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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
  1. Prashant Kant1,
  2. Anita Sainsbury1,
  3. Karen R Reed2,
  4. Stephen G Pollard3,
  5. Nigel Scott4,
  6. Alan R Clarke2,
  7. P Louise Coletta1,
  8. Mark A Hull1
  1. 1Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, UK
  2. 2Cardiff School of Biosciences, University of Cardiff, Cardiff, Wales, UK
  3. 3Department of Obesity Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  4. 4Department of Histopathology, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  1. Correspondence to Prof Mark A Hull, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK; m.a.hull{at}leeds.ac.uk

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 ApcMin/+ 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 ApcMin/+ 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.

  • Bariatric surgery
  • biomarker
  • colorectal carcinogenesis
  • macrophage migration inhibitory factor
  • obesity
  • proliferation
  • colorectal neoplasia
  • cytokines
  • epithelial kinetics
  • inflammatory mediators
  • obesity surgery

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Footnotes

  • Funding MRC (UK) Medical Research Foundation.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Leeds (East) Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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