Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium ...through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection. Antibiotic-mediated depletion of the microbiota reduces colonic butyrate and HIF expression, both of which are restored by butyrate supplementation. Additionally, germ-free mice exhibit diminished retention of O2-sensitive dyes and decreased stabilized HIF. Furthermore, the influences of butyrate are lost in cells lacking HIF, thus linking butyrate metabolism to stabilized HIF and barrier function. This work highlights a mechanism where host-microbe interactions augment barrier function in the distal gut.
Display omitted
•The mammalian colon exists in a state of relative hypoxia•Hypoxic regions of the normal colon provide a signaling axis through HIF-1•Microbial-derived butyrate depletes O2 and activates HIF-1•Microbiota-derived butyrate is barrier-protective in the mucosa
Decreased short-chain fatty acid (SCFA) production by the microbiota has been correlated with colonic inflammation and disease. Kelly et al. show that microbial-derived SCFAs, particularly butyrate, stimulate epithelial metabolism and deplete intracellular O2, resulting in stabilization of the transcription factor HIF-1 and increased epithelial barrier function.
Acute intestinal inflammation involves early accumulation of neutrophils (PMNs) followed by either resolution or progression to chronic inflammation. Based on recent evidence that mucosal metabolism ...influences disease outcomes, we hypothesized that transmigrating PMNs influence the transcriptional profile of the surrounding mucosa. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by PMN-epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O2 sufficiently to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). By utilizing HIF reporter mice in an acute colitis model, we investigated the relative contribution of PMNs and the respiratory burst to “inflammatory hypoxia” in vivo. CGD mice, lacking a respiratory burst, developed accentuated colitis compared to control, with exaggerated PMN infiltration and diminished inflammatory hypoxia. Finally, pharmacological HIF stabilization within the mucosa protected CGD mice from severe colitis. In conclusion, transcriptional imprinting by infiltrating neutrophils modulates the host response to inflammation, via localized O2 depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.
Display omitted
•Infiltrating PMNs consume sufficient O2 to render adjacent colonic epithelia hypoxic•Hypoxia reporter mice demonstrate PMN-dependent hypoxia in inflamed colitic lesions•CGD mice do not incite mucosal hypoxia and develop severe nonresolving colitis•Mucosal HIF stabilization ameliorates colitis severity in wild-type and CGD mice
Intestinal epithelial cells (IECs) are exposed to profound fluctuations in oxygen tension and have evolved adaptive transcriptional responses to a low-oxygen environment. These adaptations are ...mediated primarily through the hypoxia-inducible factor (HIF) complex. Given the central role of the IEC in barrier function, we sought to determine whether HIF influenced epithelial tight junction (TJ) structure and function. Initial studies revealed that short hairpin RNA-mediated depletion of the HIF1β in T84 cells resulted in profound defects in barrier and nonuniform, undulating TJ morphology. Global HIF1α chromatin immunoprecipitation (ChIP) analysis identified claudin-1 (CLDN1) as a prominent HIF target gene. Analysis of HIF1β-deficient IEC revealed significantly reduced levels of CLDN1. Overexpression of CLDN1 in HIF1β-deficient cells resulted in resolution of morphological abnormalities and restoration of barrier function. ChIP and site-directed mutagenesis revealed prominent hypoxia response elements in the CLDN1 promoter region. Subsequent in vivo analysis revealed the importance of HIF-mediated CLDN1 expression during experimental colitis. These results identify a critical link between HIF and specific tight junction function, providing important insight into mechanisms of HIF-regulated epithelial homeostasis.
Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are ...orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine–creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2–dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.
The Swift UV-Optical Telescope (UVOT) has been observing core-collapse supernovae (CCSNe) of all subtypes in the UV and optical since 2005. Here we present 50 CCSNe observed with the Swift UVOT, ...analyzing their UV properties and behavior. Where we have multiple UV detections in all three UV filters (lambda sub(c) = 1928-2600 A), we generate early time bolometric light curves, analyze the properties of these light curves and the UV contribution to them, and derive empirical corrections for the UV-flux contribution to optical-IR based bolometric light curves.
Abstract
The POLISH2 optical polarimeter has been in operation at the Lick Observatory 3 m Shane telescope since 2011, and it was commissioned at the Gemini North 8 m in 2016. This instrument ...primarily targets exoplanets, asteroids, and the Crab Pulsar, but it has also been used for a wide variety of planetary, galactic, and supernova science. POLISH2's photoelastic modulators, employed instead of rotating wave plates or ferroelectric liquid crystal modulators, offer the unprecedented ability to achieve sensitivity and accuracy of order 1 ppm (0.0001%), which are difficult to obtain with conventional polarimeters. Additionally, POLISH2 simultaneously measures the intensity (Stokes
I
), linear polarization (Stokes
Q
and
U
), and circular polarization (Stokes
V
), which fully describe the polarization state of incident light. We document our laboratory and on-sky calibration methodology and our archival on-sky database, and we demonstrate the conclusive detection of circular polarization of certain objects.
We present the second Swift Ultra-Violet/Optical Telescope (UVOT) gamma-ray burst (GRB) afterglow catalog, greatly expanding on the first Swift UVOT GRB afterglow catalog. The second catalog is ...constructed from a database containing over 120,000 independent UVOT observations of 538 GRBs first detected by Swift, the High Energy Transient Explorer 2 (HETE2), the INTErnational Gamma-Ray Astrophysics Laboratory (INTEGRAL), the Interplanetary Network (IPN), Fermi, and Astro-rivelatore Gamma a Immagini Leggero (AGILE). The catalog covers GRBs discovered from 2005 January 17 to 2010 December 25. Using photometric information in three UV bands, three optical bands, and a "white" or open filter, the data are optimally coadded to maximize the number of detections and normalized to one band to provide a detailed light curve. The catalog provides positional, temporal, and photometric information for each burst, as well as Swift Burst Alert Telescope and X-ray Telescope (XRT) GRB parameters. Temporal slopes are provided for each UVOT filter. The temporal slope per filter of almost half the GRBs are fit with a single power law, but one to three breaks are required in the remaining bursts. Morphological comparisons with the X-ray reveal that of the UVOT light curves are similar to one of the four morphologies identified by Evans et al. (2009). The remaining have a newly identified morphology. For many bursts, redshift- and extinction-corrected UV/optical spectral slopes are also provided at 2 × 103, 2 × 104, and 2 × 105 s.
Abstract
There are currently many large-field surveys that are operational and are being planned including the powerful Vera C. Rubin Observatory Legacy Survey of Space and Time. These surveys will ...increase the number and diversity of transients dramatically. However, for some transients, like supernovae (SNe), we can gain more understanding by directed observations (e.g., shock breakout and
γ
-ray detections) than by simply increasing the sample size. For example, the initial emission from these transients can be a powerful probe of these explosions. Upcoming ground-based detectors are not ideally suited to observing the initial emission (shock emergence) of these transients. These observations require a large field-of-view X-ray mission with a UV follow-up within the first hour of shock breakout. The emission in the first 1 hr to even 1 day provides strong constraints on the stellar radius and asymmetries in the outer layers of stars, the properties of the circumstellar medium (e.g., inhomogeneities in the wind for core-collapse SNe and accreting companions in thermonuclear SNe), and the transition region between these two areas. This paper describes a simulation for the number of SNe that could be seen by a large field-of-view lobster-eye X-ray and UV observatory.
Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of ...inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-γ.
PDF
