The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index; none of the 48 sources its claims cite is checked for support yet.
Hypoxia: an alarm signal during intestinal inflammation
Open accessAbstract
Intestinal epithelial cells that line the mucosal surface of the gastrointestinal tract are positioned between an anaerobic lumen and a highly metabolic lamina propria. As a result of this unique anatomy, intestinal epithelial cells function within a steep physiologic oxygen gradient relative to other cell types. Furthermore, during active inflammatory disease such as IBD, metabolic shifts towards hypoxia are severe. Studies in vitro and in vivo have shown that the activation of hypoxia-inducible factor (HIF) serves as an alarm signal to promote the resolution of inflammation in various mouse models of disease. Amelioration of disease occurs, at least in part, through transcriptional upregulation of nonclassic epithelial barrier genes. There is much interest in harnessing hypoxia-inducible pathways, including stabilizing HIF directly or via inhibition of prolyl hydroxylase enzymes, for therapy of IBD. In this Review, we discuss the signaling pathways involved in the regulation of hypoxia and discuss how hypoxia may serve as an endogenous alarm signal for the presence of mucosal inflammatory disease. We also discuss the pros and cons of targeting these pathways to treat patients with IBD.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that hypoxia in the inflamed intestinal mucosa acts as an endogenous alarm signal, with HIF activation promoting resolution of inflammation and barrier protection in murine colitis models. It discusses PHD inhibitors as potential IBD therapies but cautions about hematocrit elevation and cancer risk.
Key findings
- The intestinal mucosa normally exists in a steep oxygen gradient; 2-nitroimidazole dye studies in murine IBD models show physiologic hypoxia in normal colon and profoundly hypoxic or anoxic inflammatory lesions. The adult intestinal epithelium covers approximately 300 m² and absorbs at least 9 L of fluid daily; gut blood volume shifts from less than 5% during fasting to approximately 30% after a meal.
- HIF-1 is induced in inflammatory lesions. Loss of epithelial HIF-1α resulted in a more severe colitic phenotype than wild-type animals, with increased weight loss, decreased colon length and increased epithelial permeability, whereas constitutively active intestinal epithelial HIF was protective; however, another study found epithelial HIF-based signaling can promote inflammation.
- HIF-dependent barrier protection involves non-classical epithelial barrier genes, including mucins, intestinal trefoil factor, P-glycoprotein, CD73 and the adenosine A2B receptor, rather than tight junction proteins occludin or claudin. PHDs also regulate NF-κB via IKKβ hydroxylation.
- PHD inhibitors DMOG and FG-4497 reduced symptoms in at least two mouse models of colitis (TNBS or DSS) and were well tolerated; high-dose FG-4497 (>60 mg/kg) with 5 daily intervals caused occasional intestinal vascular occlusion, likely from erythrocyte sludging, rectified by lowering the dose and decreasing the dosing interval. No trials have been initiated for the treatment of IBD.
Methods
- Design: narrative review of hypoxia signaling in intestinal inflammation, synthesizing in vitro studies, murine disease models and patient-derived materials.
- Main analysis: descriptive synthesis of HIF, PHD and NF-κB pathways and preclinical therapeutic studies of PHD inhibitors in colitis models; no systematic search or quantitative meta-analysis is reported.
Limitations
- Stated: increased susceptibility to colitis after genetic deletion of intestinal epithelial HIF may be somewhat model-dependent and requires additional validation with PHD inhibitors before clinical studies can be implemented. The paper also cautions that HIF activators substantially elevate hematocrit; high-dose FG-4497 caused occasional vascular occlusion, and chronic HIF-1 and HIF-2 stabilization has been significantly associated with cancers, so safest use may be acute or short-term adjunct therapy.
- Evident from the text: this is a narrative review without systematic search or quantitative synthesis, and therapeutic evidence is largely from murine colitis models; no IBD trials have been initiated.
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0 of 48 cited sources checked · 0 supported · 0 flagged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our initial studies with murine colitis, we observed that high doses of FG-4497 (>60 mg/kg) with 5 daily intervals of dosing resulted in occasional vascular occlusion within the intestine.”
§ Hypoxia: an alarm signal during intestinal inflammation > Therapies for IBD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Intestinal epithelial cells that line the mucosal surface of the gastrointestinal tract are positioned between an anaerobic lumen and a highly metabolic lamina propria. As a result of this unique anatomy, intestinal epithelial cells function within a steep physiologic oxygen gradient relative to other cell types.”
§ Hypoxia: an alarm signal during intestinal inflammation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: There is a steep oxygen gradient from the anaerobic lumen of the intestine across the epithelium into the highly vascularized sub-epithelium.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies in vitro and in vivo have shown that the activation of hypoxia-inducible factor (HIF) serves as an alarm signal for the resolution of inflammation in various murine disease models.”
§ Hypoxia: an alarm signal during intestinal inflammation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Amelioration of disease occurs, at least in part, through transcriptional up-regulation of non-classical epithelial barrier genes.”
§ Hypoxia: an alarm signal during intestinal inflammation > Abstract
What the sources say
- Not checked yetcites [4] Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001). source
- Not checked yetcites [20] Comerford, K. M. et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 62, 3387–3394 (2002).
- Not checked yetcites [21] Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 (HIF-1) mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002). source
- Not checked yetcites [22] Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Furthermore, during active inflammatory disease such as IBD, metabolic shifts toward hypoxia are severe.”
- Also stated in: § Hypoxia and the immune response · plain
“IBD is an interesting disease for studying the metabolic changes associated with inflammation, particularly the development of hypoxia within inflammatory lesions3.”
§ Hypoxia: an alarm signal during intestinal inflammation > Abstract
What the sources say
- Not checked yetcites [3] Taylor, C. T. & Colgan, S. P. Hypoxia and gastrointestinal disease. J. Mol. Med. 85, 1295–1300 (2008). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Hypoxia and the immune response · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we review the signaling pathways involved and define how hypoxia may serve as an endogenous alarm signal for mucosal inflammatory disease.”
§ Hypoxia: an alarm signal during intestinal inflammation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“The same series of studies which identified inflammation-related hypoxia also showed that expression of HIF-1 is induced in the inflammatory lesions13.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [13] Karhausen, J. et al. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Invest. 114, 1098–1106 (2004). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Several studies have shown that HIF-1 triggers the transcription of many genes that enable intestinal epithelial cells to act as an effective barrier4,20–22.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [4] Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001). source
- Not checked yetcites [20] Comerford, K. M. et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 62, 3387–3394 (2002).
- Not checked yetcites [21] Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 (HIF-1) mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002). source
- Not checked yetcites [22] Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“These findings may be somewhat model-dependent, since epithelial HIF-based signaling has also been shown to promote inflammation in another study27.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [27] Shah, Y. M. et al. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134, 2036–2048 (2008). source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Finally, compelling evidence have revealed that HIF-1α transcriptionally controls the critical integrin important in all myeloid cell adhesion and transmigration, namely the β2 integrin (CD18)34,35.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [34] Kong, T., Eltzschig, H. K., Karhausen, J., Colgan, S. P. & Shelley, C. S. Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression. Proc. Natl Acad. Sci. USA 101, 10440–10445 (2004). source
- Not checked yetcites [35] Kong, T., Scully, M., Shelley, C. S. & Colgan, S. P. Identification of Pur alpha as a new hypoxia response factor responsible for coordinated induction of the beta 2 integrin family. J. Immunol. 179, 1934–1941 (2007). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 5
- It may state two separate claims as one. 18
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our experience, both FG-4497 and DMOG can be delivered by multiple routes of administration (intraperitoneal, oral and intravenous)., and both FG-4497 are absorbed orally with only a slight loss of efficacy compared to intraperitoneal administration.”
§ Hypoxia: an alarm signal during intestinal inflammation > Therapies for IBD
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“This problem was rectified by lowering the dose and decreasing the interval of dosing26.”
§ Hypoxia: an alarm signal during intestinal inflammation > Therapies for IBD
What the sources say
- Not checked yetcites [26] Robinson, A. et al. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134, 145–155 (2008). source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Sites of mucosal inflammation are characterized by profound changes in tissue metabolism, including local depletion of nutrients, imbalances in tissue oxygen supply and demand, and the generation of large quantities of reactive nitrogen and oxygen intermediates3.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia and the immune response
What the sources say
- Not checked yetcites [3] Taylor, C. T. & Colgan, S. P. Hypoxia and gastrointestinal disease. J. Mol. Med. 85, 1295–1300 (2008). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Notably, the PMN oxidative burst is not hindered by even relatively low O2 (as low as 4.5% O2)8, which is important, since it means that ROS can be generated in the relatively low O2 environments of inflamed intestinal mucosa3.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia and the immune response
What the sources say
- Not checked yetcites [8] Gabig, T. G., Bearman, S. I. & Babior, B. M. Effects of oxygen tension and pH on the respiratory burst of human neutrophils. Blood 53, 1133–1139 (1979). source
- Not checked yetcites [3] Taylor, C. T. & Colgan, S. P. Hypoxia and gastrointestinal disease. J. Mol. Med. 85, 1295–1300 (2008). source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Both the absorptive and barrier functions of the intestinal epithelium are regulated by the availability of O23.”
§ Hypoxia: an alarm signal during intestinal inflammation > Introduction
What the sources say
- Not checked yetcites [3] Taylor, C. T. & Colgan, S. P. Hypoxia and gastrointestinal disease. J. Mol. Med. 85, 1295–1300 (2008). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In fact, studies comparing functional responses between epithelial cells from different tissues have revealed that intestinal epithelial cells seem to be uniquely resistant to hypoxia and that an extremely low level of oxygenation within the normal intestinal epithelial barrier (so-called “physiologic hypoxia”) may be a regulatory adaptation mechanism to the steep oxygen gradient4.”
§ Hypoxia: an alarm signal during intestinal inflammation > Introduction
What the sources say
- Not checked yetcites [4] Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ongoing studies suggest that hypoxia-regulated pathways are highly associated with IBD and contribute particularly to the resolution of ongoing inflammation.”
§ Hypoxia: an alarm signal during intestinal inflammation > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“It has long been known that PMNs are primarily glycolytic cells, with few mitochondria and little energy produced from respiration6.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia and the immune response
What the sources say
- Not checked yetcites [6] Borregaard, N. & Herlin, T. Energy metabolism of human neutrophils during phagocytosis. J. Clin. Invest. 70, 550–557 (1982). source
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Loss of epithelial HIF-1α resulted in a more severe colitic phenotype than wild-type animals, with increased weight loss, decreased colon length and increased epithelial permeability, whereas constitutively active intestinal epithelial HIF was protective for these parameters.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [13] Karhausen, J. et al. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Invest. 114, 1098–1106 (2004). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Second, the inflammatory lesions seen in these mouse models are profoundly hypoxic or even anoxic, similar to that seen in some large tumors, and penetrate deep into the mucosal tissue.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia and the immune response
What the sources say
- Not checked yetcites [14] Evans, S. M. et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res. 60, 2018–2024 (2000).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In particular, these studies have shown that PMN and macrophage bacterial killing capacities are severely limited in the absence of HIF-1α, as HIF-1α is central to production of antimicrobial peptides and granule proteases.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [33] Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 9, 609–617 (2009). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Four HIF-hydroxylases termed PHD1-3 and Functional Inhibitor of HIF (FIH) have been demonstrated to be important in the hypoxic regulation of the HIF pathway37.”
§ Hypoxia: an alarm signal during intestinal inflammation > Prolyl-hydroxylases and HIF Expression
What the sources say
- Not checked yetcites [37] Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008). source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Likewise, NF-κB is thought to be largely protective in the intestinal epithelium via the inhibition of enterocyte apoptosis leading to enhanced intestinal barrier function23.”
§ Hypoxia: an alarm signal during intestinal inflammation > Prolyl-hydroxylases and HIF Expression
What the sources say
- Not checked yetcites [23] Cummins, E. P. et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134, 156–165 (2008). source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Rather, the HIF-dependent pathways are more to do with overall tissue integrity, ranging from increased mucin production,31 including molecules that modify mucins, such as, intestinal trefoil factor4, to xenobiotic clearance by P-glycoprotein,20 to nucleotide metabolism (by ecto-5′-nucleotidase and CD73)21,22 and nucleotide signaling through the adenosine A2B receptor22.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
What the sources say
- Not checked yetcites [31] Louis, N. A. et al. Selective induction of mucin-3 by hypoxia in intestinal epithelia. J. Cell Biochem. 99, 1616–1627 (2006). source
- Not checked yetcites [4] Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001). source
- Not checked yetcites [20] Comerford, K. M. et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 62, 3387–3394 (2002).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, hypoxia has been shown to activate NF-κB and this seems, at least in part to be, to be dependent on PHD-mediated hydroxylation38,49 of IKKβ.38”
§ Hypoxia: an alarm signal during intestinal inflammation > Convergence of inflammation and hypoxia
What the sources say
- Not checked yetcites [38] Cummins, E. P. et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc. Natl Acad. Sci. USA 103, 18154–18159 (2006). source
- Not checked yetcites [49] Cockman, M. E. et al. Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc. Natl Acad. Sci. USA 103, 14767–14772 (2006). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the findings confirmed that intestinal epithelial cells can adapt to hypoxia and that HIF may contribute to this.”
§ Hypoxia: an alarm signal during intestinal inflammation > Hypoxia-inducible factor
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, NF-κB has recently been reported to be regulated by HIF hydroxylases in a number of studies37,44.”
§ Hypoxia: an alarm signal during intestinal inflammation > Prolyl-hydroxylases and HIF Expression
What the sources say
- Not checked yetcites [37] Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008). source
- Not checked yetcites [44] Taylor, C. T. Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J. Physiol. 586, 4055–4059 (2008). source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In these mouse models, the drugs were well tolerated with no significant adverse side effects.”
§ Hypoxia: an alarm signal during intestinal inflammation > Therapies for IBD
What the sources say
- Not checked yetcites [23] Cummins, E. P. et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134, 156–165 (2008). source
- Not checked yetcites [26] Robinson, A. et al. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134, 145–155 (2008). source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is notable that the increased susceptibility to colitis following the genetic deletion of intestinal epithelial HIF may be somewhat model-dependent and will require additional validatation with PHD inhibitors before clinical studies can be implements.”
§ Hypoxia: an alarm signal during intestinal inflammation > Conclusions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“It is notable that conditional deletion of the NF-κB pathway in intestinal epithelial cells in mice leads to an increased susceptibility to colitis50, similar to that of the mice expressing homozygous mutant HIF1α13.”
§ Hypoxia: an alarm signal during intestinal inflammation > Convergence of inflammation and hypoxia
What the sources say
- Not checked yetcites [50] Zaph, C. et al. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This implicates epithelial NF-κB in a prominently protective role in colitis, probably through the expression of anti-apoptotic genes in intestinal epithelial cells and through enhanced epithelial barrier function.”
§ Hypoxia: an alarm signal during intestinal inflammation > Convergence of inflammation and hypoxia
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Loss of epithelial barrier function with unrestricted flux of luminal antigens to the mucosal immune system underlies the pathology of IBD and results in hypoxia within the chronically inflamed mucosa, particularly within the epithelial cell layer.
“Loss of epithelial barrier function with the resultant unrestricted flux of luminal antigens to the mucosal immune system underlies the pathology of IBD, and results in hypoxia within the chronically inflamed mucosa, particularly within the epithelial cell layer.”
The paper relies on this without support.
When activated, PMN can consume up to 10 times more O2 than any other cell in the body.
“When activated, it is estimated that PMN can consume up to 10 times more O2 than any other cell in the body.”
The paper relies on this without support.
There is a steep oxygen gradient from the anaerobic lumen of the intestine across the epithelium into the highly vascularized sub-epithelium.
“Notably, there is a steep oxygen gradient from the anaerobic lumen of the intestine across the epithelium into the highly vascularized sub-epithelium.”
The paper relies on this without support.
Chronic HIF-1 and HIF-2 stabilization are significantly associated with a number of cancers.
“As a second precautionary note, chronic HIF-1 and HIF-2 stabilization have been significantly associated with a number of cancers.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Inflammation-associated hypoxia (or inflammatory hypoxia) can result from a combination of factors that result in a shift in metabolic supply and demand.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [6]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Prolyl hydroxylase is described as both stabilizing and degrading HIF
MinorThe abstract says the prolyl-hydroxylase enzyme stabilizes HIF, but the main text says these enzymes lead to HIF degradation and that inhibiting them stabilizes HIF.
“the proyl-hydroxylase enzyme (which stabilizes HIF)”
“these enzymes hydroxylate HIF alpha subunits leading to directed ubiquitination and subsequent degradation. Hypoxia or pharmacologic agents (such as DMOG) inhibit HIF-hydroxylases leading to derepression of HIF.”
Citations
Cites
Cellular Motility Driven by Assembly and Disassembly of Actin Filaments
Pollard, T. D., & Borisy, G. G. (2003) · Cell · doi:10.1016/s0092-8674(03)00120-x · Cited by 4,334
Intestinal mucosal barrier function in health and disease
Turner, J. R. (2009) · Nature reviews. Immunology · doi:10.1038/nri2653 · Cited by 3,952
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712
NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M. (2008) · Nature · doi:10.1038/nature06905 · Cited by 1,614
Chen, Z., Hagler, J., Palombella, V. J., Melandri, F. D., Scherer, D. C., Ballard, D. W., & Maniatis, T. (1995) · Genes & Development · doi:10.1101/gad.9.13.1586 · Cited by 1,270
Ubiquitin signalling in the NF-κB pathway
Chen, Z. J. (2005) · Nature Cell Biology · doi:10.1038/ncb0805-758 · Cited by 1,184
IKK/NF- B signaling: balancing life and death - a new approach to cancer therapy
Luo, J. (2005) · Journal of Clinical Investigation · doi:10.1172/jci26322 · Cited by 898
Fuel feeds function: energy metabolism and the T-cell response
Fox, C. J., Hammerman, P. S., & Thompson, C. B. (2005) · Nature reviews. Immunology · doi:10.1038/nri1710 · Cited by 841
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Biological Aspects in Renal Cell Carcinoma
Médina, V., Aparicio, G., & Aparicio, L. M. A. (2012) · InTech eBooks · doi:10.5772/27010 · Cited by 2
Making sense of oxygen sensing
Ratcliffe, P. J., & Keeley, T. P. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00513-1 · Cited by 2
Bonner, L. B., Sadler, C. A., Lindholm, P., Scholtens, D. M., Dulai, P. S., Kochhar, L. E., Kochhar, G., Lukin, D. J., Winter, M. W., Siegel, C. A., et al. (2025) · Trials · doi:10.1186/s13063-025-08932-5 · Cited by 1
Diao, H., Qin, T., Zheng, Y., Han, L., & Zhao, Y. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.157969 · Cited by 1
Liu, B., Yang, S., Liang, J., Yao, L., Huang, B., Chen, Y., Wang, Y., & Lin, Y. (2026) · Chemical Engineering Journal · doi:10.1016/j.cej.2026.177193 · Cited by 1
Sun, S. Y., Cheng, A., Ma, L., Liang, Z., Yan, X., & Fan, K. (2026) · ACS Nano · doi:10.1021/acsnano.6c02860 · Cited by 2
The plasticity and metabolic reprogramming of macrophage in ulcerative colitis
Zhang, Y., Yang, D., Jiang, J., Wang, D., Ji, F., & Sun, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1903462 · Cited by 1
Krzystek‐Korpacka, M., Korpacki, A., Wąsowicz, A., & Neubauer, K. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27188359 · Cited by 1
Berezin, A. Е. (2015) · Biology and Medicine · doi:10.4172/0974-8369.1000231 · Cited by 1
Inflammation: The Role of Endothelial Cells
Alexander, J. S., Granger, D. N., & Harris, N. R. (2017) · Wiley-VCH eBooks · doi:10.1002/9783527692156.ch19 · Cited by 1
Necrotizing Enterocolitis of Newborns
Bajorek, S. A., & Neu, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-29489-6_235 · Cited by 1
Lung neutrophils on a paleo diet: lean, mean inflammatory machines
Cartwright, I. M., & Colgan, S. P. (2021) · Journal of Clinical Investigation · doi:10.1172/jci149495 · Cited by 1
Self-citationZhang, Y., Zhang, X., Tian, B., Ding, X., Ye, C., & Guo, C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.30.458202 · Cited by 1
Hypoxia Bi-directionally Regulates Gut Vascular Barrier through HIF-1α-dependent Mechanism in vitroPreprint
Liu, P., Dai, W., Du, J., Zhou, Y., Wang, X., & Song, H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.26.542539 · Cited by 1
Bourgeois, M. (2010) · Digital Commons - University of South Florida (University of South Florida)
Pattern of Circulating Micro Particles in Patients with Inflammatory Bowel Disease: Review
Berezin, A. Е., & Poplyonkin, E. I. (2015)
Necrotizing Enterocolitis of Newborns
Bajorek, S. A., & Neu, J. (2016) · Springer eBooks · doi:10.1007/978-3-319-18159-2_235-1
Vascular Responses to Intestinal Inflammation
Granger, D. N., & Harris, N. R. (2017) · Springer eBooks · doi:10.1007/978-3-319-33703-6_6
MECHANISMS OF COLONIZATION RESISTANCE TO SHIGELLA FLEXNERI
Kottwitz, H. (2018) · DalSpace (Dalhousie University)
The Tumor Suppressor RASSF1A Links Inflammation and Cancer
Gordon, M. (2015) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r39w0945j
Donnelly, R. P. (2016) · Arrow@dit (Dublin Institute of Technology)
Developing models of the small intestine
Dosh, R. H. (2018) · Sheffield Hallam University · doi:10.7190/shu-thesis-00131
Mavondo, G. A., Mkhwanazi, B. N., Mavondo, J., Peresuh, W., & Moyo, O. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.83529
New insights in intestinal ischemia-reperfusion
Schellekens, D. H. S. M. (2021) · doi:10.26481/dis.20210611ds
Gut Microbiota and the Liver: Interaction Shaping Interactome
Devi, P., Khan, A., Chattopadhyay, P., Garg, A., & Pandey, R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819265-8.00080-2
(2011) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0b013e3283499d5a
Elucidating the intestinal response to ischemia-reperfusion
Kip, A. M. (2022) · Research Publications (Maastricht University) · doi:10.26481/dis.20220210ak
Microenvironmental modulation of the intestinal epithelial barrier
Fagundes, R. R. (2022) · doi:10.33612/diss.204290805
Gordon, M., El‐Kalla, M., Zhao, Y., Fiteih, Y., Law, J., Volodko, N. V., Anwar‐Mohamed, A., El‐Kadi, A. O. S., Liu, L., Odenbach, J., et al. (2014) · PLoS ONE · doi:10.1371/annotation/0ed852a0-eb39-4a28-986f-81f28d870747
Research and application of hypoxia-inducible factor
Wang, X. (2022) · AIP conference proceedings · doi:10.1063/5.0095073
Wang, J., Zhang, X.-E., Chen, G.-M., Wu, Y., Yang, X. Q., Li, Z.-R., Chen, J.-X., & Chen, J. (2024) · Research Square · doi:10.21203/rs.3.rs-4590558/v1
Crosstalk between Inflammatory Hypoxia and Gut Microbiota in Inflammatory Bowel Disease (IBD)
Jing, B., & Gao, F. (2024) · Journal of Biomedical Research & Environmental Sciences · doi:10.37871/jbres1960
Wu, T., Chen, R., Ban, W., Ren, C., Bi, S., Gu, J., Geng, Z.-J., & Song, L. (2024) · Research Square · doi:10.21203/rs.3.rs-5258943/v1
Research Progress of Berberine in Treatment of Intestinal Diseases
庞, 奇. (2024) · Advances in Clinical Medicine · doi:10.12677/acm.2024.14112838
Fischer, N. (2014) · theses.fr (ABES) · doi:10.70675/7ecf88e2z7851z4354zb134z317e666a94cb
Hammoudi, N. (2021) · theses.fr (ABES) · doi:10.70675/4595a58dzcce7z43f2zbd07z10eb7653d7c5
Liang, X., Bao, Y., Liu, Z., Hu, Z., Liu, G., Li, F., & Wang, Z. (2026) · Journal of Materials Chemistry B · doi:10.1039/d5tb02692j
Deniz, Ç. D., Yücel, F., Şenay, H., Kaçar, F., Iyısoy, M. S., Baran, N., Kozanhan, B., Eryılmaz, M. A., & Koc, M. (2026) · Genel Tıp Dergisi · doi:10.54005/geneltip.1452831
Enzyme-Mimicking Atomic Zn−P Catalytic Pairs for Anti-inflammatory Therapy
Zhang, L., Li, F., Wang, Q., Zhang, Z., Than, A., Zheng, L., Ren, Y., Yang, H., Qin, Y. H., & Chen, P. (2026) · ACS Materials Letters · doi:10.1021/acsmaterialslett.6c00369
Mechanisms of gut permeability in livestock
Pearce, S. E. (2026) · Frontiers in Animal Science · doi:10.3389/fanim.2026.1880810
Ohlendieck, C. M., Matellan, C., Bauset, C., Raphael, B., Nwaezeigwe, M., Flynn, E., Okamoto, K., Winter, D., Collins, C. B., Doogan, K. L., et al. (2026) · The Journal of Physiology · doi:10.1113/jp290658
Hypoxia induces microtubule rearrangement in intestinal epithelial cells
Flood, D., Kierans, S. J., DeMichele, E., Dehantschutter, E. T., Dillon, E., Matellan, C., & Taylor, C. T. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00238.2026
Self-citationChen, Q., Xu, L., Duan, K., Song, F., Zhang, H., Huang, Z., Zheng, Z., Qiu, Y., Shi, S., Zhang, J., et al. (2026) · ACS Nano · doi:10.1021/acsnano.6c00379
Li, H., Wang, B., Shi, X., Tian, L., Li, B., Zhou, T., 邱明灿, Yuan, J., & Yin, K. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1854880
Yuan, J., Jian, C., Li, X., Li, X., Chi, S., Wang, X., Lu, L., Ge, L., Li, M., & 龙科任 (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.10.003
谭嗣伟, Luo, J., Ou, X., Guo, X., Ke, B., & Tan, S. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.10.007
Liu, P., Dai, W., Xu, J., Zhao, M., Du, J., Zhou, Y., & Wang, X. (2026) · Veterinary Sciences · doi:10.3390/vetsci13111140
Chaumery, M., Sahuc, Y., Chabaud, S., Philippe, E., & Bolduc, S. (2026) · Journal of Xenobiotics · doi:10.3390/jox16070211
Metadata
- Authors
- Colgan, S. P., & Taylor, C. T.
- Affiliations
- University of Colorado Denver (US)
- University College Dublin (IE)
- Corresponding author
- Colgan, Sean P.
- Venue
- Nature Reviews Gastroenterology & Hepatology
- Published
- 2010-04-06
- Volume
- 7
- Issue
- 5
- Pages
- 281-287
- ISSN
- 1759-5045 (ISSN-L)
- 1759-5053
- PMC
- PMC4077542
- OpenAlex
- W2018782206
- Cited by
- 461
- References
- 63
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 28 · 2023: 26 · 2022: 28 · 2021: 35 · 2020: 20 · 2019: 31 · 2018: 32 · 2017: 33 · 2016: 38 · 2015: 37 · 2014: 31 · 2013: 29 · 2012: 21
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Gastroenterology & Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Repository UCD (University College Dublin) (submittedVersion, cc-by-nc-nd)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Crohn's and Colitis Foundation of America
- Crohn's and Colitis Foundation
- National Institutes of Health (DE016191, DK-50189, HL60569)
- National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050189, R37DK050189, R29DK050189, DK-50189)
- National Institute of Dental and Craniofacial Research (P50DE016191, DE 016191)
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia, intestinal inflammation, inflammatory bowel disease, hypoxia-inducible factor, HIF stabilization, prolyl hydroxylase inhibition, intestinal epithelial barrier, oxygen gradients, inflammation resolution, mucosal inflammation
- MeSH terms
- Animals, Hypoxia, Humans, Intestinal Mucosa, Inflammatory Bowel Diseases, Oxidative Stress, Hypoxia-Inducible Factor 1
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