Background: Bowel preparation is essential for quality colonoscopy. Although most bowel preparation regimens recommend dietary restriction for 24 to 48 hours before the procedure, the evidence for this is poor. Objectives: To establish whether dietary restriction during bowel preparation improves the quality of bowel preparation. Methods: A prospective single blind, randomised controlled pilot study. The dietary restriction (DR) group was instructed not to ingest high fibre foods for 48 hours prior to the use of a polyethylene glycol (PEG) bowel preparation. The non-dietary restriction (NDR) group was not given any dietary modification, but received instructions for the use of the PEG-based preparation solution. On the day of colonoscopy, the quality of the bowel effluent was assessed, and additional preparation given as necessary. The primary endpoint was quality of bowel cleansing using the Harefield Cleansing Scale during colonoscopy. The secondary endpoint was the need for additional bowel preparation and quantity of additional bowel preparation given prior to endoscopy. Data were analysed on an intention to treat basis. Results: Twenty-three participants were randomised to the intervention group and thirty-four to the control group. Patient demographics were similar in both groups. Dietary restriction did not influence the success rate of bowel preparation: 97% successful bowel preparation in the DR group, vs 91% successful bowel preparation in the NDR group (p=0.559). Additional bowel preparation requirement were similar in both groups: 35% in DR group vs 39% in NDR group (p=0.768). Mean amount of additional bowel preparation required was similar: 560 ml in the DR group vs 460 ml in the NDR group (p=0.633). Conclusion: The quality of bowel preparation was comparable in patients with and without dietary restrictions prior to colonoscopy. Non-restrictive diets prior to bowel preparation should be considered to increase compliance. The sample size of this pilot study prohibited definite statistical conclusions but demonstrated this to be a reasonable methodology for a larger study.

Rising rates of urbanization and the global trend towards a more Western lifestyle correlates with increased incidence of both Vitamin D deficiency and Inflammatory Bowel Disease (IBD). The Vitamin D Hypothesis is the most current and prevalent theory that explains the rising cases of IBD. This hypothesis postulates that decreased ultraviolet radiation and dietary variety predispose certain populations to develop IBD. Vitamin D has an active role within the immune system, suppressing the development and function of pro-inflammatory T helper cells while promoting the development and action of immunotolerant regulatory T cells. IBD patients receive pharmaceutical immunotherapies that antagonize pro-inflammatory markers. Though Vitamin D is typically prescribed to support skeletal development, it may also be considered an adjunct therapy to prevent gastrointestinal flares in patients with IBD. However, the current standard of care for treating Vitamin D deficiency is prescribing daily Vitamin D supplements. On average, children exhibit poor compliance when prescribed a daily dosing regimen, especially when they do not experience a clear, direct benefit after taking their daily dose. An alternative to the daily dosing regimen is a high-dose, interval regimen of Vitamin D supplementation. Recent studies have demonstrated that high doses of Vitamin D are safe and effective at raising serum Vitamin D levels to optimal levels (40-60 ng/mL) in the pediatric population. Moreover, IBD patients with optimal Vitamin D levels appear to experience significantly fewer gastrointestinal flare-ups and hospitalizations. There is little existing research reporting on the use of high-dose, interval Vitamin D supplementation. As such, more longitudinal studies need to be performed to assess not only patients’ Vitamin D status but also their levels of relevant immunological markers in their serum, such as pro-inflammatory cytokines and regulatory T cells. These efforts would enable researchers to definitively conclude the effectiveness of high dose interval Vitamin D supplementation to raise serum Vitamin D levels and assess the impact of Vitamin D supplementation on the immune system in patients with IBD.

Inflammatory Bowel Disease (IBD), divided into Crohn’s disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC), is a chronic, crippling autoimmune condition characterized by gastrointestinal (GI) inflammation. The methods used to diagnose IBD and assess its activity can be invasive and costly and typically include a combination of histologic, endoscopic, radiologic, clinical, and biochemical measures. Currently, there is an increasing need for the development of noninvasive assessment measures to detect an interval response to prescribed therapy. Previous studies have found serial and fecal biomarkers to be reliable, but non-specific indicators of GI tract inflammation. At present, they cannot be used to distinguish between inflammation resulting from infection and that caused by chronic inflammation in patients with IBD. The aim of this study is to measure changes in serum and fecal biomarkers over time in individual children and adolescents with CD, UC, and IC initiating infliximab therapy while investigating any parallels between fluctuations in biomarker levels and endoscopic, clinical, and biochemical outcomes. The inflammatory biomarkers evaluated in this study include fecal and serum anti-Saccharomyces-Cerevisiae Antibody (ASCA), fecal and serum lactoferrin, fecal hemoglobin, fecal calprotectin, fecal IL1-α, fecal IL1-β, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The data for this study was collected from a multicenter longitudinal prospective cohort study following pediatric patients over the course of six consecutive infliximab infusion appointments. Study sites include Boston Children’s Hospital and Riley Children’s Hospital in Indianapolis. Participants were recruited from a pool of CD, UC, and IC patients who were either new to infliximab, had been receiving infliximab for less than six months, or had been receiving infliximab for more than one year. Patients brought in stool samples at each of their scheduled infliximab infusions, biochemical labs (ESR and CRP) were obtained, and patients completed a health-related quality of life survey (IMPACT-III Questionnaire). Forty-three patients (26 with CD, 16 with UC, and one with IC) completed this study. There was no significant difference in mean serum or fecal ASCA levels between participants with CD and those with UC. However, average serum and fecal ASCA were higher in patients with CD than those with UC at almost every infusion. The baseline mean CRP level in patients with CD was significantly higher than that observed in patients with UC (p<0.05). In patients with CD, the mean IMPACT-III score was significantly higher (improved quality of life) at Infusion 5 than at baseline. The data collected in this study suggest serial biomarker measurements may be useful in monitoring a patient’s response to infliximab therapy. This study is not yet complete and requires further data analysis to more definitively conclude if a single or a composite metric including several fecal and/or serum inflammatory biomarkers would provide a more robust assessment of disease activity in children and young adults with IBD.

Inflammatory Bowel Disease (IBD) is a chronic, idiopathic autoimmune disease characterized by the inflammation of the GI tract. The main subcategories of IBD include Crohn Disease (CD), ulcerative colitis (UC), and Indeterminate Colitis (IC). Currently, IBD is diagnosed and evaluated using clinical, endoscopic, biochemical, and histologic measures - which can be invasive and costly. Previous studies have shown that measurement of serum and fecal inflammatory biomarkers might be effective both for the assessment of intestinal infectious or inflammatory processes, as well as for gauging IBD disease activity. Inflammatory biomarkers investigated in this study include serum and fecal Anti-Saccharomyces-Cerevisiae Antibody (ASCA), serum and fecal lactoferrin, fecal calprotectin, fecal hemoglobin, IL1-𝛼, IL1-β, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). IMPACT-III questionnaires are utilized to measure the quality of life in enrolled subjects. Data collected in this study investigated the relationship between changes in serum and fecal biomarker levels, clinical disease activity, and the mental wellbeing of patients. The primary objective was to measure changes in inflammatory biomarker levels in patients with CD, UC, and IC after being treated with the anti-TNF therapy Infliximab (Remicade). The second objective is to study the relationship between changes in these biomarker levels and the clinical, biochemical, and endoscopic outcome parameters of IBD in patients. This is a multicenter, longitudinal, cohort study following 50 pediatric patients with IBD over the course of six Remicade infusion appointments. The project was conducted in partnership with Riley’s Children Hospital in Indianapolis. Patients with CD, UC, and IC were recruited for the study and stratified with respect to the temporal phase of their Remicade infusions, including: • Induction • Past induction, but less than 6 months • Those who have been receiving Remicade for over one year. A total of 58 eligible IBD patients are currently enrolled. 13 patients have withdrawn from the study, leaving 45 active patients: 27 CD, 17 UC, and 1 IC remaining in the prospective cohort. Patients provided serum and fecal samples and completed IMPACT-III questionnaires at the time of each Remicade infusion. Baseline serum ASCA levels were 0.014 ±0.029 OD from (n=15) patients with CD, 0.0083 ±0.022 OD in (n=12) patients with UC, and 0.002 OD in one patient with IC. Baseline fecal ASCA levels were 0.068 ±0.186 OD in (n=10) patients with CD, 0.0018 ±0.0013 OD in (n=9) patients with UC, and 0.001 OD in one patient with IC. At both baseline and at the time of the first infusion, CRP levels were significantly higher in patients with CD (p<0.05). At the time of the first infusion, the ESR in patients with CD was significantly higher than that in patients with UC (p<0.10). Serum lactoferrin was significantly higher in patients with UC at infusion 2 (p<0.05). ESR was significantly higher in patients with UC (p<0.10) at their fourth infusion. Our data support the hypothesis that serum and fecal biomarkers are useful in evaluating the response of intestinal inflammation to Remicade therapy. This study is ongoing, and further sample collection and data analysis are needed to more conclusively determine the accuracy of inflammatory biomarkers as a diagnostic tool for use in the diagnosis and interval assessment of patients with IBD.

Over the last couple of decades changes to pediatric inflammatory bowel disease (IBD) care may have altered health services use among these children. I used a retrospective matched cohort design and population-based health administrative data to first quantify trends in IBD health services and surgical outcomes in Ontario IBD children diagnosed between 1994-2012. I then used these results to validate the distributed network analysis method – a method being increasingly used in Canadian multi-province studies where privacy regulations prevent sharing of individual-level data across provincial borders - using Ontario’s Local Health Integration Networks. I found (1) decreasing hospitalizations and surgical outcomes but increasing outpatient visit rates, suggesting changing patterns of health care use in Ontario children with IBD, and, (2) distributed network analyses is a satisfactory privacy-preserving alternative to individual-level analysis under the conditions tested in my study, providing a tested analysis method for researchers using multi-jurisdictional data.

Recent research has highlighted the connection between dysbiosis of the gut microbiome and its role in the development of Irritable Bowel Syndrome (IBS). Over the last few years, probiotics have grown in popularity as a potential treatment option in IBS. However, most current probiotic studies are limited due to small study populations, older median age, and short study time duration. The proposed study will be a multicenter, randomized, double-blinded placebo controlled study comparing the multi-strain probiotic Bifidobacterium infantis, Bifidobacterium bifidum, Bifidobacterium breve, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Escherichia coli DSM17252 to placebo in patients diagnosed with IBS based on Rome IV criteria over a 3-months duration. The study participants will have a baseline evaluation and a final evaluation at the end of the 3-months duration. The primary outcome will be the IBS Symptom Severity Score and the secondary outcomes will the individual components of the IBS Symptom Severity Score. The results of this study will begin to fill gaps in the current knowledge of the use of probiotics in the treatment of IBS.

Hydrogen sulfide (H2S) has emerged as an important mediator of host function. In the gastrointestinal tract H2S is enzymatically produced and plays a vital role in cytoprotection, inflammation, and tissue repair. During a bout of colitis, the ability of the colon to produce H2S is markedly increased and drives the resolution of colitis. However, little is known about how the production of H2S is regulated in the colon and how dysregulated production can affect the course of colitis in vivo. Additionally, the mechanisms through which H2S can promote the resolution of colitis remain to be fully investigated. In Chapter 3 of this dissertation, the regulation of H2S production in the colon was explored by examining the contributions of three enzymatic pathways to colonic H2S synthesis. The largest source of the H2S synthesis was from a pathway previously unrecognized in the GI tract involving the enzyme 3-mercaptopyruvate sulfurtransferase (3MST). Additionally we found that the upregulation of H2S production during colitis occurred specifically at sites of mucosal ulceration. At the same time H2S inactivation via the enzyme sulfide quinone reductase (SQR) was significantly reduced at these sites. We propose that the site-specific alterations in H2S production and inactivation during colitis promote the resolution of inflammation and injury. Chapter 4 examined whether the ability of hyperhomocysteinemia (Hhcy) to exacerbate colonic inflammation occurred through impaired H2S synthesis. Hyperhomocysteinemia is often reported in patients with inflammatory bowel disease and is a consequence of decreased vitamin B intake. In all three models tested, diet-induced Hhcy significantly exacerbated colitis. Being dependent on vitamin B6 as a co-factor, the increased H2S production normally observed during colitis was abolished during Hhcy. Administration of an H2S donor to Hhcy rats significantly decreased the severity of colitis. These results also uncovered a novel role for IL-10 in promoting H2S production and homocysteine metabolism, which may have therapeutic value in conditions characterized by Hhcy. Finally, in Chapter 5 we looked for a mechanism through which H2S can promote resolution of colitis. Using CSE-deficient mice we found that H2S production was required to maintain HIF-1α signaling in the colon. Additionally, proper HIF-1α signaling was required for H2S-donating molecules to promote the resolution of colitis. These results suggest that HIF-1α signaling is a critical event through which H2S promotes resolution of colitis. Collectively, these chapters further highlight the importance of H2S production in colon during inflammation and injury and offer insight into new therapeutic targets mediated through H2S. / Dissertation / Doctor of Philosophy (PhD)

BACKGROUND: Chronic illness in children is highly disruptive to both the affected child and their parent(s). Recent literature largely supports the impact of psychosocial factors on the onset and progression of IBD. Our study aims to investigate how psychosocial factors involved in parental and child coping, such as anxiety or depression, may predict the clinical and psychological outcomes of children with newly diagnosed IBD. METHODS: We recruited and administered questionnaires to parents and children (aged 9-17) with newly diagnosed IBD. Questionnaires were administered at enrollment and at follow-up visits about one year later. The children completed four questionnaires, including IMPACT-III (measure for quality of life), SCARED (screens for anxiety), and CDI and PHQ-9 (screens for depression). The parents completed three questionnaires, including HADS (screens for anxiety and depression), PIP (assesses the burden of parental stress related to caring for an ill child), and a healthcare utilization survey (quantifies the need for medical support). Clinical data were extracted from the Boston Children’s Hospital’s electronic medical records to assess clinical outcomes. RESULTS: We recruited a total of 86 parent/child pairs. Of the 31% of children screening positive for anxiety, 61% had parents that also screened positive for anxiety (p = 0.007). However, the same relationship was not observed for depressed children and their parents. Children with anxious parents reported a significantly worse quality of life than children with non-anxious parents (119.61 vs. 137.33; p < 0.001). Although the same mean differences were not observed for children with depressed parents, there was an association between parents that scored higher for depression and children who scored lower for quality of life (r = -0.287; p < 0.010). Quality of life scores were significantly lower in children above 12 years old than in children under 12 years old (126.6 vs 137.67; p = 0.021). Furthermore, children with worse disease severity (assessed by PUCAI or PCDAI scores) also reported worse quality of life. No significant associations were observed between disease severity and parental anxiety/depression or between disease severity and child anxiety/depression. Greater healthcare utilization was significantly correlated with greater parental anxiety (r = 0.269; p = 0.017) and greater parental depression scores (r = 0.324; p = 0.004). Over a one-year period, paired survey data revealed decreased parental stress, healthcare utilization, and child anxiety. There were no significant differences in parental anxiety, parental depression, or child depression, while a significant improvement was observed in child quality of life over a one-year period. CONCLUSIONS: Greater parental anxiety, depression, and stress correlated with worse quality of life in children with newly diagnosed IBD. Similarly, higher anxiety and depression scores in children were associated with decreased quality of life. Interestingly, this association was not seen for disease severity. While this may indicate a stronger relationship with parent and child coping and a child’s behavioral outcomes rather than the child’s clinical outcome, additional studies are needed, as the PUCAI and PCDAI scores for disease severity were the only measurements for clinical outcomes. In addition, while we identified significant findings at one year, the study sample size for those who completed follow-up was relatively small. Larger studies are necessary to further investigate the longitudinal outcomes of coping in pediatric IBD. Overall, our data supports a more holistic approach to addressing the behavioral, emotional, and physical needs of both parents and children with newly diagnosed pediatric IBD.

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