Oxygen metabolism and barrier regulation in the intestinal mucosa

Glover, Louise; Lee, J. Scott; Colgan, Sean P.

doi:10.1172/jci84429

Cited by 134 publications

(119 citation statements)

References 142 publications

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“…In B cells, HIF also regulates survival, in addition to development and antibody processing 52 . Finally, in intestinal epithelial cells (a key innate immune cell), HIF modulates ion transport, antimicrobial peptide production and barrier function 44,53,54 . Although the focus of the current Review is on the role of HIF in regulating immune cell function, it should be noted that other components of the HIF pathway (including both HIF hydroxylases and pVHL) can also regulate immune cell function through HIF-independent mechanisms 55–57 .…”

Section: Hif Modulation Of Immune Cell Functionmentioning

confidence: 99%

“…This effect may be due to the increased metabolic demands triggered by inflammation and diminished vascular supply resulting from inflammation-induced vascular dysfunction, which can ultimately lead to tissue fibrosis 117 . Intestinal epithelial cell hypoxia leads to barrier protection through mechanisms that involve multiple HIF target genes, which are expressed in epithelial cells 44 . Alternatively, in mucosal immune cells, hypoxia can promote immune cell activity and survival through HIF activation.…”

Section: Hypoxia In Pathological Immune Nichesmentioning

confidence: 99%

“…First, physiological oxygen gradients exist in the intestinal mucosa due to the anatomical juxtaposition of the outermost mucosal surface with the oxygen-depleted lumen of the gut and a counter-current oxygen exchange system in the intestinal villi 44 . Second, the renal medulla experiences physiological hypoxia, probably as a result of a combination of the high oxygen demand that is associated with active ion transport events and the counter-current exchange of oxygen in the medulla 140 .…”

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Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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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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Section: Hif Modulation Of Immune Cell Functionmentioning

confidence: 99%

Section: Hypoxia In Pathological Immune Nichesmentioning

confidence: 99%

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confidence: 99%

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Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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“…An example of such is butyrate, an SFCA secreted by gut flora and subsequently absorbed by the intestinal epithelial cells. Butyrate is believed to act on the mitochondria to alter cell metabolism in a slight way to keep the concentration of oxygen in the epithelial cell in a range which is below normal for other cells [31]. This slightly hypoxic environment stabilizes hypoxia-inducible factor (HIF), a polypeptide signaling molecule which is necessary for the production and maintenance of several epithelial cell barrier proteins [31].…”

Section: Normal and Abnormal Gut Physiology: Implications For Patientmentioning

confidence: 99%

“…Butyrate is believed to act on the mitochondria to alter cell metabolism in a slight way to keep the concentration of oxygen in the epithelial cell in a range which is below normal for other cells [31]. This slightly hypoxic environment stabilizes hypoxia-inducible factor (HIF), a polypeptide signaling molecule which is necessary for the production and maintenance of several epithelial cell barrier proteins [31]. Loss of butyrate production in the gut lumen has been associated with reduced intestinal barrier function, and improvement in available butyrate has been the target of some therapies for inflammatory bowel disease [31].…”

Section: Normal and Abnormal Gut Physiology: Implications For Patientmentioning

confidence: 99%

Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment

Polsinelli

Sinha

Shah

2017

Curr Heart Fail Rep

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Purpose of review Visceral venous congestion of the gut may play a key role in the pathogenesis of right-sided heart failure (HF) and cardiorenal syndromes. Here we review the role of right ventricular (RV) dysfunction, visceral congestion, splanchnic hemodynamics, and the intestinal microenvironment in the setting of right-sided HF. We review recent literature on this topic, outline possible mechanisms of disease pathogenesis, and discuss potential therapeutics. Recent Findings There are several mechanisms linking RV-gut interactions via visceral venous congestion which could result in (1) hypoxia and acidosis in enterocytes, which may lead to enhanced sodium-hydrogen exchanger 3 (NHE3) expression with increased sodium and fluid retention; (2) decreased luminal pH in the intestines which could lead to alteration of the gut microbiome which could increase gut permeability and inflammation; (3) alteration of renal hemodynamics with triggering of the cardiorenal syndrome; and (4) altered phosphate metabolism resulting in increased pulmonary artery stiffening, thereby increasing RV afterload. A wide variety of therapeutic interventions that act on the RV, pulmonary vasculature, intestinal microenvironment, and the kidney could alter these pathways and should be tested in patients with right-sided HF. Summary The RV-gut axis is an important aspect of HF pathogenesis that deserves more attention. Modulation of the pathways interconnecting the right heart, visceral congestion, and the intestinal microenvironment could be a novel avenue of intervention for right-sided HF.

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A Microphysiological System with an Anaerobic Air‐Liquid Interface and Functional Mucus Layer for Coculture of Intestinal Bacteria and Primary Human Colonic Epithelium

Kim,

Allbritton

2024

Adv Materials Inter

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Coculture of intestinal bacteria with primary human intestinal epithelium provides a valuable tool for investigating host‐colon bacterial interactions and for testing and screening therapeutics. However, most current intestinal model systems lack key physiological features of the in vivo colon, such as both a proper oxygen microenvironment and a mucus layer. In this work, a new in vitro colonic microphysiological system is demonstrated with a cell‐derived, functional mucus that closely resembles the in vivo colonic mucosa and apical microenvironment by employing an anaerobic air‐liquid interface culture. The human primary colon epithelial cells in this new in vitro system exhibit high cell viability (>98%) with ≈100 µm thick functional mucus layer on average. Successful coculture of model anaerobic gut bacterial strains Lactobacillus rhamnosus GG and Anaerobutyricum hallii without loss in human cell viability demonstrates that this new model can be an invaluable tool for future studies of the impact of commensal and pathogenic bacteria on the colon.

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Oxygen metabolism and barrier regulation in the intestinal mucosa

Cited by 134 publications

References 142 publications

Regulation of immunity and inflammation by hypoxia in immunological niches

Regulation of immunity and inflammation by hypoxia in immunological niches

Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment

A Microphysiological System with an Anaerobic Air‐Liquid Interface and Functional Mucus Layer for Coculture of Intestinal Bacteria and Primary Human Colonic Epithelium

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