title: Tetrahydrobiopterin Attenuates DSS-evoked Colitis in Mice by Rebalancing Redox and Lipid Signalling.
abstract: OBJECTIVE
  Guanosine triphosphate cyclohydrolase [GCH1] governs the production of the enzyme cofactor tetrahydrobiopterin [BH4] which is essential for biogenic amine synthesis, lipid metabolism via alkylglycerol monooxygenase [AGMO], and redox coupling of nitric oxide synthases [NOSs]. Inflammation-evoked unequal regulation of GCH1 and NOS or AGMO may cause redox stress and lipid imbalances.
  
  
  METHODS
  The present study assessed potential therapeutic effects of rebalancing these systems with BH4 in experimental colitis in mice.
  
  
  RESULTS
  Oral treatment with BH4 as a suspension of crushed tablets attenuated colitis, whereas inhibition of its production had opposite effects: aggravated weight loss, epithelial haemorrhages and ulcers, neutrophil infiltrates, production of reactive oxygen species, and unfavourable profile changes of endocannabinoids, ceramides, and lysophosphatidic acids. Conversely, oral BH4 normalised biopterin, reduced in vivo activity of oxidases and peroxidases in the inflamed gut, favoured nitric oxide over hydrogen peroxide, and maintained normal levels of lipid signalling molecules. BH4 favoured thereby resident CD3+CD8+ and regulatory CD3+CD25+ intraepithelial T cells that are important for epithelial integrity.
  
  
  CONCLUSIONS
  BH4 protected against colitis in mice via two major pathways: [i] by reduction of oxidative stress; and [ii] by re-orchestration of alkyl- and acylglycerolipid signalling via AGMO. Oral treatment with BH4 is a safe approved supplementary therapy for genetic BH4 deficiency and did not excessively increase systemic BH4 levels. Therefore, one may consider repurposing of oral BH4 as an adjunctive treatment for colitis.
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Zschiebsch
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Geethanjali
authors.initials: G
authors.lastname: Pickert
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.affiliation: Department of Experimental Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Heinfried
authors.initials: H
authors.lastname: Radeke
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Division of Biological Chemistry, Medical University of Innsbruck, Austria.
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Werner
authors.affiliation: Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany tegeder@em.uni-frankfurt.de.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016264:Dextran Sulfate; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D005765:Gastrointestinal Agents; D001708:Biopterins; D016264:Dextran Sulfate; C003402:sapropterin
keywords: AGMO; Tetrahydrobiopterin; glycerophospholipids; inflammatory bowel disease; lipid signalling molecules; nitric oxide; redox stress