Efficacy and Mechanistic Evaluation of Hewei Anchang Formula for Overlapping Gastrointestinal Symptoms in Patients With Coexisting Functional Dyspepsia and Diarrhea-Predominant Irritable Bowel Syndrome

Functional gastrointestinal disorders (FGIDs) comprise a group of gastrointestinalconditions characterized predominantly by gastrointestinal symptom complexes in theabsence of identifiable structural abnormalities or clearly defined pathophysiologicalmechanisms. Individual FGIDs are diagnosed primarily on the basis of symptom profiles andcommonly present with manifestations such as reflux, heartburn, dyspepsia, abdominalpain, bloating, diarrhea, and constipation. The boundaries between different FGIDs arenot distinct, and symptom overlap is common. Such overlap not only increases diseasecomplexity and substantially complicates clinical diagnosis and management, but alsoincreases healthcare utilization and imposes a considerable adverse impact on patients'quality of life. According to the Rome IV criteria, each patient with an FGID receives,on average, 1.5 FGID diagnoses, and approximately 36% of patients have FGIDs involvingtwo or more gastrointestinal regions, representing a typical pattern of symptom overlap.Among the various overlapping phenotypes of FGIDs, the coexistence of functionaldyspepsia (FD) and diarrhea‐predominant irritable bowel syndrome (IBS‐D) is one of themost common. These patients experience both typical upper gastrointestinal symptoms ofFD, including postprandial fullness, early satiety, and epigastric pain, and core lowergastrointestinal manifestations of IBS‐D, such as abdominal pain, diarrhea, and alteredstool form, making this overlap phenotype a major challenge in gastroenterologicalpractice. Compared with patients with FD or IBS‐D alone, those with coexisting FD andIBS‐D tend to experience more persistent, frequent, and severe symptoms. These symptomscan substantially affect eating habits, daily routines, social activities, and otheraspects of everyday life, thereby markedly impairing quality of life. Repeatedhealthcare‐seeking behavior also increases both individual medical expenditures and theconsumption of healthcare resources, making this condition an important clinical andpublic health concern requiring effective intervention.The clinical management of overlapping gastrointestinal symptoms in FGIDs remainschallenging. Conventional pharmacological treatments often act on limited therapeutictargets and may therefore provide suboptimal efficacy in patients with overlappingsymptom profiles, while also contributing to a substantial socioeconomic burden. Commonlyused medications, including prokinetic agents, proton pump inhibitors, antidiarrhealagents, and anticholinergic antispasmodics, generally target symptoms arising from asingle gastrointestinal region. Consequently, treatment outcomes may be unsatisfactorywhen upper and lower gastrointestinal symptoms coexist. Although combinationpharmacotherapy may address multiple symptoms, it may also increase the risk of adversedrug reactions, and some patients discontinue treatment because of poor tolerability oradverse effects, resulting in limited overall clinical benefit. In addition, thepathophysiology of coexisting FD and IBS‐D is complex and has been associated withmultiple interacting mechanisms, including gastrointestinal dysmotility, gut microbialdysbiosis, and dysregulation of the neuroendocrine‐immune network. Thus, single‐targetpharmacotherapy may be poorly suited to the multifactorial pathophysiological features ofthis overlap phenotype, which may partly explain its limited therapeutic effectiveness.Patients with FD and IBS‐D frequently experience psychological disturbances, includinganxiety and depression. From the perspective of traditional Chinese medicine (TCM), liverqi stagnation is considered a key underlying pathogenesis, while spleen‐stomachdeficiency and liver stagnation with spleen deficiency are among the most common syndromepatterns in patients with overlapping FD and IBS‐D. Accordingly, strengthening the spleenand regulating qi, as well as soothing the liver and strengthening the spleen, areregarded as core therapeutic principles. Owing to its holistic regulatory effects andindividualized treatment based on syndrome differentiation, TCM may be particularly wellsuited to the multifactorial pathophysiology of overlapping FGIDs. Guided by the TCMprinciple of "treating different diseases with the same therapeutic approach," TCMinterventions may target the shared pathogenesis of liver stagnation with spleendeficiency through multicomponent, multitarget, and multipathway mechanisms, therebyexerting integrated effects on gastrointestinal function, emotional well‐being, andinternal homeostasis. This therapeutic model may offer advantages over conventionalsingle‐target symptomatic treatment.Chaihu Shugan San has the traditional actions of regulating qi, relieving stagnation,harmonizing the stomach, and redirecting rebellious qi downward, and has been stronglyrecommended in several expert consensuses and clinical guidelines for the treatment of FDwith liver‐stomach disharmony syndrome. Based on more than four decades of clinicalexperience, Professor Xudong Tang of Xiyuan Hospital, China Academy of Chinese MedicalSciences, proposed the theory of "regulating the middle and restoring balance." Under theguidance of this theory, Chang'an I Formula was developed according to the corepathogenesis of IBS‐D. Hewei Anchang Formula is an optimized herbal formula derived fromChang'an I Formula and modified Chaihu Shugan San, with modifications tailored to thepathophysiological characteristics of liver‐stomach disharmony syndrome in FD and liverstagnation with spleen deficiency syndrome in IBS‐D. The formula has demonstratedpromising clinical effects. Based on the theory of "regulating the middle and restoringbalance," Hewei Anchang Formula is designed to address the core pathogenesis ofoverlapping gastrointestinal symptoms in FD and IBS‐D, with therapeutic actions aimed atstrengthening the spleen, soothing the liver, regulating qi, and alleviating diarrhea.Its composition is therefore closely aligned with the principles of TCM syndromedifferentiation and provides a suitable intervention for investigating TCM‐basedtreatment of this overlap phenotype.This study is designed as a multicenter, randomized, double‐blind, placebo‐controlledclinical trial and will enroll 120 patients with overlapping gastrointestinal symptoms ofFD with liver‐stomach disharmony syndrome and IBS‐D with liver stagnation‐spleendeficiency syndrome. The study aims to evaluate the clinical efficacy and potentialtherapeutic advantages of Hewei Anchang Formula in the treatment of coexisting FD andIBS‐D. Metagenomic and metabolomic approaches will also be used to investigate itspotential mechanisms of action, with particular emphasis on the gut microbial ecosystemand the neuroendocrine‐immune network. The findings are expected to provide a practicalTCM‐based therapeutic strategy for improving the overall management of overlappinggastrointestinal symptoms in FGIDs and reducing the associated medical and socioeconomicburden.