Publications by authors named "Sean P Colgan"

166 Publications

Lung neutrophils on a paleo diet: lean, mean inflammatory machines.

J Clin Invest 2021 May;131(10)

Sites of acute inflammation become austere environments for the procurement of energy. The combination of oxygen depletion (hypoxia) and decreased glucose availability requires surprising metabolic adaptability. In this issue of the JCI, Watts et al. examined the metabolic adaptability of murine neutrophils to the setting of acute pulmonary inflammation elicited by exposure to nebulized endotoxin. While neutrophils are generally considered a primarily glycolytic cell type, Watts et al. used a combination of labeled amino acids and high-resolution proteomics to reveal that the harsh environment of the inflammatory lesion drives neutrophils toward de novo protein synthesis and extracellular protein scavenging as a primary fuel. This study provides compelling evidence that tissue neutrophils scavenge extracellular proteins to fuel carbon metabolism, which aids in de novo protein synthesis and the promotion of an inflammatory phenotype. These observations reveal the surprisingly creative extent to which cells and tissues might adapt to energy-deficient inflammatory environments.
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http://dx.doi.org/10.1172/JCI149495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121505PMC
May 2021

Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation.

Proc Natl Acad Sci U S A 2021 May;118(20)

Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enriched in cyclic AMP response element-binding protein (CREB)-regulated gene targets. Utilizing loss- and gain-of-function approaches in cultured epithelia and murine colonoids, we demonstrate that EA elicits prominent CREB phosphorylation through cyclic AMP-independent mechanisms that requires elements of the mitogen-activated protein kinase signaling pathway. Further analysis revealed that EA signals through the G protein-coupled receptor GPR31 to promote induction of FosB, NR4A1, and DUSP1. These studies were extended to an in vivo murine model in conjunction with colonization of a pH reporter strain that demonstrated significant mucosal acidification in the TNFΔARE model of murine ileitis. Herein, we observed a strong correlation between the expression of acidosis-associated genes with bacterial reporter sfGFP intensity in the distal ileum. Finally, the expression of this unique EA-associated gene signature was increased during active inflammation in patients with Crohn's disease but not in the patient control samples. These findings establish a mechanism for EA-induced signals during inflammation-associated acidosis in both murine and human ileitis.
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http://dx.doi.org/10.1073/pnas.2023871118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157950PMC
May 2021

Creatine Supplementation for Patients with Inflammatory Bowl Diseases: A Scientific Rationale for a Clinical Trial.

Nutrients 2021 Apr 23;13(5). Epub 2021 Apr 23.

Comparative Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D2 Dublin, Ireland.

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that "oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn's disease". A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3-5 g of Cr per day for a time of 3-6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn's disease.
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http://dx.doi.org/10.3390/nu13051429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145094PMC
April 2021

Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage.

FASEB J 2021 May;35(5):e21552

Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

During episodes of acute inflammation, polymorphonuclear leukocytes (PMNs) are actively recruited to sites of inflammation or injury where they provide anti-microbial and wound-healing functions. One enzyme crucial for fulfilling these functions is myeloperoxidase (MPO), which generates hypochlorous acid from Cl and hydrogen peroxide. The potential exists, however, that uncontrolled the extracellular generation of hypochlorous acid by MPO can cause bystander tissue damage and inhibit the healing response. Previous work suggests that the microbiota-derived tryptophan metabolites 1H-indole and related molecules ("indoles") are protective during intestinal inflammation, although their precise mechanism of action is unclear. In the present work, we serendipitously discovered that indoles are potent and selective inhibitors of MPO. Using both primary human PMNs and recombinant human MPO in a cell-free system, we revealed that indoles inhibit MPO at physiologic concentrations. Particularly, indoles block the chlorinating activity of MPO, a reliable marker for MPO-associated tissue damage, as measured by coulometric-coupled HPLC. Further, we observed direct interaction between indoles and MPO using the established biochemical techniques microscale thermophoresis and STD-NMR. Utilizing a murine colitis model, we demonstrate that indoles inhibit bystander tissue damage, reflected in decreased colon 3-chlorotyrosine and pro-inflammatory chemokine expression in vivo. Taken together, these results identify microbiota-derived indoles that acts as endogenous immunomodulatory compounds through their actions on MPO, suggesting a symbiotic association between the gut microbiota and host innate immune system. Such findings offer exciting new targets for future pharmacological intervention.
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http://dx.doi.org/10.1096/fj.202100027RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078834PMC
May 2021

Intestinal Inflammation as a Dysbiosis of Energy Procurement: New Insights into an Old Topic.

Gut Microbes 2021 Jan-Dec;13(1):1-20

Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine , Aurora, United States.

Inflammatory bowel disease (IBD) coincides with profound shifts in microbiota and host metabolic energy supply and demand. The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic luminal microbiota and host lamina propria, with the microbiota and epithelium participating in an intricate energy exchange necessary for homeostasis. Maintenance and restoration of the barrier requires high energy flux and places significant demands on available substrates to generate ATP. It is recently appreciated that components of the microbiota contribute significantly to a multitude of biochemical pathways within and outside of the mucosa. Decades-old studies have appreciated that byproducts of the microbiota provide essential sources of energy to the intestinal epithelium, especially the colon. More recent work has unveiled the existence of numerous microbial-derived metabolites that support energy procurement within the mucosa. It is now appreciated that disease-associated shifts in the microbiota, termed dysbiosis, places significant demands on energy acquisition within the mucosa. Here, we review the topic of host- and microbial-derived components that influence tissue energetics in health and during disease.
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http://dx.doi.org/10.1080/19490976.2021.1880241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889129PMC
February 2021

Eosinophils attenuate hepatic ischemia-reperfusion injury in mice through ST2-dependent IL-13 production.

Sci Transl Med 2021 Feb;13(579)

Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.
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http://dx.doi.org/10.1126/scitranslmed.abb6576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167890PMC
February 2021

The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.

The G/T transversion rs35705950, located approximately 3 kb upstream of the MUC5B start site, is the cardinal risk factor for idiopathic pulmonary fibrosis (IPF). Here, we investigate the function and chromatin structure of this -3 kb region and provide evidence that it functions as a classically defined enhancer subject to epigenetic programming. We use nascent transcript analysis to show that RNA polymerase II loads within 10 bp of the G/T transversion site, definitively establishing enhancer function for the region. By integrating Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis of fresh and cultured human airway epithelial cells with nuclease sensitivity data, we demonstrate that this region is in accessible chromatin that affects the expression of MUC5B. Through applying paired single-nucleus RNA- and ATAC-seq to frozen tissue from IPF lungs, we extend these findings directly to disease, with results indicating that epigenetic programming of the -3 kb enhancer in IPF occurs in both MUC5B-expressing and nonexpressing lineages. In aggregate, our results indicate that the MUC5B-associated variant rs35705950 resides within an enhancer that is subject to epigenetic remodeling and contributes to pathologic misexpression in IPF.
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http://dx.doi.org/10.1172/jci.insight.144294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934873PMC
January 2021

Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis.

Mucosal Immunol 2021 03 1;14(2):479-490. Epub 2020 Oct 1.

Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2 mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2/DSS). Mdr2 mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.
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http://dx.doi.org/10.1038/s41385-020-00347-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954872PMC
March 2021

The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis.

Mol Biol Cell 2020 09 29;31(20):2249-2258. Epub 2020 Jul 29.

Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO 80045.

Intestinal epithelial cells (IECs) exist in a metabolic state of low oxygen tension termed "physiologic hypoxia." An important factor in maintaining intestinal homeostasis is the transcription factor hypoxia-inducible factor (HIF), which is stabilized under hypoxic conditions and mediates IEC homeostatic responses to low oxygen tension. To identify HIF transcriptional targets in IEC, chromatin immunoprecipitation (ChIP) was performed in Caco-2 IECs using HIF-1α- or HIF-2α-specific antibodies. ChIP-enriched DNA was hybridized to a custom promoter microarray (termed ChIP-chip). This unbiased approach identified autophagy as a major HIF-1-targeted pathway in IEC. Binding of HIF-1 to the ATG9A promoter, the only transmembrane component within the autophagy pathway, was particularly enriched by exposure of IEC to hypoxia. Validation of this ChIP-chip revealed prominent induction of ATG9A, and luciferase promoter assays identified a functional hypoxia response element upstream of the TSS. Hypoxia-mediated induction of ATG9A was lost in cells lacking HIF-1. Strikingly, we found that lentiviral-mediated knockdown (KD) of ATG9A in IECs prevents epithelial barrier formation by >95% and results in significant mislocalization of multiple tight junction (TJ) proteins. Extensions of these findings showed that ATG9A KD cells have intrinsic abnormalities in the actin cytoskeleton, including mislocalization of the TJ binding protein vasodilator-stimulated phosphoprotein. These results implicate ATG9A as essential for multiple steps of epithelial TJ biogenesis and actin cytoskeletal regulation. Our findings have novel applicability for disorders that involve a compromised epithelial barrier and suggest that targeting ATG9A may be a rational strategy for future therapeutic intervention.
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http://dx.doi.org/10.1091/mbc.E20-05-0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550696PMC
September 2020

Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function.

iScience 2020 Jun 2;23(6):101226. Epub 2020 Jun 2.

Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, 12700 East 19th Avenue, MS B-146, Aurora, CO 80045, USA. Electronic address:

The intestinal mucosa requires high levels of nucleotides for energy procurement, proliferation, and innate immunity. This need for nucleotide substrates substantially increases during injury, infection, and wound healing. In the present studies, we profile potential sources of purine nucleotides in murine mucosal tissue. This work reveals the gut microbiota as a prominent source of exogenous purines and that such microbiota-sourced purines (MSPs) are available to the intestinal mucosa. The MSPs are utilized for nucleotide genesis and promote energy balance. Further analyses reveal that colitic tissues lacking MSPs are proliferatively stunted, with notable energetic and endoplasmic reticulum stress to the detriment of mucous barrier integrity. Purine reconstitution either directly or through colonization of germ-free/antibiotic-treated mice with MSP-sufficient E. coli alleviates such deficits, establishing MSP as a critical source of substrate for tissue metabolism, wound healing, and mucous barrier sterile integrity.
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http://dx.doi.org/10.1016/j.isci.2020.101226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303675PMC
June 2020

Creatine Transporter, Reduced in Colon Tissues From Patients With Inflammatory Bowel Diseases, Regulates Energy Balance in Intestinal Epithelial Cells, Epithelial Integrity, and Barrier Function.

Gastroenterology 2020 09 17;159(3):984-998.e1. Epub 2020 May 17.

Mucosal Inflammation Program, University of Colorado, Aurora, Colorado; Division of Gastroenterology and Hepatology, University of Colorado, Aurora, Colorado. Electronic address:

Background & Aims: Patients with inflammatory bowel diseases (IBDs) have intestinal barrier dysfunction. Creatine regulates energy distribution within cells and reduces the severity of colitis in mice. We studied the functions of the creatine transporter solute carrier family 6 member 8 (SLC6A8, also called CRT) in intestinal epithelial cells (IECs) and mice, and we measured levels in mucosal biopsies from patients with IBD.

Methods: Colon biopsy specimens from patients with IBD (30 with Crohn's disease and 27 with ulcerative colitis) and 30 patients without IBD (control individuals) and colon tissues from mice (with and without disruption of Crt) were analyzed by immunofluorescence, immunoblots, and/or quantitative reverse-transcription polymerase chain reaction (qRT-PCR). CRT was knocked down or overexpressed in T84 cells, which were analyzed by immunofluorescence, immunoblots, high-performance liquid chromatography (to measure creatine levels), qRT-PCR, transepithelial electrical resistance, barrier function, actin localization, wound healing, mitochondrial oxygen consumption, and glycolysis extracellular acidification rate assays. Organoids from colon cells of CRT-knockout mice and control mice were analyzed by qRT-PCR, immunoblot, and transepithelial electrical resistance.

Results: CRT localized around tight junctions (TJs) of T84 IECs. In analyses of IECs with CRT knockdown or overexpression, we found that CRT regulates intracellular creatine, barrier formation, and wound healing. CRT-knockout organoids also had diminished barrier formation. In the absence of adequate creatine, IECs transition toward a stressed, glycolysis-predominant form of metabolism; this resulted in leaky TJs and mislocalization of actin and TJ proteins. Colon tissues from patients with IBD had reduced levels of CRT messenger RNA compared with those from control individuals.

Conclusions: In an analysis of IEC cell lines and colonoids derived from CRT-knockout mice, we found that CRT regulates energy balance in IECs and thereby epithelial integrity and barrier function. Mucosal biopsy specimens from patients with ulcerative colitis and inactive Crohn's disease have lower levels of CRT, which might contribute to the reduced barrier function observed in patients with IBD.
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http://dx.doi.org/10.1053/j.gastro.2020.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891846PMC
September 2020

Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin.

Proc Natl Acad Sci U S A 2020 05 12;117(21):11648-11657. Epub 2020 May 12.

Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;

The intestinal mucosa exists in dynamic balance with trillions of luminal microbes. Disruption of the intestinal epithelial barrier, commonly observed in mucosal inflammation and diseases such as inflammatory bowel diseases (IBDs), is often associated with dysbiosis, particularly decreases in species producing short-chain fatty acids (SCFAs), such as butyrate. It remains unclear to what extent microbiota-derived factors contribute to the overall maintenance of intestinal homeostasis. Initial studies revealed that butyrate selectively promotes epithelial barrier function and wound healing. We aimed to define the specific mechanism(s) through which butyrate contributes to these epithelial responses. Guided by an unbiased profiling approach, we identified the dominant regulation of the actin-binding protein synaptopodin (SYNPO). Extensions of this work revealed a role for SYNPO in intestinal epithelial barrier function and wound healing. SYNPO was localized to the intestinal epithelial tight junction and within F-actin stress fibers where it is critical for barrier integrity and cell motility. Butyrate, but not other SCFAs, induced SYNPO in epithelial cell lines and murine colonic enteroids through mechanisms possibly involving histone deacetylase inhibition. Moreover, depletion of the microbiota abrogated expression of SYNPO in the mouse colon, which was rescued with butyrate repletion. Studies in -deficient mice demonstrated exacerbated disease susceptibility and increased intestinal permeability in a dextran sulfate sodium colitis model. These findings establish a critical role for the microbiota and their products, specifically butyrate, in the regulated expression of SYNPO for intestinal homeostasis and reveal a direct mechanistic link between microbiota-derived butyrate and barrier restoration.
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http://dx.doi.org/10.1073/pnas.1917597117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260972PMC
May 2020

Resolvins resolve to heal mucosal wounds.

Authors:
Sean P Colgan

Proc Natl Acad Sci U S A 2020 05 5;117(20):10621-10622. Epub 2020 May 5.

Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045;

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http://dx.doi.org/10.1073/pnas.2005652117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245065PMC
May 2020

Platelet activating factor receptor acts to limit colitis-induced liver inflammation.

FASEB J 2020 06 15;34(6):7718-7732. Epub 2020 Apr 15.

Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.

Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut-liver axis inflammation remain poorly understood. IBD leads to a breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut-derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis-associated liver damage using dextran sulfate sodium (DSS) and anti-CD40-induced colitis models. Both DSS and anti-CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re-localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co-localized with toll-like receptor 4. DSS activated the NLRP3-inflammasome and increased interleukin (IL)-1β in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase-1, and IL-1β protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase-1 proteins. Interestingly, KCs depletion also increased IL-1β protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR-expressing KCs during colitis and that regulation of PAFR is important for gut-liver axis homeostasis.
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http://dx.doi.org/10.1096/fj.201901779RDOI Listing
June 2020

Markers of Hypoxia Correlate with Histologic and Endoscopic Severity of Colitis in Inflammatory Bowel Disease.

Hypoxia (Auckl) 2020 10;8:1-12. Epub 2020 Feb 10.

Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Inflammation results in significant shifts in tissue metabolism. Recent studies indicate that inflammation and hypoxia occur concomitantly. We examined whether circulating and tissue markers of hypoxia could serve as surrogate indicators of disease severity in adult and pediatric patients with inflammatory bowel disease (IBD).

Methods: Serum and colonic biopsies were obtained from pediatric subjects with active IBD colitis and adult subjects with active and inactive ulcerative colitis, along with healthy non-colitis controls of all ages. Disease activity was evaluated by endoscopy and histopathology. Levels of serum hypoxia markers (macrophage inflammatory protein-3α [MIP-3α], vascular endothelial growth factor [VEGF], and erythropoietin [EPO]) were measured.

Results: Children with active IBD colitis had higher levels of serum MIP-3α and VEGF compared to non-colitis controls (p<0.01 and p<0.05, respectively). In adult subjects with endoscopically active ulcerative colitis, serum MIP-3α and EPO were significantly elevated compared to non-colitis controls (both p<0.01). In parallel, analysis of colon tissue MIP-3α mRNA and protein in pediatric subjects revealed increased expression in those with IBD colitis compared to controls (p<0.05 and p<0.01 for mRNA and protein, respectively). Serum MIP-3α and VEGF significantly increased with histology grade.

Conclusion: Peripheral blood hypoxia markers may be useful indicators of disease activity for pediatric and adult IBD patients.
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http://dx.doi.org/10.2147/HP.S219049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026141PMC
February 2020

Hypoxia and Innate Immunity: Keeping Up with the HIFsters.

Annu Rev Immunol 2020 04 21;38:341-363. Epub 2020 Jan 21.

UCD Conway Institute, Systems Biology Ireland and School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.

Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF.
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http://dx.doi.org/10.1146/annurev-immunol-100819-121537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924528PMC
April 2020

Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.

Mucosal Immunol 2020 03 2;13(2):230-244. Epub 2019 Dec 2.

Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.

Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units. Using unbiased approaches, we sought to define acid-adaptive pathways elicited by PMN TEM. Given the significant amount of adenosine (Ado) generated during PMN TEM, we profiled the influence of Ado on IECs gene expression by microarray and identified the induction of SLC26A3, the major apical Cl/HCO exchanger in IECs. Utilizing loss- and gain-of-function approaches, as well as murine and human colonoids, we demonstrate that Ado-induced SLC26A3 promotes an adaptive IECs phenotype that buffers local pH during active inflammation. Extending these studies, chronic murine colitis models were used to demonstrate that SLC26A3 expression rebounds during chronic DSS-induced inflammation. In conclusion, Ado signaling during PMN TEM induces an adaptive tissue response to inflammatory acidification through the induction of SLC26A3 expression, thereby promoting pH homeostasis.
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http://dx.doi.org/10.1038/s41385-019-0237-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044055PMC
March 2020

Hypoxia-Inducible Factor-2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin-6.

Hepatology 2020 06 4;71(6):2105-2117. Epub 2020 Feb 4.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO.

Background And Aims: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.

Approach And Results: We observed that APAP challenge caused stabilization of hypoxia-inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particularly HIF-2α. Genetic deletion of the HIF-2α gene in myeloid cells (HIF-2α ) markedly exacerbated APAP-induced liver injury (AILI) without affecting APAP bioactivation and detoxification. In contrast, hepatic and serum levels of the hepatoprotective cytokine interleukin 6 (IL-6), its downstream signal transducer and transcription factor 3 activation in hepatocytes, as well as hepatic MΦ IL-6 expression were markedly reduced in HIF-2α mice compared to wild-type mice post-APAP challenge. In vitro experiments revealed that hypoxia induced IL-6 production in hepatic MΦs and that such induction was abolished in HIF-2α-deleted hepatic MΦs. Restoration of IL-6 by administration of exogenous IL-6 ameliorated AILI in HIF-2α mice. Finally, IL-6-mediated hepatoprotection against AILI was abolished in hepatocyte-specific IL-6 receptor knockout mice.

Conclusions: The data demonstrate that APAP treatment leads to HIF-2α stabilization in hepatic MΦs and that HIF-2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL-6, thereby ameliorating AILI.
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http://dx.doi.org/10.1002/hep.30954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075728PMC
June 2020

Intense Light-Mediated Circadian Cardioprotection via Transcriptional Reprogramming of the Endothelium.

Cell Rep 2019 08;28(6):1471-1484.e11

Mucosal Inflammation Program, Departments of Medicine and Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Graduate Training Program in Cell Biology, Stem Cells, and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. Here, we investigate the intersection between light-sensing (Period 2 [PER2]) and oxygen-sensing (hypoxia-inducible factor [HIF1A]) pathways in cellular adaptation to myocardial ischemia. We demonstrate that intense light is cardioprotective via circadian PER2 amplitude enhancement, mimicking hypoxia-elicited adenosine- and HIF1A-metabolic adaptation to myocardial ischemia under normoxic conditions. Whole-genome array from intense light-exposed wild-type or Per2 mice and myocardial ischemia in endothelial-specific PER2-deficient mice uncover a critical role for intense light in maintaining endothelial barrier function via light-enhanced HIF1A transcription. A proteomics screen in human endothelia reveals a dominant role for PER2 in metabolic reprogramming to hypoxia via mitochondrial translocation, tricarboxylic acid (TCA) cycle enzyme activity regulation, and HIF1A transcriptional adaption to hypoxia. Translational investigation of intense light in human subjects identifies similar PER2 mechanisms, implicating the use of intense light for the treatment of cardiovascular disease.
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http://dx.doi.org/10.1016/j.celrep.2019.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708043PMC
August 2019

Cholestatic liver disease results increased production of reactive aldehydes and an atypical periportal hepatic antioxidant response.

Free Radic Biol Med 2019 11 1;143:101-114. Epub 2019 Aug 1.

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, United States.

Cholangiopathies such as primary sclerosing cholangitis (PSC) are chronic liver diseases characterized by increased cholestasis, biliary inflammation and oxidative stress. The objective of this study was to elucidate the impact of cholestatic injury on oxidative stress-related factors. Using hepatic tissue and whole cell liver extracts (LE) isolated from 11-week old C57BL/6J (WT) and Mdr2 mice, inflammation and oxidative stress was assessed. Concurrently, specific targets of carbonylation were assessed in LE prepared from murine groups as well as from normal and human patients with end-stage PSC. Identified carbonylated proteins were further evaluated using bioinformatics analyses. Picrosirius red staining revealed extensive fibrosis in Mdr2 liver, and fibrosis colocalized with increased periportal inflammatory cells and both acrolein and 4-HNE staining. Western blot analysis revealed elevated periportal expression of antioxidant proteins Cbr3, GSTμ, Prdx5, TrxR1 and HO-1 but not GCLC, GSTπ or catalase in the Mdr2 group when compared to WT. From immunohistochemical analysis, increased periportal reactive aldehyde production colocalized with elevated staining of Cbr3, GSTμ and TrxR1 but surprisingly not with Nrf2. Mass spectrometric analysis revealed an increase in carbonylated proteins in the Mdr2 and PSC groups compared to respective controls. Gene ontology and KEGG pathway analysis of carbonylated proteins revealed a propensity for increased carbonylation of proteins broadly involved in metabolic processes as well more specifically in Rab-mediated signal transduction, lysosomes and the large ribosomal subunit in human PSC. Western blot analysis of Rab-GTPase expression revealed no significant differences in Mdr2 mice when compared to WT livers. In contrast, PSC tissue exhibited decreased levels of Rabs 4, 5 and increased abundance of Rabs 6 and 9a protein. Results herein reveal that cholestasis induces stage-dependent increases in periportal oxidative stress responses and protein carbonylation, potentially contributing to pathogenesis in Mdr2. Furthermore, during early stage cholestasis, there is cell-specific upregulation of some but not all, antioxidant proteins.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.07.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848778PMC
November 2019

Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis.

J Clin Invest 2019 07 2;129(8):3224-3235. Epub 2019 Jul 2.

Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α-dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α's critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.
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http://dx.doi.org/10.1172/JCI126744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668670PMC
July 2019

Oral vitamin B supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting in C57BL/6 mice.

Gut Microbes 2019 7;10(6):654-662. Epub 2019 May 7.

Mucosal Inflammation Program, University of Colorado, Aurora, CO, USA.

Vitamin B is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B supplements are largely unabsorbed and reach the distal gut where they are available to interact with the microbiota. The aim of this study was to determine if oral B supplementation in mice alters 1) the concentration of B and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis. C57BL/6 mice (up to 24 animals/group) were supplemented with oral 3.94 µg/ml cyanocobalamin (B), a dose selected to approximate a single 5 mg supplement for a human. Active vitamin B (cobalamin), and four B-analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba, CN-Cbi) were analyzed in cecal and fecal contents using liquid chromatography/mass spectrometry (LC/MS), in parallel with evaluation of fecal microbiota, cecal SCFA, and susceptibility to dextran sodium sulfate (DSS) colitis. At baseline, active B was a minor constituent of overall cecal (0.86%) and fecal (0.44%) corrinoid. Oral B supplementation increased active B at distal sites by >130-fold (cecal B increased from 0.08 to 10.60 ng/mg, fecal B increased from 0.06 to 7.81 ng/ml) and reduced microbe-derived fecal corrinoid analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba). Oral B had no effect on cecal SCFA. Microbial diversity was unaffected by this intervention, however a selective decrease in was observed with B treatment. Lastly, no difference in markers of DSS-induced colitis were detected with B treatment.
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http://dx.doi.org/10.1080/19490976.2019.1597667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866687PMC
February 2020

Control and dysregulation of redox signalling in the gastrointestinal tract.

Nat Rev Gastroenterol Hepatol 2019 02;16(2):106-120

Division of Gastroenterology and Hepatology, Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.

Redox signalling in the gastrointestinal mucosa is held in an intricate balance. Potent microbicidal mechanisms can be used by infiltrating immune cells, such as neutrophils, to protect compromised mucosae from microbial infection through the generation of reactive oxygen species. Unchecked, collateral damage to the surrounding tissue from neutrophil-derived reactive oxygen species can be detrimental; thus, maintenance and restitution of a breached intestinal mucosal barrier are paramount to host survival. Redox reactions and redox signalling have been studied for decades with a primary focus on contributions to disease processes. Within the past decade, an upsurge of exciting findings have implicated subtoxic levels of oxidative stress in processes such as maintenance of mucosal homeostasis, the control of protective inflammation and even regulation of tissue wound healing. Resident gut microbial communities have been shown to trigger redox signalling within the mucosa, which expresses similar but distinct enzymes to phagocytes. At the fulcrum of this delicate balance is the colonic mucosal epithelium, and emerging evidence suggests that precise control of redox signalling by these barrier-forming cells may dictate the outcome of an inflammatory event. This Review will address both the spectrum and intensity of redox activity pertaining to host-immune and host-microbiota crosstalk during homeostasis and disease processes in the gastrointestinal tract.
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http://dx.doi.org/10.1038/s41575-018-0079-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919748PMC
February 2019

Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells.

Cancer Cell 2018 10 27;34(4):659-673.e6. Epub 2018 Sep 27.

Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA. Electronic address:

From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-level production of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss, and incretin inactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease.
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http://dx.doi.org/10.1016/j.ccell.2018.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177322PMC
October 2018

Neutrophils as sources of dinucleotide polyphosphates and metabolism by epithelial ENPP1 to influence barrier function via adenosine signaling.

Mol Biol Cell 2018 11 6;29(22):2687-2699. Epub 2018 Sep 6.

Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.

Extracellular adenosine signaling is established as a protective component in mucosal inflammatory responses. The sources of extracellular adenosine include enzymatic processing from nucleotides, such as ATP and AMP, that can be liberated from a variety of cell types, including infiltrating leukocytes. Here we demonstrate that activated human neutrophils are a source of diadenosine triphosphate (Ap3A), providing an additional source of nucleotides during inflammation. Profiling murine enteroids and intestinal epithelial cell lines revealed that intestinal epithelia prominently express apical and lateral ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a member of the ENPP family of enzymes that metabolize diadenosine phosphates, especially Ap3A. Extensions of these studies demonstrated that intestinal epithelia metabolize Ap3A to ADP and AMP, which are further metabolized to adenosine and made available to activate surface adenosine receptors. Using loss and gain of ENPP1 approaches, we revealed that ENPP1 coordinates epithelial barrier formation and promotes epithelial wound healing responses. These studies demonstrate the cooperative metabolism between Ap3A and ENPP1 function to provide a significant source of adenosine, subserving its role in inflammatory resolution.
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http://dx.doi.org/10.1091/mbc.E18-06-0377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249842PMC
November 2018

A Central Role for Heme Oxygenase-1 in the Control of Intestinal Epithelial Chemokine Expression.

J Innate Immun 2018 23;10(3):228-238. Epub 2018 May 23.

In mucosal inflammatory disorders, the protective influence of heme oxygenase-1 (HO-1) and its metabolic byproducts, carbon monoxide (CO) and biliverdin, is a topic of significant interest. Mechanisms under investigation include the regulation of macrophage function and mucosal cytokine expression. While there is an increasing recognition of the importance of epithelial-derived factors in the maintenance of intestinal mucosal homeostasis, the contribution of intestinal epithelial cell (IEC) HO-1 on inflammatory responses has not previously been investigated. We examined the influence of modulating HO-1 expression on the inflammatory response of human IECs. Engineered deficiency of HO-1 in Caco-2 and T84 IECs led to increased proinflammatory chemokine expression in response to pathogenic bacteria and inflammatory cytokine stimulation. Crosstalk with activated leukocytes also led to increased chemokine expression in HO-1-deficient cells in an IL-1β dependent manner. Treatment of Caco-2 cells with a pharmacological inducer of HO-1 led to the inhibition of chemokine expression. Mechanistic studies suggest that HO-1 and HO-1-related transcription factors, but not HO-1 metabolic products, are partly responsible for the influence of HO-1 on chemokine expression. In conclusion, our data identify HO-1 as a central regulator of IEC chemokine expression that may contribute to homeo-stasis in the intestinal mucosa.
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http://dx.doi.org/10.1159/000488914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008212PMC
September 2019

Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function.

J Biol Chem 2018 04 27;293(16):6039-6051. Epub 2018 Feb 27.

From the Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado 80045 and

Intestinal epithelial cells form a selectively permeable barrier to protect colon tissues from luminal microbiota and antigens and to mediate nutrient, fluid, and waste flux in the intestinal tract. Dysregulation of the epithelial cell barrier coincides with profound shifts in metabolic energy, especially in the colon, which exists in an energetically depleting state of physiological hypoxia. However, studies that systematically examine energy flux and adenylate metabolism during intestinal epithelial barrier development and restoration after disruption are lacking. Here, to delineate barrier-related energy flux, we developed an HPLC-based profiling method to track changes in energy flux and adenylate metabolites during barrier development and restoration. Cultured epithelia exhibited pooling of phosphocreatine and maintained ATP during barrier development. EDTA-induced epithelial barrier disruption revealed that hypoxanthine levels correlated with barrier resistance. Further studies uncovered that hypoxanthine supplementation improves barrier function and wound healing and that hypoxanthine appears to do so by increasing intracellular ATP, which improved cytoskeletal G- to F-actin polymerization. Hypoxanthine supplementation increased the adenylate energy charge in the murine colon, indicating potential to regulate adenylate energy charge-mediated metabolism in intestinal epithelial cells. Moreover, experiments in a murine colitis model disclosed that hypoxanthine loss during active inflammation correlates with markers of disease severity. In summary, our results indicate that hypoxanthine modulates energy metabolism in intestinal epithelial cells and is critical for intestinal barrier function.
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http://dx.doi.org/10.1074/jbc.RA117.000269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912467PMC
April 2018

Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor.

Am J Pathol 2018 05 16;188(5):1183-1194. Epub 2018 Feb 16.

Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. Electronic address:

Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.
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http://dx.doi.org/10.1016/j.ajpath.2018.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906738PMC
May 2018

Regulation of immunity and inflammation by hypoxia in immunological niches.

Nat Rev Immunol 2017 Dec 3;17(12):774-785. Epub 2017 Oct 3.

Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, 80045 Colorado, USA.

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.
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http://dx.doi.org/10.1038/nri.2017.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799081PMC
December 2017

Epithelial Barrier Regulation by Hypoxia-Inducible Factor.

Ann Am Thorac Soc 2017 Sep;14(Supplement_3):S233-S236

1 Department of Medicine and.

Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and the lung are lined by layer(s) of epithelial cells that, when organized in three dimensions, provide a critical barrier to the flux of luminal contents. This selective barrier is provided through the regulated expression of junctional proteins and mucins. Tissue oxygen metabolism is central to the maintenance of homeostasis in the mucosa. In some organs (e.g., the colon), low baseline Po determines tissue metabolism and results in basal expression of the transcription factor, hypoxia-inducible factor (HIF), which is enhanced after ischemia/inflammation. Recent studies have indicated that HIF contributes fundamentally to the expression of barrier-related genes and in the regulation of barrier-adaptive responses within the mucosa. Here, we briefly review recent literature on the topic of hypoxia and HIF regulation of barrier in mucosal health and during disease.
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http://dx.doi.org/10.1513/AnnalsATS.201608-610MGDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711342PMC
September 2017