title: Enteral glutamine differentially regulates Nrf 2 along the villus-crypt axis of the intestine to enhance glutathione levels.
abstract: OBJECTIVE
  Glutamine is an important energy source for the intestinal epithelium, and its supplementation protects intestinal epithelial cells by induction of glutathione. However, mechanisms of glutathione induction in cells at various stages of differentiation along the crypt to villus axis are not well understood. This study examined induction of glutathione in response to glutamine along the intestinal villus-crypt axis and evaluated regulatory mediators involved in the process.
  
  
  METHODS
  Animals were administered 4% glutamine in feed for 7 days, following which enterocytes at various stages of differentiation were isolated and glutathione levels and signaling mediators involved in its regulation were studied.
  
  
  RESULTS
  In control animals, glutathione levels were higher in the intestinal crypt than in the villus or middle region. This was accompanied by elevated expression of the modifier subunit of glutathione synthetase (GCLM) and the transcription factor Nrf2 when compared with cells from the villus and middle regions. These levels were further enhanced by glutamine throughout the intestine, although the effects were more dramatic in the crypt. In parallel to glutathione induction, glutamine supplementation also altered actin dynamics and proliferation in cells of the crypt.
  
  
  CONCLUSIONS
  These results suggest that the variation of glutathione levels along the villus-crypt axis in the intestine is due to gradients in expression of mediators such as glutamate cysteine ligase modifier subunit and Nrf2. The protective effects of glutamine supplementation seem to be most pronounced in the crypt, where it upregulates proliferation, glutathione levels and alters actin dynamics.
authors.affiliation: Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
authors.forename: Raghupathy
authors.initials: R
authors.lastname: Venoji
authors.affiliation: Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
authors.forename: Gnanaraj Jayakumar
authors.initials: GJ
authors.lastname: Amirtharaj
authors.affiliation: Center for Stem Cell Research, Christian Medical College, Vellore, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Kini
authors.affiliation: Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Vanaparthi
authors.affiliation: Center for Stem Cell Research, Christian Medical College, Vellore, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Venkatraman
authors.affiliation: Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
authors.forename: Anup
authors.initials: A
authors.lastname: Ramachandran
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D008841:Actin Cytoskeleton / Q000378:metabolism; D000284:Administration, Oral; D002454:Cell Differentiation; D002469:Cell Separation; D020895:Enterocytes / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005973:Glutamine / Q000008:administration & dosage / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005981:Glutathione Synthase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D017208:Rats, Wistar; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D005721:Glutamate-Cysteine Ligase; D005973:Glutamine; D005978:Glutathione; D005981:Glutathione Synthase; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat
keywords: Nrf2; actin; glutamine; glutathione; intestine