Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function

Manresa, Mario C.; Taylor, Cormac T.

doi:10.1016/j.jcmgh.2017.02.004

Cited by 75 publications

(57 citation statements)

References 171 publications

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“…In basal conditions, the intestinal epithelium is already in a state of physiological hypoxia due to changes in blood flow and tissue oxygenation. This hypoxic state is potentiated in IBD by increased oxygen demand and decreased blood supply . It is shown that HIF1α has an important role in UC.…”

Section: Crosstalk Between Hif and Sepsismentioning

confidence: 99%

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

2020

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Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia-inducible factor-1a (HIF1a), and its family members, plays an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the HIF pathway. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway.

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Section: Crosstalk Between Hif and Sepsismentioning

confidence: 99%

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

2020

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“…HIF-1 is believed to control barrier integrity by regulating multiple barrierprotective genes, and its dysregulation may be involved in GI disorders 52,53 .…”

Section: Discussionmentioning

confidence: 99%

Complex human gut microbiome cultured in anaerobic human intestine chips

Baharvand

et al. 2018

Preprint

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The diverse bacterial populations that comprise the commensal microbiota of the human intestine play a central role in health and disease, yet no method is available to sustain these complex microbial communities in direct contact with living human intestinal cells and their overlying mucus layer in vitro. Here we describe a human Organ-on-a-Chip (Organ Chip) microfluidic platform that permits control and real-time assessment of physiologically-relevant oxygen gradients, and which enables co-culture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota. When compared to aerobic co-culture conditions, establishment of a transluminal hypoxia gradient sustained higher microbial diversity with over 200 unique operational taxonomic units (OTUs) from 11 different genera, and an abundance of obligate anaerobic bacteria with ratios of Firmicutes and Bacteroidetes similar to those observed in human feces, in addition to increasing intestinal barrier function. The ability to culture human intestinal epithelium overlaid by complex human gut microbial communities within microfluidic Intestine Chips may enable investigations of host-microbiome interactions that were not possible previously, and serve as a discovery tool for development of new microbiome-related therapeutics, probiotics, and nutraceuticals. ____________________________________________________________________________ One of the major recent paradigm shifts in medicine relates to the recognition of the central role that the microbiome, composed of host-specific communities of commensal microbes, plays in human health and disease 1 . While human microbiota colonize mucosal surfaces of various tissues, the gastrointestinal tract supports the

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“…However, to advance the use of hydroxylase inhibitors for human IBD, potential unwanted adverse side effects of PHIs need to be considered. These include HIF‐mediated induction of erythropoiesis as well as potentially pro‐tumourigenic effects related to HIF activation (Manresa & Taylor, ). A viable strategy to circumvent systemic exposure has been provided by developing a targeted colonic release formulation (Tambuwala et al .…”

Section: Molecular Oxygen Sensing In Metazoan Cellsmentioning

confidence: 99%

The PHD1 oxygen sensor in health and disease

Kennel

Burmeister

Schneider

et al. 2018

The Journal of Physiology

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The hypoxia-inducible factor (HIF) co-ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen-sensing enzymes termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1-3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non-redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies. Pharmacological HIF-hydroxylase inhibitors have recently proven to be both tolerated and therapeutically effective in patients. In this review, we focus on the physiology, pathophysiology and therapeutic potential of the PHD1 isoform, which has recently been implicated in diseases including inflammatory bowel disease, ischaemia and cancer.

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Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function

Cited by 75 publications

References 171 publications

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Complex human gut microbiome cultured in anaerobic human intestine chips

The PHD1 oxygen sensor in health and disease

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