Harnessing Gut Microbial Modulation in Chronic Inflammatory Gastrointestinal Disease

• Author / Creator

  Mocanu, Valentin

• Background A growing body of work has emerged which suggests that not only is the gut microbiome integral to maintaining human health, but also promising in the treatment of chronic inflammatory gastrointestinal diseases. Obesity and inflammatory bowel disease (IBD) are two such conditions with perhaps the greatest evidence for microbial intervention. However, our understanding of the role gut microbial modulation has in the management of these diseases remains in its infancy thereby limiting our ability to harness its therapeutic potential. Aims The aim of this thesis is to explore the role of gut microbial modulation for two chronic inflammatory gastrointestinal diseases in which we face the biggest therapeutic challenges to date - obesity and inflammatory bowel disease. HypothesisThe overarching hypothesis of the enclosed thesis is that gut microbial modulation can be utilized to improve metabolic and gastrointestinal health in obesity and inflammatory bowel disease. MethodsIn our first study, a randomized double-blinded placebo-controlled trial was performed to evaluate whether gut microbial modulation through fecal microbial transplantation (FMT) combined with fiber supplementation could improve insulin resistance in patients with severe obesity and metabolic syndrome. Secondly, we conducted a systematic review and pooled proportion meta-analysis to evaluate whether two gut microbial modulation strategies, repeated FMT delivery and antibiotic pre-treatment, could improve IBD response and remission. Lastly, we utilized an established murine model of ileocecal resection to evaluate if peri-operative tributyrin supplementation, an adjunct chosen to restore luminal hypoxia and gut barrier integrity, could improve post-operative inflammation by fostering a recolonization of anti-inflammatory anaerobic microbes. ResultsResults of our randomized trial demonstrated that microbial modulation imparted improvements on insulin resistance using a safe and tolerable oral FMT delivery method in a North American bariatric population undergoing concurrent medical therapy. Interestingly, fiber fermentability was found to differentially modulate metabolic response, with patients receiving low-fermentability fiber following FMT demonstrating significant improvements for insulin resistance, insulinemia, and enteroendocrine physiology. These benefits were associated with increased microbial richness and a bloom in select microbial taxa such as Phascolarctobacterium, Christensellaceae, Bacteroides, and Akkermansia.Results of our systematic review on the efficacy of repeated FMT and antibiotic pre-treatment with respect to improvement of IBD outcomes revealed a potential for both strategies in modulating IBD response and remission rates. That these benefits were also associated with an enrichment in select bacterial taxa like Bifidobacterium, Roseburia, Lachnospiraceae, Prevotella, Ruminococcus, and Clostridium related species which are associated with anti-inflammatory metabolite production further supports an adoption of these strategies in future clinical trials. Lastly, our ileocecal mouse model study provided evidence that timing of tributyrin delivery in the peri-operative period was associated with differences in gastrointestinal inflammation and gut microbial recolonization. Notably, mice receiving tributyrin postoperatively demonstrated improvements in colonic inflammation and a bloom of anti-inflammatory anaerobic taxa including Bacteroides thetaiotomicorn, Bacteroides caecimuris, Parabacteroides distasonis, Clostridia, and Turicibacter.ConclusionThese studies add further backing to the growing body of evidence supporting the ongoing pursuit of gut microbial modulation strategies as a novel therapeutic modality for management of chronic inflammatory gastrointestinal diseases. In so doing, they also serve as a framework for the ongoing development of novel microbial biotherapeutic strategies aimed at combatting the growing obesity and IBD epidemics through the future delivery of safe, effective, and affordable designer bacterial consortia.

• Subjects / Keywords

  • microbiome
  • obesity
  • metabolic syndrome
  • inflammatory bowel disease
  • IBD
  • Crohn's
  • Ulcerative Colitis
  • ileocecal resection

• Graduation date

  Fall 2021

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-5jtj-me16

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.