Mechanisms of action of the duodenal-jejunal bypass sleeve Jessica Jade McMaster BSc, MDietSt A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2019 Faculty of Medicine ABSTRACT The prevalence of obesity and related comorbidities, such as type 2 diabetes mellitus (T2DM) have reached epidemic proportions globally. Weight loss improves morbidity and mortality in people with obesity and T2DM. However, effective long-term obesity treatments are limited. Lifestyle modification is the first line treatment, but long-term data suggest a return to baseline weight after successful weight loss. In contrast, bariatric surgery causes permanent anatomical changes in the gastrointestinal tract (GIT) to facilitate weight loss. This is the most effective long-term treatment for obesity and T2DM. However, compared to the large number of eligible individuals, very few patients undergo bariatric surgery. Minimally invasive treatment options have been developed to fill the treatment gap between conservative and surgical measures. One treatment option is the duodenal-jejunal bypass sleeve (DJBS; EndoBarrier®; GI Dynamics, Lexington, MA, USA). This is a 60 cm impermeable sleeve device, which is placed endoscopically into the duodenal bulb, extending to the jejunum and left in place for up to 48 weeks. The device separates bile and pancreatic secretions from chyme, reducing the contact of ingested food with the small intestinal mucosa. Significant weight loss and improvements in glycaemic control have been reported after DJBS treatment, but little is known about the mechanisms of action of the device. The device dwells in the GIT, but the impact of implantation on gastrointestinal function has undergone limited investigation. Obesity and T2DM are associated with derangements in normal physiology. We currently have a poor understanding of the impact of DJBS treatment on these parameters, and how this might be linked to device mechanisms of action. The effect of DJBS implantation on the upper GIT microbiota or the local or systemic immune response is unknown. Therefore, this thesis addresses the mechanisms of action of the DJBS in terms of clinical response, gastrointestinal function and microbial and immune parameters. The clinical effects of DJBS treatment, in addition to dietary intake, lifestyle factors and long-term outcomes after device removal were assessed. DJBS treatment for up to 48 weeks resulted in significant improvements in anthropometric and metabolic measures. In parallel, reductions in dietary intake were observed. One year after device removal, the majority of patients were unable to sustain clinically significant weight loss. Despite this, some beneficial metabolic effects remained. Investigation of the effect of DJBS treatment on gastrointestinal function revealed no significant impact of DJBS treatment on gastric emptying or intraluminal lipolytic activity. However, gastrointestinal symptoms were significantly increased following DJBS implantation. In particular, there was a significant increase in epigastric pain symptoms after device placement. When considered in combination with the dietary intake results, a key mechanism of action of the i device for inducing weight loss appears to be the induction of gastrointestinal symptoms. This occurs primarily in relation to meals and may facilitate weight loss by reducing dietary intake. Changes to patients’ gastrointestinal microbiota during DJBS treatment was investigated using 16S rRNA gene sequencing technology. The gastric and duodenal mucosa-associated microbiota (MAM), stool microbiota and the device biofilm microbial community were characterised. DJBS treatment induced significant changes in the gastric and duodenal MAM, such as decreases in organisms typical of the proximal GIT and increases in organisms typical of the distal intestine. A distinct microbial community was formed on the device, characterised largely by organisms typical of the distal intestine. DJBS treatment induced transient changes in the stool microbiota. This was mirrored by changes in the predicted functional capacity of the microbiota, suggesting an alteration in energy metabolism, with a preference for carbohydrate metabolism. Finally, the systemic and local immune response to DJBS treatment was assessed. There was no significant change in circulating pro-inflammatory cytokines following DJBS treatment. There were changes in T cell phenotype that were broadly suggestive of an increase in immune activation. In the duodenum, modest changes in morphology occurred following DJBS treatment, with villous blunting observed in a number of patients. In parallel, there was a significant increase in eosinophils and intraepithelial lymphocytes. This suggest the DJBS, a foreign body in the duodenum that is colonised by microbes typical of the distal intestine, induces a local immune response. In summary, this thesis has demonstrated the DJBS was clinically effective in the study population, resulting in weight loss and broad metabolic improvements. The DJBS induces significant gastrointestinal symptoms (including meal-related symptoms) in parallel with a significant reduction in dietary intake that may facilitate weight loss. There was no evidence of change in gastric emptying or altered absorption of fat. There were significant changes in the gastrointestinal microbiota following DJBS treatment, with a proliferation of more distal bowel organisms compared to those typically observed in the duodenum. In concert, a local immune response was observed, with potential implications for device safety. These results may provide insight into DJBS efficacy and tolerability and provide avenues of future research. ii DECLARATION BY AUTHOR This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. iii PUBLICATIONS INCLUDED IN THIS THESIS No publications included. SUBMITTED MANUSCRIPTS INCLUDED IN THIS THESIS No manuscripts submitted for publication. OTHER PUBLICATIONS DURING CANDIDATURE Peer-reviewed papers von Wulffen M, Talley NJ, Hammer J, McMaster J, Rich G, Shah A, Koloski N, Kendall BJ, Jones M, Holtmann G. Overlap of Irritable Bowel Syndrome and Functional Dyspepsia in the Clinical Setting: Prevalence and Risk Factors. Dig Dis Sci. 2018. 64:480-486 DOI: 10.1007/s10620-018- 5343-6 Conference Abstracts and Presentations Oral Presentations Chapter 1: McMaster JJ, Rich GG, Shanahan ER, Do AT, Fletcher LM, Kutyla MJ, Tallis C, Macdonald GA, Chachay VS, Morrison M, Holtmann GJ. Mechanisms of action for weight reduction in patients treated with a duodenal-jejunal bypass sleeve. Asia Pacific Digestive Week, Seoul, South Korea, November 2018 Chapter 2: McMaster JJ, Rich GG, Shanahan ER, Do AT, Fletcher LM, Kutyla MJ, Tallis C, Macdonald GA, Chachay VS, Morrison M, Holtmann GJ. Perturbation of the gut-brain-axis as the mechanism of action for weight reduction in patients treated with a duodenal-jejunal bypass sleeve. Australian Gastroenterology Week, Brisbane, Australia, September 2018 Chapter 3: McMaster J, Rich G, Shanahan E, Fletcher L, Macdonald G, Koloski N, Morrison M, Chachay V, Holtmann G. Metabolic improvements following treatment with a duodenal-jejunal bypass sleeve in patients with obesity and type 2 diabetes Australia and New Zealand Obesity Society/ Obesity Surgery Society of Australia and New Zealand/Asia-Oceania Conference on Obesity Annual Scientific Meeting, Adelaide, Australia, October 2017 iv Chapter 4: McMaster J, Rich G, Fletcher L, Gandhi A, Macdonald G, Shanahan E, Koloski N, Morrison M, Chachay V, Holtmann G. Metabolic and nutrition-related effects of a duodenal- jejunal bypass sleeve in patients with obesity and type 2 diabetes: preliminary results of a pilot study Australia and New Zealand Obesity Society Annual Scientific Meeting, Brisbane, Australia, October 2016 Poster Presentations 1. McMaster J.J, Shanahan E.R, Do A.T, Rich G.G, Chachay V.S, Macdonald G.A, Holtmann G.J.