title: Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.
abstract: BACKGROUND
  Rectal epithelial cell mitosis and crypt size, as well as expression of proinflammatory genes including macrophage migration inhibitory factor (MIF), are increased 6 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients. Tests were carried out to determine whether these putative colorectal cancer risk biomarkers remained elevated long term after RYGB, and the mechanistic basis, as well as the functional consequences, of Mif upregulation in intestinal epithelial cells was investigated.
  
  
  METHODS
  Rectal mucosa and blood were obtained a median of 3 years after RYGB from the original cohort of patients with RYGB (n = 19) for crypt microdissection, real-time PCR, immunohistochemistry for MIF and immunoassay of proinflammatory markers. Immunohistochemistry for Mif and bromodeoxyuridine labelling were performed on AhCre⁺ mouse and Apc(Min/⁺) mouse (with and without functional Mif alleles) intestine, respectively.
  
  
  RESULTS
  Rectal epithelial cell mitosis and crypt size remained elevated 3 years after RYGB compared with preoperative values (1.7- and 1.5-fold, respectively; p < 0.05). There was a 40-fold (95% CI 13 to 125) increase in mucosal MIF transcript levels at 3 years associated with increased epithelial cell MIF protein levels. Conditional Apc loss in AhCre⁺ mice led to increased epithelial cell Mif content. Mif deficiency in Apc(Min/⁺) mice was associated with a combined defect in intestinal epithelial cell proliferation and migration, which was reflected by the longitudinal clinical data.
  
  
  CONCLUSIONS
  Mucosal abnormalities persist 3 years after RYGB and include elevation of the protumorigenic cytokine MIF, which is upregulated following Apc loss and which contributes to intestinal epithelial cell homeostasis. These observations should prompt clinical studies of colorectal neoplastic risk after RYGB.
authors.affiliation: Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kant
authors.forename: Anita
authors.initials: A
authors.lastname: Sainsbury
authors.forename: Karen R
authors.initials: KR
authors.lastname: Reed
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Pollard
authors.forename: Nigel
authors.initials: N
authors.lastname: Scott
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.forename: P Louise
authors.initials: PL
authors.lastname: Coletta
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hull
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000209:etiology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D015390:Gastric Bypass / Q000009:adverse effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D009767:Obesity, Morbid / Q000601:surgery*; D011184:Postoperative Period; D012007:Rectum / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors