Understanding the mechanisms for the variation in beneficial effects of dietary fibre in Irritable Bowel Syndrome (IBS): an old concept in new light

肠易激综合征是一个日益严重的重大公共卫生问题，影响着全世界10-15%的成年人。这种严重的发病率给个人、医疗保健系统和工作场所带来了巨大的经济负担。例如，患有肠易激综合症的墨西哥人平均将其收入的20%用于与肠易激综合症相关的医疗费用，报告就诊次数增加的可能性高出50%，缺勤的风险高出3倍。药物和饮食干预对肠易激综合症有一定疗效，尽管后者鼓励自我管理。最近，饮食管理的重点是饮食限制（例如低FODMAP饮食），但这些限制包括生理后遗症（例如营养摄入受损，肠道细菌改变）以及建议的复杂性，获得营养师和可理解性（例如，识字率低的人）。管理肠易激综合征的饮食方法需要易于实施且价格低廉，因此广泛适用于社会经济和种族群体——这是本提案旨在解决的挑战。近年来，我们对膳食纤维的了解有了很大的进展，发现了适用于肠易激综合征的潜在治疗机会。目前，国家和国际指南对肠易激综合征的纤维补充提供了有限且经常相互矛盾的建议。这些指南是基于膳食纤维治疗IBS症状的试验，这些试验报告了相反的效果，反映了本提案解决的四个关键问题：(1)在历史试验中使用的纤维类型的变化，由于过时的膳食纤维的粗略分类，不支持生理作用；(2)我们对不同纤维在IBS中的生理和功能影响的理解有限；(3)对新纤维或不同纤维共同施用的生理效应的有限研究；(4) IBS不同亚型（即IBS- d、IBS- c）的生理变化。鉴于这些限制，我们认为膳食纤维作为一种低成本管理策略的治疗潜力尚未得到充分开发。为了获得对纤维特性的有力理解，可能为肠易激综合征提供治疗益处，本研究将包括两项研究，调查纤维在肠易激综合征中的急性（研究1）和长期（研究2）生理和治疗效果。研究1将探索人工膳食纤维组合（抗性淀粉+马头草）和自然存在的组合（墨西哥本地作物nopal）（由我们的碳水化合物化学、肠道生理学和肠道微生物学专家团队提供信息）如何使用无创MRI技术影响肠道生理学（例如结肠气体产生）。这将对不同纤维之间和IBS亚型之间的潜在作用机制、耐受性和反应变化提供独特的见解。这些关键原则将用于指导选择最佳膳食纤维配方以及最敏感的肠易激综合征亚型，以进行为期2个月的临床试验（研究2）。研究2旨在评估膳食纤维补充的长期微生物学和生理学影响，以及这是否转化为IBS的症状缓解。这项研究将在英国和墨西哥的IBS人群中进行，分别使用最新的测序和胃肠运动技术，探索所选纤维对肠道微生物群和肠道运输时间等基本机制的具体影响。此外，这项研究将在实验工作的基础上转化一些新的机制，以更好地了解膳食纤维如何发挥益处。最后，研究2将调查我们小组开发的非侵入性诊断模型是否可以用于识别最有可能对膳食纤维有反应的肠易激综合征患者，如果成功，将有助于更好地表征肠易激综合征人群，并为个性化治疗计划铺平道路。

IBS is a major, growing public health problem affecting 10-15% of adults worldwide. The profound morbidity places a huge financial burden on individuals, the healthcare system and the workplace. For example, Mexicans with IBS on average spend 20% of their income on IBS-related medical expenses, are 50% more likely to report increased medical visits and have a 3-fold greater risk of absenteeism. Pharmaceutical and dietary interventions have some efficacy in IBS, although the latter encourage self-management. More recently dietary management has focussed on dietary restriction (e.g. the low FODMAP diet), but the limitations of these include physiological sequelae (e.g. impaired nutrient intake, altered gut bacteria) as well as the complexity of advice, access to dietitians and comprehensibility (e.g. people with low literacy). Dietary approaches to manage IBS that are easy to implement and inexpensive, therefore widely applicable across socio-economic and ethnic groups are required - a challenge this proposal aims to address. In recent years, our understanding of dietary fibre has progressed considerably uncovering potential therapeutic opportunities applicable in IBS. At present national and international guidelines provide limited and often conflicting recommendations regarding fibre supplementation in IBS. These guidelines are based upon trials of dietary fibre in IBS symptoms that report opposing effects reflecting four key issues that this proposal addresses: (1) variations in the types of fibres used in historic trials, which due to out-dated crude classification of dietary fibre were not supported physiological actions; (2) our limited understanding of the physiological and functional impacts of different fibres specifically in IBS; (3) limited investigation of the physiological effects of novel fibres or the co-administration of different fibres; and (4) variations in the physiology of different sub-types of IBS (i.e. IBS-D, IBS-C). Given these limitations, we believe the therapeutic potential of dietary fibre as a low-cost management strategy is underexploitedIn order to gain a robust understanding of the fibre characteristics that may offer therapeutic benefit for IBS this research will consist of two studies investigating the acute (Study 1) and longer-term (Study 2) physiological and therapeutic effects of fibres in IBS. Study 1 will explore how artificial dietary fibre combinations (resistant starch + psyllium) and naturally occurring combinations (nopal, a native crop to Mexico) (informed by our team of experts in carbohydrate chemistry, gut physiology and gut microbiology) affect gut physiology (e.g. colonic gas production) using non-invasive MRI techniques. This will provide unique insight into underlying mechanisms of action, tolerances and variations in response both between different fibres and within IBS subtypes. These key principles will be used to guide selection of an optimal dietary fibre formulation as well as the most responsive sub-type of IBS to inform a 2-month clinical trial (Study 2). Study 2 will aim to assess the longer-term microbiological and physiological effects of dietary fibre supplementation and whether this translates into symptom relief in IBS. This study will be undertaken in both the UK and Mexico IBS populations exploring specific impacts of the selected fibres on fundamental mechanisms including gut microbiota and gut transit time using the latest sequencing and gastrointestinal motility technology, respectively. In addition, this study will translate several novel mechanisms, based on experimental work, to gain a better understanding of how dietary fibre may exert a benefit. Lastly, study 2 will investigate whether a non-invasive diagnostic model developed by our group can be used to identify IBS patients most likely to respond to dietary fibre, which, if successful will help better characterise the IBS population and pave the way towards personalised treatment plans.