Exploring the relationship between stress/distress reduction, inflammatory markers and relapse in relapsing remitting Inflammatory Bowel Disease (IBD)

炎症性肠病（IBD）是一种慢性自身免疫性炎症。生物医学模型表明，炎症水平和疾病并发症与腹痛相关（Basso et al., 2015; Docherty et al., 2011）；然而，心理神经免疫学框架有助于IBD症状学的概念化。IBD患者表现出内分泌和免疫反应失调（Mackner et al., 2010; Pellissier et al., 2010）。此外，在IBD中，症状与心理功能之间似乎存在双向关系(Sweeney et al .；2018)。脑肠轴为这些关系提供了一个生理框架（Bonaz & Bernstein, 2013）。最近的一项系统综述表明，心理因素与疾病进展之间存在双向关系（Fairbrass et al., 2021）；尽管它没有调查疾病活动的生物学标记。横断面研究已经确定了促炎细胞因子与抑郁之间的关联，但对IBD中炎症和抑郁症状的方向性了解有限（Moulton et al., 2019）。研究表明，下丘脑-垂体-肾上腺（HPA）轴活性与IBD的进展相关（Sun et al., 2019）。此外，下丘脑轴过度活跃是抑郁症的一致生物学标志物（Gold et al., 2015; Iob et al., 2020; Pariante & Lightman, 2008; Stetler et al., 2013），因此IBD患者的抑郁症状可能与下丘脑轴过度活跃有关。然而，许多调查该领域的研究都缺乏动力，并且得出了相互矛盾的结果。文献需要建立测量关键生物标志物的标准方法，需要更大的样本量。主要导师罗娜·莫斯-莫里斯教授对IBD人群进行了广泛的研究，包括一项跨诊断在线认知行为治疗干预的随机对照试验。她和她的团队开发了一个在线认知行为治疗项目COMPASS，专门用于治疗与疾病相关的长期困扰。COMPASS的治疗时间超过3个月，RCT数据显示其在减少IBD患者焦虑和抑郁方面的有效性。然而，迄今为止，还没有关于COMPASS（和其他CBT干预）通过心理神经免疫途径影响关键疾病生物标志物的有效性的研究。此外，第二位主管Valeria Mondelli博士是精神神经免疫学领域的首席研究员，她研究了炎症生物标志物（如皮质醇和外周免疫生物标志物）与治疗反应（Mondelli等人，2015；Enache等人，2021）、环境压力源（Zajkowska等人，2021）、疾病症状（McLaughlin等人，2021）和心理症状严重程度(Murri等人，2016；Sforzini et al., 2019)。乔安娜·哈德森博士被任命为第三位主管。她与罗娜·莫斯-莫里斯教授一道，为COMPASS的发展发挥了重要作用。本文的目的是研究心理社会因素、炎症生物标志物和疾病相关痛苦减少之间的关系。首先，系统回顾将建立目前已知的IBD中精神和身体健康结果与炎症生物标志物之间的关系，并澄清文献中的空白。第二个目的是横断面调查已确定的炎症生物标志物与关键的社会心理和临床变量之间的关联。第三个目的是调查在线CBT干预（COMPASS）后IBD患者痛苦的减少，并探讨在干预后和1年随访中，痛苦的减少是否与与疾病发作相关的炎症标志物的减少有关。

Inflammatory bowel disease (IBD) is a chronic, autoimmune, inflammatory condition. Biomedical models stipulate that inflammation levels and disease complications correlate with abdominal pain (Basso et al., 2015; Docherty et al., 2011); however, psychoneuroimmunological frameworks are helpful to conceptualise IBD symptomatology. IBD patients demonstrate dysregulated endocrine and immunological responses (Mackner et al., 2010; Pellissier et al., 2010). Additionally, in IBD it appears that there are bidirectional relationships between symptoms and psychological function (Sweeney et al,. 2018). The brain-gut axis provides a physiological framework for these relationships (Bonaz & Bernstein, 2013). A recent systematic review has demonstrated the bidirectional relationship between psychological factors and disease progression (Fairbrass et al., 2021); although it did not investigate biological markers of disease activity. Cross-sectional studies have identified associations between pro-inflammatory cytokines and depression, but there is a limited understanding of the directionality of inflammation and depressive symptoms in IBD (Moulton et al., 2019).Studies have suggested that hypothalamic-pituitary-adrenal (HPA) axis activity is correlated with the progression of IBD (Sun et al., 2019). Moreover, HPA axis hyperactivity is a consistent biological marker of depression (Gold et al., 2015; Iob et al., 2020; Pariante & Lightman, 2008; Stetler et al., 2013), therefore it is plausible that the depression symptoms in IBD patients may contribute to HPA axis hyperactivity. However, many studies investigating the area are underpowered and demonstrate conflicting results. The literature needs to establish standard ways of measuring key biomarkers and requires larger sample sizes.The primary supervisor, Prof Rona Moss-Morris, has done extensive research in IBD populations, including a randomised-controlled trial of a transdiagnostic online cognitive-behavioural therapy intervention. She and her team have developed an online CBT program, COMPASS, tailored to treat illness-related distress in the context of long-term conditions. COMPASS is delivered over 3 months, and RCT data demonstrate its effectiveness at reducing anxiety and depression in people with IBD However, to date there has been no investigations regarding the effectiveness of COMPASS (and other CBT interventions) at influencing critical disease biomarkers via psychoneuroimmunological pathways.Moreover, the second supervisor Dr Valeria Mondelli is a lead researcher in the field of psychoneuroimmunology and has investigated the relationship between inflammatory biomarkers, such as cortisol and peripheral immune biomarkers, with key disease factors such as treatment response (Mondelli et al., 2015; Enache et al., 2021), environmental stressors (Zajkowska et al., 2021), disease symptoms (McLaughlin et al., 2021) and severity of psychological symptoms (Murri et al., 2016; Sforzini et al., 2019).Dr Joanna Hudson has been added as a third supervisor. Alongside Prof Rona Moss-Morris, she was instrumental in the development of COMPASS.The aim of the thesis is to investigate the relationship between psychosocial factors, inflammatory biomarkers and reductions in illness-related distress following an online CBT investigation.Firstly, a systematic review will establish what is currently known about the relationships between mental and physical health outcomes and inflammatory biomarkers in IBD and clarify gaps in the literature.The second aim is to investigate cross-sectionally the associations between the identified inflammatory biomarkers and key psychosocial and clinical variables.The third aim is to investigate reductions in distress following an online CBT intervention (COMPASS) in IBD patients and to explore if reductions in distress are associated with reductions in inflammatory markers related to disease flares at post-intervention and 1year follow up.