title: Riboflavin depletion impairs cell proliferation in adult human duodenum: identification of potential effectors.
abstract: OBJECTIVE
  Riboflavin (vitamin B2) is an essential dietary component with a known function in oxidative metabolism. Our previous data using a rat model of riboflavin deficiency suggested that riboflavin also functions as a luminal signaling molecule regulating crypt development and cell turnover. Riboflavin deficiency is prevalent in both high- and low-income countries across the globe. This study aims to establish whether riboflavin deficiency has consequences for gastrointestinal (GI) morphology in adults and what the effects and effectors of any such alteration may be.
  
  
  METHODS
  Duodenal biopsies and blood samples were collected from a cross-section of gastroscopy patients. Crypt morphology and cell division were studied by immunohistochemistry, and biochemical riboflavin status was determined. Additionally a cell culture model of riboflavin deficiency was developed and analyzed using a combination of flow cytometry, and microarray and clonogenic assays.
  
  
  RESULTS
  Duodenal crypts from subjects in the lowest quartile of riboflavin status were significantly shorter (P=0.023), less cellular (P=0.007), and had fewer cell divisions (P=0.034) than the crypts of subjects in the top quartile of riboflavin status. Following riboflavin depletion of colon cells in culture, cell cycle slowed. Microscopy revealed impaired mitosis and accumulation of aneuploid cells. Alterations in gene expression profiles reflected this alteration, with several mitosis-related genes altered, including AspM, cyclin B1, and Birc5 downregulated and Kif23 upregulated. Riboflavin depletion in vitro caused irreversible loss of proliferative potential of cells.
  
  
  CONCLUSIONS
  Riboflavin depletion in adult humans impairs proliferation and proliferative potential of intestinal cells, which may have implications for gastrointestinal function.
authors.affiliation: Human Nutrition Unit; Faculty of Medicine, Dentistry and Health, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. e.nakano@sheffield.ac.uk
authors.forename: Emi
authors.initials: E
authors.lastname: Nakano
authors.forename: Sohail
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Lee
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bury
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Riley
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Powers
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Corfe
mesh_terms: D000328:Adult; D000368:Aged; D018938:Caco-2 Cells; D049109:Cell Proliferation; D003430:Cross-Sectional Studies; D056744:Cyclin B1 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D004386:Duodenum / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005773:Gastroscopy; D020869:Gene Expression Profiling; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D012257:Riboflavin Deficiency / Q000473:pathology*; D000077022:Survivin; D015854:Up-Regulation
chemical_list: C467202:ASPM protein, human; C107489:BIRC5 protein, human; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; C092935:KIF23 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D000077022:Survivin