IBD-RESPONSE: Defining microbial predictors of responsiveness to biological therapies in Crohn's disease and ulcerative colitis

克罗恩病和溃疡性结肠炎（UC）是一种肠道疾病，称为炎症性肠病（IBD），症状（腹泻，疼痛，疲劳）对日常生活有重大影响。IBD影响英国约1/125的人，预计到2028年将上升到1/100。“生物制剂”是用于减轻IBD炎症的强效药物。这些治疗可能是有效的，但高达40%的患者没有反应，而在那些有反应的患者中，许多人在治疗一年后没有足够的反应来继续使用药物。不幸的是，我们无法预测哪些患者最有可能从治疗中受益（称为应答者），我们也不完全了解药物如何在应答者中发挥作用。由于这些药物可能有严重的副作用，并且对英国医疗保健系统来说是昂贵的，这种缺乏了解是决定哪种治疗最好给予个体患者以及何时给予他们以获得最大益处和最小风险的主要障碍。最近来自IBD患者的小型研究和癌症患者的大型研究的数据，表明粪便中的某些细菌可以预测谁对治疗有反应或无反应。在动物研究中，改变这些细菌的数量和类型可以影响治疗结果。这些研究强烈表明，某些细菌的数量和类型可以预测哪些患者对IBD治疗有反应或无反应。然而，这些研究在不同的患者群体中使用了不同的技术，并且太小而无法给出明确的答案，尽管如此，它们确实表明，如果对足够大的患者群体进行研究，应该可以确定哪些特定细菌对于理解IBD的治疗反应是重要的，以及这些细菌的功能是什么。我们是一群在临床、细菌、免疫和遗传研究方面拥有世界领先记录的研究人员。在过去的5年里，我们成功招募了27，500名患者参加一项名为IBD Bioresource的研究，以研究与IBD发展或行为有关的人类基因。我们现在寻求资金，开始一项单独的研究，重点是肠道细菌，称为IBD-反应。这项研究将受益于我们已经从IBD Bioresource获得的知识和设施。我们将从英国30个中心招募1，125名IBD患者开始生物治疗，作为常规NHS护理的一部分。我们将收集粪便，并在常规内窥镜检查（摄像机进入肠道）过程中（如可能）进行肠道活检，以研究这些治疗前和治疗期间的肠道细菌。通过使用最先进的机器和尖端的计算机分析技术，我们将识别这些微生物，研究它们的功能，并研究微生物如何与人类免疫系统相互作用。我们的研究结果将是开发一种工具，预测哪些患者可能或不可能对IBD的不同治疗方案产生反应。我们将创建世界上最大的粪便和肠道组织标本库（生物库），在多个时间点收集这些重要患者的详细临床信息，将来将开放给其他研究人员使用。通过创建治疗反应的预测工具，IBD-RESPONSE将导致临床试验，可以塑造IBD未来的治疗途径。这可能是通过允许开发测试（生物标志物）来帮助医疗保健专业人员决定哪种治疗最适合个体患者，或者确定肠道中的哪些细菌可以作为目标（减少或增加存在），以改善患者的治疗结果。这有可能提高生活质量，降低患者风险，并减少NHS对这种使人衰弱的疾病进行无效治疗的不必要支出。

Crohn's disease and ulcerative colitis (UC) are types of a bowel condition known as inflammatory bowel disease (IBD) and the symptoms (diarrhoea, pain, fatigue) have a major impact on daily life. IBD affects around 1 in 125 people in the UK and this is expected to rise to 1 in 100 by 2028. "Biologicals" are powerful medications that are given to reduce inflammation in IBD. These treatments can be effective but up to 40% of patients don't respond, and in those that do, many don't respond well enough to stay on the drug after one year of treatment. Unfortunately, we have no way to predict which patients are most likely to benefit from treatment (known as responders), and we do not fully understand how medications work in responders. As these drugs may have serious side effects and are expensive to the UK healthcare system, this lack of understanding is a major obstacle in deciding which treatment is best to give to an individual patient, and when to give it to them in order to have the greatest benefit and the least risk.Recent data from small studies in people with IBD and larger studies of people with cancer, show that certain bacteria in stool (faeces) may predict who will respond or fail to respond to treatments. In animal studies, changing the number and type of these bacteria can influence treatment outcomes. These studies strongly suggest the number and types of certain bacteria may predict which patients do and do not respond to IBD treatment. However, these studies used different techniques in varied groups of patients and were too small to give a definite answer, Nonetheless, they do suggest that if a large enough group of patients were studied it should be possible to identify which specific bacteria are important for understanding treatment response in IBD, and what the function of these bacteria are. We are a group of researchers with a world-leading track record in clinical, bacterial, immune and genetic research. For the last 5 years we have successfully recruited 27,500 patients into a research study called the IBD Bioresource to study the human genes involved in the development or behaviour of IBD. We now seek funds to begin a separate study focussing on gut bacteria called IBD-RESPONSE. This study will benefit from the knowledge and facilities we already have from the IBD Bioresource. We will recruit 1,125 patients starting biological therapy in IBD as part of routine NHS care from 30 centres across the UK. We will collect stool, and where possible intestinal biopsies during routine endoscopy (camera into the gut), to study the gut bacteria before, and during, these treatments. By using state-of-the-art machinery and cutting-edge computer analysis techniques we will identify these microbes, study their function, and examine how microbes may interact with the human immune system. The outcome of our study will be to develop a tool that predicts which patients are likely or unlikely to respond to the different treatment options in IBD. We will create the largest collection (biobank) in the world of stool and intestinal tissue specimens, at multiple timepoints and with detailed clinical information, from this important group of patients that will be open to other researchers to use in the future. By creating a predictive tool for response to treatment, IBD-RESPONSE will lead to clinical trials that can shape future treatment pathways in IBD. This may be by allowing the development of a test (biomarker) to help healthcare professionals decide which treatment is best suited to an individual patient, or to identify which bacteria in the intestine could be targeted (either to reduce or increase presence) in order to improve treatment outcomes for patients. This has the potential to improve quality of life, reduce patient risk and reduce unnecessary expenditure on ineffective treatments by the NHS for this debilitating disease.