Factors associated with the post-operative recurrence of Crohn's disease

• Author / Creator

  Michael Laffin

• Background- Crohn's disease (CD) is a type of inflammatory bowel disease that can cause inflammation throughout the alimentary tract. Many individuals diagnosed with CD ultimately require intestinal resection. Unfortunately, disease often recurs following surgery. The pathophysiology of the post-operative recurrence of CD is incompletely understood, but thought to be multifactorial, involving environmental, genetic, microbial, and immunologic factors. Aims- To identify genetic, microbial, or immunologic factors in humans that predict recurrence of CD following intestinal resection, and to modify inflammation following ileocecal resection (ICR) in a murine model using a prebiotic fiber. Methods- Three distinct cohorts of human subjects were analyzed to determine the effect of genetic loci (n=191), microbial populations (n=45), and locoregional immunologic factors (n=26) in recurrent disease following intestinal resection. An interleukin (IL)-10 knockout murine model of ICR was utilized to assess the effect of fructooligosaccaride on post-ICR inflammation and microbial composition. Results- A single nucleotide polymorphism associated with BACH2 (rs1847472) predicted recurrence in our cohort (HR-1.24 CI-1.00-1.54 p<0.05), as did an elevation of the cytokine CCL2 in the intestinal mucosa (p<0.01). A lack of IL-5 and IL-16 in the regional lymph nodes of resected specimens was associated with disease recurrence (p<0.01). A decreased ratio of endospore-forming bacteria at the time of surgical resection was associated with disease recurrence (OR-9.2 95% CI 1.8-47.7 p<0.01). Supplementation of a prebiotic fiber following ICR led to increased intestinal inflammation (p<0.05) and a loss of microbial diversity (p<0.05). Conclusion- The identification of genetic, microbial, and immunologic risk factors in the post-operative recurrence of CD supports the hypothesis that the process is multifactorial. Given the importance of BACH2, IL-16, and IL-5 in T-cell and B-cell development, adaptive immunity is implicated in disease recurrence. The apparent importance of endospore-forming bacteria in the prevention of disease recurrence suggests a role for pre-operative microbial manipulation in the prevention of recurrent CD following intestinal resection, though the introduction of fructooligosaccharide was not successful in reducing post-ICR inflammation.

• Subjects / Keywords

  • Inflammatory bowel disease
  • Crohn's disease
  • Recurrence
  • Surgery

• Graduation date

  Spring 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3RN30P5R

• License

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