BACKGROUND: During the mid to late 20th century, parts of Europe and North America began experiencing increasing incidence of inflammatory bowel disease for unknown reasons. Epidemiological studies carried out at the time determined that incidence rates and disease severity were higher in the northern latitudes than in the southern latitudes. LITERATURE REVIEW: In the ensuing years, an inverse association was established between ultraviolet radiation and incidence of Crohn’s disease, a finding that has not proven to be as robust for ulcerative colitis. This association was explored further and vitamin D was implicated to be the factor of ultraviolet radiation which was associated with increased incidence. Currently, all evidence implicating vitamin D in the pathogenesis of Crohn’s disease comes from epidemiological, animal, and in vitro studies, providing strong evidence for an association, but none of which can prove causality. Causality must be proven in prospective clinical trials, which, at present, have come up short in providing statistically significant findings. METHODS: The proposed trial outlined below provides a method of studying the question at hand in a way that has not been previously studied. This is a randomized, double blind, controlled trial which assesses the effect of supplementation of vitamin D in patients with active Crohn’s disease. DISCUSSION: Acceptance of the alternative hypothesis would be a big step forward in the management of Crohn’s disease. It would have wide-ranging implications, resulting in decreased healthcare costs, decreased use of toxic medications, and increased quality of life.

Introduction. Inflammatory bowel disease (IBD) is a condition affecting more than 3 million people in Europe and the USA combined. Patients report pain as one of the most severe and debilitating symptoms leading to a lower quality of life. Current analgesics lack efficacy for the treatment of visceral pain or produce unacceptable side effect profiles. New targets are needed. Aims and methods. The aim of this thesis was to examine the activation of primary visceral afferents in C57BL/6 mice in response to biopsy supernatants from paediatric patients with IBD (Crohn's disease and ulcerative colitis) and functional abdominal pain syndrome (FAPS). By comparing the expression of pro-inflammatory and pro-nociceptive mediators in these biopsy samples with patient pain scores and afferent nerve recording activation, we identified putative mediators likely to be responsible for causing pain. The ability of inflammatory mediators to drive visceral nociception was then examined by their exogenous application in recordings of mouse and human visceral nociceptor activity. Results. Nerve activation increased significantly in response to biopsy supernatants from FAPS, CD, and UC patients, when compared to controls. Supernatant IL-8, TNFα, IL-6 and IL-1β, levels were increased in IBD samples compared with control patients. Analysis of mRNA expression also showed high levels of pro-inflammatory cytokines and raised MMP-1, MMP-3, MMP-9, MMP-12, and MMP-19 in IBD samples. The expression of MMP-12 in biopsy samples from Crohn's patients significantly correlated with afferent firing suggesting a causative role. This was confirmed by exogenously application of MMP-12 stimulated afferent firing and sensitised responses to mechanical stimulation and inflammatory mediators. UC samples showed TIMP-1 as an effective inhibitor of afferent firing. Conclusion. Data from this study demonstrates that the bowel of patients with IBD and FAP releases pro-nociceptive mediators which stimulate visceral afferents. MMP's play an important role in the afferent activation mediated by IBD samples suggesting that exploiting the endogenous inhibitor TIMP-1 could be a key target for future therapeutic strategies.

Background: Not only does IBD lead to nutritional deficiencies, but also nutrients influence its pathophysiology: exclusive enteral nutrition (EEN) is an effective primary treatment in Crohn's disease; and vitamin D (VitD) is involved in its pathogenesis and course. Aims: We hypothesised that nutrients impact on the course of IBD. We therefore studied the effect of EEN i) on long term clinical course in children; ii) on CD58, a costimulatory molecule at the intestinal epithelial cell (IEC) lines, iii) adults with Crohn's disease. We examined the possible effect of serum vitamin D levels on the course of IBD and also the possible role of ethnicity in our paediatric and adult populations that were treated with EEN but also in our general adult population. Results Chapter II: 56 paediatric patients with Crohn's disesase were followed up for 5 years. 57% of patients achieved remission after 6 weeks of EEN. Achievement of clinical remission within 6 weeks of EEN was significantly associated with a longer time to relapse and to treatment escalation. VitD deficiency was common; and those patients who were deficient were significantly more likely to require corticosteroids and also needed thiopurines sooner. Chapter III: CD58 was expressed in the IEC isolated from IBD patients and healthy controls. EN down-regulated the expression of CD58 on IEC lines. Chapter IV: 22 adult patients with Crohn's disease with a mean age of 30.8 years were given EEN and followed up for a mean time of 1.9 years. 22.7% of patients went into clinical remission and 77.3% experienced a clinical response. By the end of follow up 63.6% (14/22) of patients had clinically relapsed and 36.4% required surgery during their follow up. There was no difference between South Asian and Caucasian patients in the disease outcomes after administration of EEN. Chapter V: Bangladeshis were more often vitamin D deficient than white Caucasian patients; however vitamin D status was not associated with the course of IBD. Bangladeshis developed perianal disease and required thiopurines earlier in their disease course. Bangladeshi patients with UC had more extensive disease. Conclusions: EEN, when successful, improves the long term outcome of Crohn's disease in children, possibly in part, by down-regulating CD58 on the IEC. VitD deficiency may influence the clinical course of IBD; however our results were contradictory between children and adults and significantly limited by the assessment of the vitamin D level at a single time point.

A Doença de Crohn (CD) e a Colite Ulcerativa (UC) são as principais enfermidades componentes das Doenças Inflamatórias Intestinais (DII). Embora existam vários medicamentos atualmente empregados para atenuar a inflamação descontrolada no intestino, tratar as complicações ou prolongar os períodos de remissão clínica, não há, ainda, uma terapia que seja totalmente efetiva para estas doenças. Os glicocorticoides (GCs), anti-inflamatórios comumente usados nas DII, possuem eficácia limitada e mais da metade dos pacientes se tornam refratários ou dependentes da medicação. Por outro lado, as estatinas são conhecidas por possuírem propriedades pleiotrópicas e seu uso concomitante com os GCs tem gerado boas perspectivas em várias doenças autoimunes e inflamatórias, inclusive nas DII. Apesar de já existirem indicativos de melhora de pacientes com DII pela utilização combinada destas drogas, ainda há escassez de dados que mostrem as alterações causadas no sistema imunológico. Assim, o objetivo desse trabalho foi avaliar os efeitos imunomoduladores do uso concomitante de GCs e estatinas na colite experimental induzida por dextran sulfato de sódio (DSS) em camundongos C57BL/6. Os resultados mostraram que o uso contínuo de GCs (dexametasona - DX), associados ou não a estatinas (atorvastatina - ATO), não alterou o curso da doença e antecipou a morte dos camundongos, enquanto que o oposto foi observado com o uso isolado de ATO. Tratamentos em curto prazo (3 doses) contendo ATO (isolada ou associada à DX) causaram melhora clínica e histológica dos animais doentes, diminuíram o número de leucócitos circulantes (principalmente monócitos) e de células mononucleares na lâmina própria (LP), a frequência de células CD11b+ na LP, a frequência de células dendríticas (DCs) CD11b+CD11c+ e CD11b-CD11c+ no baço e a frequência de células CD4+ produtoras de IFN- nos linfonodos mesentéricos (LNM). Entretanto, ambos os esquemas terapêuticos aumentaram a frequência de linfócitos T CD8+ no baço e LNM. Ainda, as terapias inibiram a proliferação de esplenócitos tratados in vitro, diminuíram a síntese de IL-6 e, quando em baixas concentrações, aumentaram a produção de IL-10. Diferencialmente, o tratamento combinado pareceu exercer os efeitos acima descritos de modo mais pronunciado do que o uso isolado de estatina. Adicionalmente, diminuiu os níveis de expressão de RNAm das citocinas IL-1, IL-17 e IFN- no local da inflamação, reduziu o número de linfócitos circulantes, de leucócitos no baço e LNM e de linfócitos T CD4+ nos LNM, além de ter aumentado a frequência de DCs CD11b-CD11c+ na LP e a concentração de Fas-L no intestino grosso. Considerando o uso em curto prazo com ATO isolada, foi observado aumento da frequência de DCs CD11b-CD11c+ nos LNM e de células Natural killer (NK) no baço dos camundongos doentes e diminuição dos níveis de expressão de RNAm de PPAR- no intestino grosso. O uso isolado de DX em curto prazo melhorou os aspectos histológicos, diminuiu o número de macrófagos e os níveis de IFN- no cólon, diminuiu o número de leucócitos circulantes (principalmente linfócitos), aumentou a frequência de células CD11b+ no baço e a síntese de IL-10 por esplenócitos ex vivo. Apesar da frequência de células T reguladoras (Treg) e da susceptibilidade dos esplenócitos à sinais reguladores não terem sido modificados após os diferentes tratamentos, nossos resultados sugerem que as estatinas usadas isoladamente preservaram a resposta inflamatória do organismo de modo eficiente e controlado, enquanto que o uso associado das drogas causou a imunossupressão dos animais doentes, contribuindo para as complicações clínicas decorrentes da colite experimental induzida por DSS. / Crohn\'s disease (CD) and Ulcerative colitis (UC) are the main conditions that comprise the Inflammatory Bowel Diseases (IBD). The conventional drug therapies for IBD aim to attenuate the uncontrolled inflammation in the intestinal mucosa, to treat the complications and to extend clinical remission. However, all available drugs have unpredictable or limited effects. Glucocorticoids (GCs) are commonly anti-inflammatory drugs, which are associated to refractoriness and/or dependence in over half of IBD patients. On the other hand, statins have pleiotropic properties and the concomitant use with GCs has shown good prospects in several autoimmune and inflammatory diseases, including IBD. Despite the putative clinical improvement after combined use of GCs and statins in IBD, there is a lack of data indicating their additive effects on the immune system. Therefore, the purpose of this study was to evaluate the immune modulatory effects of the concomitant use of statins and GCs in experimental colitis induced by dextran sulfate sodium (DSS). The results showed that long-term use of GCs (dexamethasone - DX), alone or associated to statins (atorvastatin - ATO), did not improve the clinical signs and increased the death rates of C57BL/6 mice exposed to DSS, while the opposite was observed after treatment with statins alone. Short-term use of ATO (3 doses), alone or associated to DX, improved the clinical signs and histological parameters in DSS-exposed mice, decreased the number of white blood cells (mainly monocytes), the number of mononuclear cells in the lamina propria (LP), the frequency of CD11b+ cells in the LP, the frequency of CD11b+CD11c+ and CD11b-CD11c+ dendritic cells (DCs) in the spleen and the frequency of IFN--producing CD4+ T cells in the mesenteric lymph nodes (MLN). However, ATO alone or associated to DX lead to increased CD8+ T lymphocytes in the spleen and MLN. Moreover, both therapies containing ATO inhibited the proliferation of in vitro-treated splenocytes, besides decreasing IL-6 and increasing IL-10 synthesis. Differentially, the association of drugs led to a more pronounced effects over the changes mentioned above than the single use of statin and additionally decreased IL-1, IL-17 and IFN- mRNA expression levels at the intestinal tissue, the number of circulating lymphocytes, the number of leukocytes in spleen and MLN and the frequency of CD4+ T lymphocytes in the MLN. In addition, statins and GCs increased the frequency of CD11b-CD11c+ DCs in LP and the Fas-L concentrations in the large intestine. Considering the short-term use of ATO there was increased frequency of CD11b-CD11c+ DCs in MLN, increased frequency of natural killer (NK) cells in the spleen and decreased mRNA expression of PPAR- in the large intestine. The short-term use of DX improved the histology parameters, decreased the number of macrophages and IFN- levels in the colon, reduced the number of circulating leukocytes (mainly lymphocytes), and increased the frequency of CD11b+ cells in spleen and IL-10 synthesis by ex vivo splenocytes. Finally, since both regulatory T cells (Treg) frequency and the splenocytes susceptibility to regulatory signals have not been modified after the different treatments, our findings suggest that single use of statins preserved an efficient and controlled inflammatory response, while the combined use of GCs and statins led to immunosuppression, which probably contributed to long-term clinical complications of DSS-induced colitis.

In this thesis, I explore the meanings and experience of health and well-being in the lives of individuals with Inflammatory Bowel Disease (IBD). Taking an auto/biographical approach and utilising in-depth qualitative online interviews, I draw on the experience and narratives of seventeen individuals with IBD, including myself. The three main themes addressed are 'Living with IBD', 'Becoming a Patient', and 'Coping and Control'. I explore how IBD influences individuals' experience of personal relationships, and their medical encounters and treatments. I reflect on how and why these factors arise and the effect they may have upon the disease and its management and on individuals' feelings of well-being more generally. I look at the resulting illness narratives and the impact of IBD on the daily life experience and the identity of the individual. I interrogate existing research and add to it from my analysis. Throughout, the research highlights the importance of acknowledging the impact of biographical disruption on the life experience and identity of individuals along with changing illness narratives. There are implications for future research and for policy, including the time taken to reach diagnosis, the use of IBD guidelines in diagnosis and treatment, and patient control and choice as a contributing factor to influence future guidelines and treatment plans.

Introduction: There is an urgent need to find new ways of improving the quality and safety of healthcare whilst achieving efficiencies of service. E-health technologies offer exciting opportunities to support patients in managing chronic disease. Following continuous advances and increasing use, the Internet provides an ideal platform to empower patients. Previous studies have demonstrated that people taking a more active role in managing their health, experience improved outcomes. Based on these principles and funded by Crohn's and Colitis UK, a new web-based care package was designed for adults with inflammatory bowel disease. Specifically 'My IBD Portal' aimed to provide greater access to information, improved communication and encourage greater engagement. Following its implementation at a single centre NHS Trust, the new IBD patient portal was evaluated in the clinical setting. Methods: Following a literature review and significant patient involvement, 'My IBD Portal' was designed and implemented within a single centre setting. The system was evaluated over a 6-month period using a pre-post observational designed study. The primary objective was to examine patient experience. Usage, usability and satisfaction were measured. Secondary objectives included assessing factors that predicted use, analysed using logistic regression models. Changes in IBD knowledge, patient engagement, medication adherence and health utilisation were also explored using univariate analysis and multiple regression models. Results: 183 participants enrolled in the 6-month observational study. 63.4% of participants visited the IBD Portal more than once and were defined as users. In total there were 2080 individual visits to the Portal. The mean number of logins was 11.4 (SD 21.5) and median 3 (IQR 1-12). The mean duration of each visit was over 5 minutes. Individual use was highly variable. Approximately a quarter of participants never or only once used the IBD Portal, with an equal proportion visiting over 10 times. Satisfaction amongst users was high. 98% of respondents were either satisfied or very satisfied. 90% perceived the IBD Portal supported their management and 32% felt it helped with treatment decisions. An overwhelming majority expressed a desire to continue using the IBD Portal after completion of the study. Viewing test results (23%) was the most common section visited, followed by clinic letters (21%). 29% of participants reported sharing their access with a partner or family member. The qualitative data supported the quantitative findings. Many users expressed considerable benefit from online provision to their IBD health record. Comparing users to non-users, logistic regression modeling showed active disease was significantly associated with use. Changes in health outcomes were explored using both univariate and regression analyses. Following multiple regression modeling, an increase in patient activation was significantly associated with Portal use (p < 0.02). A positive trend was observed in perceived support (p=0.06). Improvements in IBD knowledge and medication adherence were not observed. Health utilisation was greater amongst users with more frequent outpatient and helpline contacts observed. Conclusion: Design and implementation of an IBD Portal within the NHS setting is feasible. Technological, human and organisational factors need to be carefully considered during development to support adoption. The IBD Portal was used by a majority of participants and was perceived to support their care. Following adoption in other NHS clinical settings, a cluster randomised controlled study would provide the optimal study design to complete the evaluation process.

Doenças inflamatórias intestinais (DII) em humanos são reações crônicas de etiologia complexa. Trata-se de uma reação imunológica exacerbada e depende da microbiota. O sistema nervoso interage com a imunidade do intestino de um modo bidirecional. Relatos clínicos e poucos achados experimentais apontam para uma ligação entre transtornos depressivos e doenças inflamatórias intestinais, sugerindo interação neuroimunológica na patogenia deste processo. Ainda, o tratamento de Doenças inflamatórias intestinais (DIIDoença de Crohn e Colite Ulcerativa) com antidepressivos em modelos murino de colite têm sugerido bons resultados na redução da inflamação. O mecanismo da inflamação na DII e a participação do sistema nervoso ou da modulação de tal processo pelo emprego de antidepressivos ainda não está totalmente elucidado. Este estudo teve como objetivo estudar o efeito do antidepressivo amitriptilina em um modelo murino de colite. A colite foi induzida em camundongos C57BL/6 por Dextrano Sulfato de Sódio (DSS) e a amitriptilina (AMT) foi administrada por via oral, em regime profilático ou terapêutico. Avaliamos a dose de AMT no teste de suspensão da cauda (TSC), o acúmulo de neutrófilos pela atividade de mieloperoxidase (MPO), burst oxidativo, curva de sobrevida, histopatologia do intestino, atividade da doença por sintomas clínicos, a depleção de muco intestinal, citocinas inflamatórias no cólon e no soro, fenotipagem de linfócitos T CD4+, T CD8+, e monócitos CD14+,. Resultados: A dose de AMT (200 &mu;g/ml) e os regimes de tratamento utilizados aqui foram capazes de impedir ou diminuir a histopatologia da colite, os sinais clínicos (ganho de peso (%), comprimento e peso do cólon) e a mortalidade dos animais no modelo terapêutico do grupo inflamado e tratado com AMT. A atividade de MPO, níveis circulantes de IL- 1 &beta;, IL- 6 e TNF- &alpha; foram reduzidas nos dois protocolos experimentais (profilático e terapêutico). Conclusões: Este estudo incluiu um período de tratamento prolongado, visto que os antidepressivos são conhecidos por serem eficazes em seres humanos depois de várias semanas a meses de prescrição, e confirmou a eficiência da via de administração oral, uma vez que os antidepressivos são geralmente administrados por via oral a seres humanos. Este regime de tratamento melhorou o potencial anti-inflamatório de AMT na redução DSS-colite em camundongos, com base nos parâmetros estudados / Inflammatory bowel disease (IBD) in humans is a complex etiology of chronic reactions. It is an exacerbated immune reaction and depends on the microflora. The nervous system interacts with the intestinal immunity of a bidirectional fashion. Clinical reports and few experimental findings point to a link between depressive disorders and inflammatory bowel disease, suggesting neuroimmunological interaction in the pathogenesis of this process. Also, treatment of inflammatory bowel diseases (Crohn\'s disease DII- and Ulcerative Colitis) with antidepressants in murine models of colitis have pointed to positive results in reducing inflammation. The mechanism of inflammation in IBD and the involvement of the nervous system or modulation of this process by the use of antidepressants is not yet fully elucidated. This study aimed to study the effect of amitriptyline in a murine model of colitis. Colitis was induced in C57BL / 6 mice by Dextran Sodium Sulfate (DSS) and amitriptyline (AMT) were orally administered in a prophylactic or therapeutic regimen. We evaluated the AMT dose in the tail suspension test (TST), the accumulation of neutrophils by myeloperoxidase activity (MPO), oxidative burst, survival curve, bowel histopathology, disease activity by clinical symptoms, depletion of intestinal mucus, colon and inflammatory cytokines in the serum phenotype of CD4+ T lymphocytes, CD8+ and CD14+ monocytes. Results: The dose of AMT (200 &mu;g / ml) and treatment regimens used herein are able to prevent or decrease the pathology of colitis, clinical signs (weight gain (%), colon weight and length) and mortality animals in the therapeutic model inflamed group and treated with AMT. MPO activity, circulating levels of IL- 1 &beta;, IL- 6 and TNF- &alpha; were reduced in both experimental protocols (prophylactic and therapeutic). Conclusions: This study included a prolonged period of treatment, as antidepressants are known to be effective in humans after several weeks or months of limitation, and confirmed the effectiveness of oral administration route, since antidepressants are generally administered orally to humans. This treatment scheme has improved potential anti-inflammatory AMT in reducing DSS colitis in mice based on the study parameters

Youth with inflammatory bowel disease (IBD) have higher rates of depression than healthy youth. A cognitive-behavioral treatment, primary and secondary control enhancement training-physical illness (PASCET-PI), for depressed adolescents with IBD was associated with reductions in depressive symptoms. The purpose of this study was to examine the salience of nonspecific processes (factors inherent in any human relationship) and specific processes (factors related to therapy content) during PASCET-PI sessions and their association with improvements in psychological functioning. Participants included 10 adolescent patients with IBD with mean illness duration of 31.9 months. At intake, eight participants qualified for a diagnosis of major depressive disorder and two for a diagnosis of minor depression. Participants completed measures of depressive symptomatology and clinicians completed the Children's Global Assessment Scale (CGAS). Measures were completed at posttreatment, 6 months posttreatment, and 1 year posttreatment. Independent judges used the Psychotherapy Process Q-sort (PQS) to rate the salience of therapeutic processes for PASCET-PI sessions #2 and #8 for each subject. PQS ratings of PASCET-PI sessions were con-elated with ideal prototypes of cognitive-behavioral treatment (CBT), inteqnrsonal therapy (IPT), and psychodynamic (PD) orientations that were previously developed based on PQS ratings of an ideal session, according to expert therapists. Findings indicate that PASCET-PI sessions most closely resembled the CBT prototype (r = .51, p < .05). Change scores on outcome measures were correlated with PQS-prototype correlates to determine which processes were associated with improved psychological functioning. Findings suggest that reductions in depressive symptomatology were associated with processes characteristic of various orientations. Thus, CBT processes were not exclusive in promoting change. There were strong positive relationships between change scores of the PCS and prototypes of all orientations (CBT, IPT, and PD) at posttreatment and between the CDI and ASQ and all orientations at 6-months follow-up (r = .62 -.72, p < .05). Comparisons of specific process-outcome correlates and nonspecific process-outcome correlates did not reveal significant differences.

Abdominal pain is a common symptom of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although the extent differs, visceral inflammation is thought to play a significant role in nociception in these disorders. This thesis describes studies examining mechanisms of inflammation-induced changes in nociceptive signaling from the colon using human colonic biopsy and animal models of the conditions. Citrobacter rodentium infection in mice produced profound colitis at day 10 post-infection which resolved by day 30. Perforated current clamp recordings showed that inflammation induced hyperexcitability of colonic DRG neurons that persisted at day 30 post-infection. Similarly, multi-unit afferent nerve recordings revealed enhanced firing of colonic afferents following colon distension at this time. In voltage clamp studies, suppression of IA K+ currents in post-infected C. rodentium neurons was observed. Combining water-avoidance stress (WAS) and C. rodentium infection exaggerated these effects. Interactions between proteases and stress mediators underlie these actions. In vivo studies revealed WAS combined with C. rodentium post-infection induced visceral hyperalgesia and allodynia. A separate series of studies examined the possible role of cysteine proteases in post-infectious IBS. The cysteine protease cathepsin-s (Cat-S) induced neuronal excitability and, provoked visceral hypersensitivity in mice. Human IBS supernatants increased neuronal excitability, but this was reversed in neurons pre-treated with the cysteine protease inhibitor E-64. Together these data suggest that Cat-S is a secreted neuromodulator in human IBS supernatants and could be important in nociceptive signaling in IBS. In studies examining whether similar mechanisms operate in a traditional inflammatory condition, IBD, human ulcerative colitis (UC) supernatants showed elevated TNF-α levels. Exogenous TNF-α and UC-supernatants increased colonic nociceptor excitability, which was attenuated in neurons from TNFR knock-out animals. TNF-α and UC-supernatants both increased TTX-R Nav1.8 and suppressed IA and IK K+ currents. Together these results suggest that inflammation significantly increases and sustains peripheral nociceptive signaling in IBD and IBS. These effects involve changes in the properties of nociceptive DRG neurons through actions of specific secreted factors which modulate specific voltage-gated ion channels. Chronic stress exaggerates these changes through synergistic actions of stress hormones and local mediators, suggesting an interplay between central and peripheral mechanisms. / Thesis (Ph.D, Physiology) -- Queen's University, 2011-07-28 10:17:58.863

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