Chronic unexplained gastrointestinal symptoms impact more than 1 in 5 Americans and their families; these disorders include the irritable bowel syndrome (IBS) and functional dyspepsia (FD), currently classified by Rome IV as functional gastrointestinal disorders. By definition, IBS and FD have no established pathology, but emerging evidence suggests this paradigm may need revision. Immune activation and, in subsets, subtle intestinal pathology have been identified in FD (most notably, postprandial distress syndrome) and IBS-diarrhea. A disease model is proposed that accounts for all of the intestinal and extraintestinal symptoms, relationship to food and infection, and the overlap with gastroesophageal reflux disease. It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the intestine with low-grade intestinal inflammation and subsequently neuronal structural and functional alterations, producing regional intestinal hypersensitivity and motor dysfunction. Immune activation may explain the female predominance and fluctuations in immune activity for symptom variability over time. In the future, as further evidence accumulates, the management paradigm may potentially shift to objective pathology-based subtyping based on serological, microbiological, and clinical assessments to identify when targeted therapies should be deployed in subsets. Potential targeted interventions may include therapies to dampen down immune activation or block release of key mediators such as histamine, specific microbial targeted treatments that may reverse disease, and dietary advice to eliminate relevant food antigens after objective in vivo testing. Only by identifying causation can we eventually anticipate cure, and as the true pathology unravels in subsets, this may become a reality.

中文翻译：

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什么导致功能性胃肠道疾病？建议的疾病模型

超过五分之一的美国人及其家人患有慢性无法解释的胃肠道症状；这些疾病包括肠易激综合征 (IBS) 和功能性消化不良 (FD)，目前罗马 IV 将其归类为功能性胃肠道疾病。根据定义，IBS 和 FD 没有既定的病理学，但新出现的证据表明这种范式可能需要修改。在 FD（最值得注意的是，餐后窘迫综合征）和 IBS 腹泻中，已经发现免疫激活和细微的肠道病理。提出了一种疾病模型，可以解释所有肠道和肠外症状、与食物和感染的关系以及与胃食管反流病的重叠。据推测，抗原呈递到粘膜（例如，急性胃肠炎后的微生物抗原或食物蛋白）在基因引发的宿主中诱导肠道免疫激活，伴有低度肠道炎症，随后神经元结构和功能改变，产生局部肠道过敏和运动功能障碍。免疫激活可以解释女性在免疫活动中的优势和波动随时间的症状变异性。未来，随着进一步证据的积累，管理范式可能会转变为基于血清学、微生物学和临床评估的客观病理亚型，以确定何时应在亚组中部署靶向治疗。潜在的有针对性的干预措施可能包括抑制免疫激活或阻止关键介质（如组胺、可以逆转疾病的特定微生物靶向治疗，以及在客观的体内测试后消除相关食物抗原的饮食建议。只有通过确定因果关系，我们才能最终预期治愈，随着真正的病理在亚组中解开，这可能成为现实。