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

Hall, Caroline; Lee, J. Scott; Murphy, Emily M.; Gerich, Mark E.; Dran, Rachael; Glover, Louis E.; Abdulla, Zuhair I.; Skelton, Matthew R.; Colgan, Sean P.

doi:10.1053/j.gastro.2020.05.033

Cited by 53 publications

(49 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Notably, in intestinal epithelial cells (IECs), CrT1 localized specifically around tight junctions and knockdown or overexpression of CrT1 in these cells corroborated the idea that CrT1, besides regulating the intracellular creatine concentration in IECs, was also modulating epithelial barrier formation and wound healing [ 14 ]. In CrT1 knockdown IECs—that is, in the absence of adequate creatine transport—these cells transformed to a stressed, glycolysis-predominant energy metabolism, resulting in leaky tight junctions and mislocalization of actin and tight junction proteins [ 14 ]. Despite the significant impacts of CrT1 loss, proliferation was not altered in CrT1 knockdown intestinal epithelial cells [ 14 ].…”

Section: Scientific Rationale Specifically For Intestinal Tissuementioning

confidence: 74%

“…Since the CK/PCr system, as well as the creatine transporter (CrT1) are involved in a plethora of processes that are important for cellular energetics [ 3 , 8 ], also in intestinal epithelial cells [ 16 , 17 , 62 ] it is interesting that the investigation of mucosal biopsied from 30 patients with Crohn’s disease and 27 patients with ulcerative colitis both showed lower expression levels of CrT1, which might contribute to the reduced barrier function of intestinal epithelium [ 14 ] (see Figure 3 ). Notably, in intestinal epithelial cells (IECs), CrT1 localized specifically around tight junctions and knockdown or overexpression of CrT1 in these cells corroborated the idea that CrT1, besides regulating the intracellular creatine concentration in IECs, was also modulating epithelial barrier formation and wound healing [ 14 ]. In CrT1 knockdown IECs—that is, in the absence of adequate creatine transport—these cells transformed to a stressed, glycolysis-predominant energy metabolism, resulting in leaky tight junctions and mislocalization of actin and tight junction proteins [ 14 ].…”

Section: Scientific Rationale Specifically For Intestinal Tissuementioning

confidence: 99%

“…In CrT1 knockdown IECs—that is, in the absence of adequate creatine transport—these cells transformed to a stressed, glycolysis-predominant energy metabolism, resulting in leaky tight junctions and mislocalization of actin and tight junction proteins [ 14 ]. Despite the significant impacts of CrT1 loss, proliferation was not altered in CrT1 knockdown intestinal epithelial cells [ 14 ]. It is noteworthy that metabolomic analysis has revealed that the actin cytoskeleton demands nearly 20% of total available energy within the epithelium [ 26 ].…”

Section: Scientific Rationale Specifically For Intestinal Tissuementioning

confidence: 99%

“…Cr is derived from dietary sources in the gastrointestinal tract, or by de novo synthesis primarily in the kidney and in the liver [ 12 ]. The Na + and Cl − dependent creatine transporter (CrT1), expressed in the apical membrane of intestinal epithelial cells, facilitates Cr uptake from the gut lumen [ 11 , 14 ]. Potential routes for Cr absorption into systemic circulation include paracellular movement by solvent drag transport, or via basolateral Cr transport by the monocarboxylate transporter 12 (MCT12) [ 15 ].…”

Section: Figurementioning

confidence: 99%

See 3 more Smart Citations

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

Wallimann

Hall

Colgan³

et al. 2021

Nutrients

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Scientific Rationale Specifically For Intestinal Tissuementioning

confidence: 74%

Section: Scientific Rationale Specifically For Intestinal Tissuementioning

confidence: 99%

Section: Scientific Rationale Specifically For Intestinal Tissuementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

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

Wallimann

Hall

Colgan³

et al. 2021

Nutrients

Self Cite

View full text Add to dashboard Cite

show abstract

“…As autophagy is central to cellular energy homeostasis, it is possible that ATG9A KD cells simply lack the necessary energy capacity to establish barrier ( Singh and Cuervo, 2011 ). Further experiments will seek to examine the energetic state of ATG9A-depleted cells, in the mode of previous studies that have probed the energetic state of intestinal epithelial monolayers ( Lee et al ., 2018 ; Hall et al ., 2020 ; Lee et al ., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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

Dowdell¹,

Cartwright²,

Goldberg³

et al. 2020

MBoC

Self Cite

View full text Add to dashboard Cite

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 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 knockdown cells have intrinsic abnormalities in the actin cytoskeleton, including mislocalization of the TJ binding protein vasodilator-stimulated phosphoprotein (VASP). 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.

show abstract

Phytoestrogen arctigenin preserves the mucus barrier in inflammatory bowel diseases by inhibiting goblet cell apoptosis via the ERβ/TRIM21/PHB1 pathway

Qiao

et al. 2022

Phytotherapy Research

View full text Add to dashboard Cite

Intestinal mucus barrier dysfunction is closely involved in the pathogenesis of inflammatory bowel diseases (IBD). To investigate the protective effect and underlying mechanism of arctigenin, a phytoestrogen isolated from the fruits of Arctium lappa L., on the intestinal mucus barrier under colitis condition. The role of arctigenin on the intestinal mucus barrier and the apoptosis of goblet cells were examined by using both in vitro and in vivo assays. Arctigenin was demonstrated to promote the mucus

show abstract

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

Cited by 53 publications

References 50 publications

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

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

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

Phytoestrogen arctigenin preserves the mucus barrier in inflammatory bowel diseases by inhibiting goblet cell apoptosis via the ERβ/TRIM21/PHB1 pathway

Contact Info

Product

Resources

About