the developing intestine. Together, these data suggest that high-fat diet intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in increased maternal circulating LPS, which may ultimate contribute to changes in placental vasculariza-tion and fetal gut development.Funding informationFarncombe Family Digestive Health Research Institute (KMK); Canadian Institute of Health Research (CJB); Canada Research Chairs Program (MGS, DMS); Natural Sciences and Engineering Research Council of Canada, Genome Canada (PBM).

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