Metabolomics Insights Into Traditional Chinese Medicine For Functional Constipation — Implications For Herbal Product Development (Focus On Cistanche)

 

Story-driven opening - Customer pain points & market insight

Imagine a middle-aged customer, Ms. Li, who has tried fiber supplements, over‑the‑counter laxatives and even prescription pro‑motility agents. She reports temporary relief but worries about long‑term dependence, unpleasant side effects, and relapses. She wants a natural product that supports bowel regularity, addresses underlying causes, and improves vitality without harsh stimulation. For manufacturers and R&D teams in the herbal and nutraceutical space - especially producers of Cistanche (Cistanche deserticola) - Ms. Li's case highlights three urgent market pain points:

 

Efficacy with sustainability: consumers want products that relieve constipation without causing dependence or rebound symptoms.

Mechanism-backed claims: regulators and discerning buyers expect plausible biological mechanisms (microbiome modulation, metabolite restoration) rather than anecdote alone.

Differentiation and positioning: brands need evidence-based, targeted formulations (e.g., for elderly slow‑transit constipation, or constipation linked to metabolic imbalance) with clear biomarkers to support marketing and clinical substantiation.

This review of metabolomics research on Traditional Chinese Medicine (TCM) interventions for functional constipation (FC) provides actionable insights: it identifies disturbed metabolic pathways (tryptophan metabolism, short‑chain fatty acid production, carbohydrate and bile acid metabolism), links specific TCM formulas and herbs (including Cistanche polysaccharides) to corrective metabolic effects, and suggests R&D strategies - multi‑omics integration, targeted metabolite assays, and product claims built on measurable endpoints - that an herbal manufacturer can adopt to create differentiated, mechanism‑driven constipation care products.

Keywords (SEO): functional constipation, metabolomics, Traditional Chinese Medicine, Cistanche, short‑chain fatty acids, tryptophan metabolism, bile acid, herbal product development

 

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Abstract

Functional constipation (FC) is a common functional gastrointestinal disorder with prevalence between 10.1% and 15.3%, severely affecting patients' quality of life. Traditional Chinese Medicine (TCM) treatments for FC offer individualized prescriptions, stable efficacy, and low relapse rates, but their mechanisms remain incompletely elucidated. Metabolomics - primarily using liquid chromatography–mass spectrometry (LC‑MS), gas chromatography–mass spectrometry (GC‑MS), and nuclear magnetic resonance (NMR) - detects changes in small‑molecule metabolites in urine, feces, and blood, providing an effective approach to clarify the mechanisms of TCM in FC. This review summarizes metabolomics applications in TCM treatments for FC, finding that FC pathogenesis is closely associated with disturbances in multiple pathways including amino acid metabolism (notably tryptophan), short‑chain fatty acid (SCFA) metabolism, carbohydrate metabolism and bile acid metabolism. TCM interventions such as Maren Pill (Maren Wan), Zengye Decoction (Zengye Tang), Atractylodes macrocephala (Bai Zhu), Cistanche (Rou Cong Rong) and astragalus polysaccharides, as well as acupuncture, can correct these metabolic disturbances, protect the intestinal mucosal barrier, and restore microbiome balance to improve constipation symptoms. Despite progress, limitations include insufficient metabolomics studies aligned with TCM syndrome differentiation, scarce acupuncture and combined therapy metabolomics research, and lack of standardization in metabolite detection. Future work should integrate multi‑omics and machine learning to deepen understanding of metabolic signatures across TCM syndromes and reveal metabolic mechanisms of TCM treatment for FC.

 

 

Introduction: clinical importance of FC

Functional constipation (FC) is a functional gastrointestinal disease without clear organic lesions, clinically characterized by hard stools, decreased defecation frequency, and often accompanied by bloating and abdominal pain [1]. Children may present fecal incontinence, while adults can experience anorectal obstruction or a sense of blockage requiring manual maneuvers to assist defecation [2]. According to Rome criteria, FC prevalence ranges from 10.1%–15.3%, with higher rates in females [3]. FC seriously impacts quality of life and mental health and may be associated with an increased risk of Parkinson's disease [4]. Western medicine commonly uses osmotic laxatives, stimulant laxatives and prosecretory agents; these can relieve symptoms short term but may cause dependence, high relapse and adverse effects over long‑term use, and rare complications such as melanosis coli [5–7]. TCM shows advantages of individualized therapy, symptom relief, reduced relapse and lower dependence, improving patient quality of life [8]. However, complex herbal constituents challenge sensitivity of traditional efficacy evaluation and obscure mechanisms. Metabolomics can track metabolite changes before and after treatment to elucidate mechanisms. This review integrates recent metabolomics studies on TCM treatment of FC, summarizes major metabolic pathways corrected by TCM, and provides reference for future studies.

Metabolomics overview

Metabolomics aims to identify small‑molecule metabolites (typically <1500 Da) including carbohydrates, lipids, amino acids, nucleotides and fatty acids [11]. Common sample types: serum, plasma, cerebrospinal fluid, saliva, feces, sweat, tears, urine, breast milk and vaginal secretions [12]. Advanced analytical platforms allow detection, quantification and characterization of metabolites involved in synthesis, transformation and degradation. Metabolites are downstream products of gene expression and protein activity, acting as a bridge between genotype and environment and reflecting phenotype directly [13]. As signaling molecules and cofactors, metabolites participate in energy production/storage and regulatory processes [14]. Metabolomics has advantages in biomarker discovery, disease diagnosis/treatment and elucidation of metabolic regulation, inferring disease mechanisms and identifying therapeutic targets [15].

Primary analytical platforms: LC‑MS, GC‑MS and NMR [16]. Chromatography–mass spectrometry allows reproducible, high‑sensitivity analysis of hundreds to thousands of metabolites. Different chromatographic methods differ in coverage (polar, nonpolar, volatile), so LC or GC conditions may detect specific metabolites better. Ultra‑high performance LC‑MS (UPLC‑MS) offers high sensitivity and resolution [17]; GC‑MS excels for volatile and semi‑volatile compounds [18]. Because disease often involves coordinated changes among many metabolites, combined LC‑MS and GC‑MS provide broad coverage for untargeted screens and phenotype‑defining markers [19]. NMR quantifies sugars, organic acids, alcohols and polyols without derivatization and enables real‑time analysis; NMR (1H, 13C, 15N, 31P) offers unlabelled atomic‑level structural information [20].

Metabolomics strategies: targeted (sensitive quantification of specified metabolites) and untargeted (global metabolic profiling to reveal functional changes) [21].

Applications of metabolomics in FC
Metabolomics detects metabolite differences in various biofluids to infer altered metabolic pathways and those corrected by interventions [22]. Urine, feces and blood are most commonly used in clinical and animal FC studies.

3.1 Urine

Urine metabolomics is widely used for FC due to noninvasive collection and reflection of systemic metabolism. Studies cover biomarker discovery, intervention evaluation and drug metabolite identification. Chojnacki et al. used LC‑MS/MS to measure urinary homovanillic acid (HVA), 5‑HIAA, para‑hydroxyphenylacetic acid and sulfated indoxyl, markers of dopamine, serotonin and indole pathways, finding elevated HVA and decreased 5‑HIAA in FC patients, indicating disrupted dopamine and serotonin balance [23]. Liu et al. used 1H NMR on animal urine and identified 12 metabolites associated with Zengye Decoction; compared to model, Zengye raised 2‑hydroxyisobutyrate, formate, β‑glucose, cysteine, glutamate, glycine, taurine, benzoate and acetate, while lowering succinate, malonate and creatinine-suggesting metabolic restoration [24]. Gu et al. identified a deglycosylated azithromycin metabolite in rat urine, providing data for novel laxative development [25].

 

3.2 Feces

Fecal metabolomics assesses gut microbiota effects and reflects intestinal pathological state. Wang et al. identified 28 fecal metabolites associated with FC, with disturbances in carbohydrate, amino acid and SCFA metabolism [26]. Chen et al. found reduced fecal acetate and propionate in FC, with levels negatively correlated with constipation severity [27]. Fan et al. observed differences in bile acids and lipids - including taurocholic acid, taurodeoxycholic acid, taurine, deoxycholic acid, cholic acid and arachidonic acid derivatives - linking BA metabolism to gut microbiome and fecal metabolite alterations in slow‑transit constipation [28].

 

3.3 Blood

Serum metabolomics reflects systemic metabolic changes and is key for biomarker discovery and efficacy evaluation. Kim et al. reported reductions in alanine, glutamate, glutamine and glycine, and decreases in acetate, glucose, glycerol, lactate, succinate and taurine in loperamide‑induced constipated rats [29]. Zhao et al. found elevated serotonin and 5‑hydroxyindoleacetic acid in early FC mouse serum using untargeted metabolomics [30]. Yang et al. showed phenylalanine remodels gut microbiota and metabolites to improve FC symptoms [31]. Luo et al. demonstrated rifaximin restores serum metabolic disturbances in loperamide‑induced rats, affecting BA and steroid metabolism [32].

TCM correction of metabolic dysregulation in FC

4.1 Amino acid metabolism (focus on tryptophan)

Amino acid metabolism supports protein synthesis, provides nutrients to intestinal cells, promotes mucus secretion, repairs mucosa and regulates barrier and immune functions. Tryptophan (Trp) - the only indole‑containing essential amino acid - activates epithelial G‑protein coupled receptors to promote colonic secretion [33,34]. Trp metabolism includes kynurenine, serotonin and indole pathways; indoles and derivatives modulate the gut barrier and microbiota [35].

Qin et al. using UPLC‑Q‑TOF‑MS found Atractylodes macrocephala (Bai Zhu) reverses five abnormal Trp metabolites (4,6‑dihydroxyquinoline, indole‑4,8‑dihydroxyquinoline, 5‑HT and kynurenine) in loperamide‑induced constipated rats, and modulates expression of rate‑limiting Trp metabolic enzymes (Trp hydroxylase, monoamine oxidase, indoleamine 2,3‑dioxygenase) in colon-suggesting Bai Zhu may improve FC via Trp metabolism regulation [36]. Wang et al. reported electroacupuncture increased fecal levels of 5‑hydroxykynurenine, 5‑hydroxyindoleacetic acid derivatives and indole derivatives; antibiotic pretreatment abolished this effect, indicating EA acts via microbiota–Trp metabolism interactions [37]. NMR analysis showed Ophiopogon japonicus (Mai Dong) extracts restored 15 endogenous metabolites (including seven amino acids) and colonic pathology in FC rats, implying potential biomarkers for Mai Dong therapy. Dahuang (Rhei radix) may modulate branched‑chain amino acid metabolism to improve constipation [38]. Other formulas (e.g., Kuaichong Yin) also affect amino acid metabolism and shorten defecation time [39].

 

4.2 SCFA metabolism

SCFAs influence gut motility, transit time, mucus secretion and gut–brain axis signaling; mainly produced by Firmicutes and Bacteroidetes during carbohydrate fermentation and can stimulate 5‑HT release. Butyrate maintains epithelial integrity and reduces inflammation; SCFA abnormalities can damage enteric nervous system and cause FC [40,41]. Hempseed oil increased acetate and butyrate in the cecum and improved constipation in rats [42]. Astragaloside IV increased fecal butyrate and mitigated slow‑transit constipation by modulating microbiota [43]. Maren Pill elevated colonic SCFAs, improved mucosal barrier and microbiota, increasing luminal fluid and motility [44]. Electroacupuncture restored Firmicutes/Bacteroidetes ratio and boosted butyrate production [45]. Acupuncture at specific sacral points increased fecal acetate and butyrate with symptom improvement [46]. Atractylodes (Bai Zhu) increased fecal SCFAs and tight junction protein expression, suggesting barrier enhancement [47]. Zhishi (Citrus) formulas, modified Huangqi Tang and other herbs (cinnamic acid, atractylenolide I) act partly via SCFA modulation [48–53].

4.3 Carbohydrate metabolism

Carbohydrate pathways - fructose and mannose metabolism, pyruvate metabolism, pentose phosphate pathway - interconnect with glycolysis, TCA and amino acid synthesis. In aged FC rats, elevated fructose and mannose metabolism suggest accelerated conversion of carbohydrates; changes include glucose depletion and lactate accumulation. Cistanche polysaccharides correct dysregulated glycolysis/gluconeogenesis, aminoacyl‑tRNA biosynthesis, and branched amino acid biosynthesis; they lowered butyrate, acetate, glucose and alpha‑xylose while increasing isoleucine, methionine and propionate. Cistanche polysaccharides also raised beneficial gut bacteria and reduced pathogens, improved immunity, and alleviated constipation and aging phenotypes in elderly rats, indicating potential as a new therapeutic agent for elderly constipation [54,55]. Astragalus polysaccharides similarly modulated glycolysis/ gluconeogenesis and pyruvate metabolism, improving constipation and cognitive deficits in aged models [54]. Dahuang‑Fuzi combinations modulate amino acid and carbohydrate metabolism and protect the mucosal barrier [57].

 

4.4 Bile acid metabolism

Bile acids (BAs) synthesized in liver and metabolized by gut microbiota regulate digestion and maintain metabolic homeostasis. Primary BAs (cholic acid, chenodeoxycholic acid) are conjugated with glycine or taurine and undergo enterohepatic circulation. BAs influence glucose, lipid and energy balance [58,59]. Cistanche total alditols increased expression of CYP8B1, FGF15, TGR5 and FXR to modulate BA synthesis and enterohepatic cycling, improving FC [60]. Shouhui Tongbian Capsule regulated BA metabolism to adjust serum and fecal bile acids and restore gut function [61]. Different TCM formulations may oppositely affect BA reabsorption and 5‑HT release; for example, Shang‑Er‑Huang formula inhibited ileal BA reabsorption and improved motility via 5‑HT [62]. Areca nut (and its processing) also affects primary BA biosynthesis and gut transit [63].

4.5 Other pathways

Buzhong Yiqi Decoction reversed 17 aberrant metabolites and regulated arachidonic acid metabolism, downregulated COX‑2 expression, reduced proinflammatory PGE2, inhibited NF‑κB phosphorylation, lowered IL‑1β and TNF‑α in colon, and increased serum myo‑inositol, motilin and gastrin to promote GI motility [64]. Shouhui Tongbian Capsule also regulates galactose and purine/pyrimidine metabolism [65]. Hu Huang Lian modulates glutathione, purine and pyrimidine metabolism [66]. Jichuan Decoction affects taurine and hypotaurine metabolism and AKT signaling, suppresses enteric glial cell apoptosis, increases acetylcholine levels, reduces intestinal inflammation and improves motility in slow‑transit constipation [67].

 

Conclusions and perspectives

Multiple studies converge to show FC involves disturbances in amino acid metabolism, SCFA metabolism, carbohydrate metabolism and BA metabolism. TCM can correct these metabolic perturbations, protect the mucosal barrier, restore physiological function and microbiome balance. Metabolomics provides molecular‑level evidence to clarify TCM mechanisms and supports TCM modernization [68].

However, current metabolomics research in TCM for FC faces limitations: (1) TCM emphasizes syndrome differentiation (bianzheng lunzhi) to tailor individualized treatments, yet most metabolomics studies do not align medication choices with syndrome types; few focus on different TCM syndromes beyond yang‑deficiency. Future studies should investigate metabolic signatures across TCM syndromes; (2) metabolomics research on acupuncture is limited and largely focused on single therapies; combined acupuncture‑herbal therapy studies are lacking despite potential synergy; (3) metabolite complexity and dynamics create challenges for simultaneous identification and reliable quantification. Sampling and analytical variability produce significant differences. Future work should target accurate sensitive metabolites and validate findings in vivo and in vitro, leveraging machine learning and deep learning and integrating multi‑omics to enhance detection coverage of low‑abundance metabolites and reveal metabolic reprogramming in disease.

 

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