Qingchang Wenzhong Decoction ameliorates intestinal inflammation and intestinal barrier dysfunction in ulcerative colitis via the GC-C signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa, accompanied with abdominal pain, and bloody diarrhea. Currently, clinical treatment options for UC are limited. Qingchang Wenzhong Decoction (QCWZD) is an effective prescription of traditional Chinese medicine for the treatment of UC. However, the mechanism of QCWZD in alleviating intestinal barrier dysfunction in UC has not been clearly explained. AIM OF THE STUDY: To determine the mechanism whereby QCWZD promotes the recovery of intestinal barrier dysfunction in UC. MATERIALS AND METHODS: A secondary analysis of colonic mucosa from UC patients acquired from a prior RCT clinical trial was performed. The effects of QCWZD on intestinal mucus and mechanical barriers in UC patients were evaluated using colon tissue paraffin-embedded sections from UC patients. The mechanism was further investigated by in vivo and in vitro experiments. UC mice were established in sterile water with 3.0% dextran sodium sulfate (DSS). Meanwhile, mice in the treatment group were dosed with QCWZD or mesalazine. In vitro, an intestinal barrier model was constructed using Caco-2 and HT29 cells in co-culture. GC-C plasmid was used to overexpress/knock down GC-C to clarify the target of QCWZD. HE, AB-PAS, ELISA, immunohistochemistry and immunofluorescence assays were used to assess the level of colonic inflammation and intestinal barrier integrity. Rt-qPCR, Western Blot were used to detect the expression of genes and proteins related to GC-C signaling pathway. Molecular docking was used to simulate the binding sites of major components of QCWZD to GC-C. RESULTS: In UC patients, QCWZD increased mucus secretion, goblet cell number, and promoted MUC2 and ZO-1 expression. QCWZD accelerated the recovery of UC mice from DSS-induced inflammation, including weight gain, reduced disease activity index (DAI) scores, colon length recovery, and histological healing. QCWZD promoted mucus secretion and increased ZO-1 expression in in vivo and in vitro experiments, thereby repairing mucus mechanical barrier damage. The effects of QCWZD are mediated through regulation of the GC-C signaling pathway, which in turn affects CFTR phosphorylation and MUC2 expression to promote mucus secretion, while inhibiting the over-activation of MLCK and repairing tight junctions to maintain the integrity of the mechanical barrier. Molecular docking results demonstrate the binding of the main components of QCWZD to GC-C. CONCLUSION: Our study demonstrated that QCWZD modulates the GC-C signaling pathway to promote remission of mucus-mechanical barrier damage in the UC. The clarification of the mechanism of QCWZD holds promise for the development of new therapies for UC.

International clinical practice guideline on the use of traditional Chinese medicine for ulcerative colitis by Board of Specialty Committee of Digestive System Disease of World Federation of Chinese Medicine Societies (2023).

Ulcerative colitis (UC), a chronic and nonspecific inflammatory disease of the intestine, has become a prevalent global health concern. This guideline aims to equip clinicians and caregivers with effective strategies for the treatment and management of adult UC patients using traditional Chinese medicine (TCM). The guideline systematically evaluated contemporary evidence through the Grading of Recommendations Assessment, Development, and Evaluation framework. Additionally, it incorporated insights from ancient Chinese medical sources, employing the evidence grading method found in traditional TCM literature. The development process involved collaboration with multidisciplinary experts and included input from patients with UC. The guideline, based on a comprehensive review of available evidence, present 40 recommendations. They offer a condensed overview of TCM's role in understanding the pathogenesis, diagnosis, and treatment of UC, along with an assessment of the efficacy of various TCM-based treatments. TCM exhibits promising outcomes in the treatment of UC. However, to establish its efficacy conclusively, further high-quality clinical studies on TCM for UC are essential.

Fermented Angelica sinensis activates Nrf2 signaling and modulates the gut microbiota composition and metabolism to attenuate D-gal induced liver aging.

Aging is an inevitable physiological process associated with an imbalance in the oxidative defense system. Angelica sinensis, a kind of traditional Chinese medicine (TCM), has anti-oxidant effects and has been considered as a potential supplement in anti-aging treatment. Nevertheless, it has the disadvantages of slow efficacy and long duration of treatment. Fermentation, as an efficient biotechnological approach, is beneficial for improving the nutritional capacity of the material. Fermented TCMs are considered to be more effective. In this study, fermented Angelica sinensis (FAS) and non-fermented Angelica sinensis (NFAS) were used to investigate changes in the chemical constituents. Furthermore, the improvement effect of FAS on D-galactose-induced aging in mice and the potential mechanisms were explored. The results revealed that FAS and NFAS had different constituents under the influence of fermentation, such as 3-phenyllactic acid, L-5-hydroxytryptophan, taxifolin and methyl gallate. These elevated constituents of FAS might help increase the ability of FAS to improve aging. The aging model was established by intraperitoneal injection of D-galactose (2.5 g kg-1 day-1) for 44 days, and FAS (3 g kg-1 day-1) was administered daily by oral gavage after 2 weeks of induction with D-galactose. FAS was observed to significantly ameliorate changes associated with liver aging, such as reduction of MDA, AGEs and 8-OHdG. The contents of pro-inflammatory cytokines containing TNF-α, IL-1ß and IL-6 were significantly suppressed in the FAS group. In addition, FAS activated Nrf2 signaling better than NFAS, improved the expression of Nrf2, HO-1, NQO1, GCLC, GCLM and GSS, and further increased the activities of SOD, CAT and other antioxidant enzymes in the liver. Simultaneously, it had a certain repair effect on the liver tissues of mice. The intestinal microbiota analysis showed that FAS could regulate the microbiota imbalance caused by aging, increase the ratio of Firmicutes/Bacteroidetes by 95% and improve the relative abundance of beneficial bacteria related to Nrf2 signaling, such as Lactobacillus. Besides, fecal metabolite analysis identified uric acid as an evidential metabolite, suggesting that FAS participates in purine metabolism to improve aging. Therefore, the regulation of intestinal microbiota and metabolism may be one of the important mechanisms of FAS in alleviating hepatic oxidative stress via the gut-liver axis. The results of this study could provide information for the future development of postbiotic products that may have beneficial effects on the prevention or treatment of aging.

Fermented Astragalus and its metabolites regulate inflammatory status and gut microbiota to repair intestinal barrier damage in dextran sulfate sodium-induced ulcerative colitis.

Fermentation represents an efficient biotechnological approach to increase the nutritional and functional potential of traditional Chinese medicine. In this study, Lactobacillus plantarum was used to ferment traditional Chinese medicine Astragalus, the differential metabolites in the fermented Astragalus (FA) were identified by ultra-performance liquid chromatography-Q Exactive hybrid quadrupole-Orbitrap mass spectrometry (UPLC-Q-Exactive-MS), and the ameliorating effect of FA on dextran sulfate sodium (DSS)-induced colitis in mice were further explored. The results showed that 11 differential metabolites such as raffinose, progesterone and uridine were identified in FA, which may help improve the ability of FA to alleviate colitis. Prophylactic FA supplementation effectively improved DAI score, colon length and histopathological lesion in DSS-treated mice. The abnormal activation of the intestinal immune barrier in mice was controlled after FA supplementation, the contents of myeloperoxidase (MPO) and IgE were reduced and the contents of IgA were increased. The intestinal pro-inflammatory factors TNF-α, IL-1ß, IL-6, and IL-17 were down-regulated and the anti-inflammatory factors IL-10 and TGF-ß were up-regulated, suggesting that FA can intervene in inflammatory status by regulating the balance of Th1/Th2/Th17/Treg related cytokines. In addition, FA supplementation modified the structure of the intestinal microbiota and enriched the abundance of Akkermansia and Alistipes, which were positively associated with the production of short-chain fatty acids. These microbes and their metabolites induced by FA also be involved in maintaining the intestinal mucosal barrier integrity by affecting mucosal immunity. We observed that intestinal tight junction protein and mucous secreting protein ZO-1, occludin, and MUC2 genes expression were more pronounced in mice supplemented with FA compared to unfermented Astragalus, along with modulation of intestinal epithelial cells (IECs) apoptosis, verifying the intestinal mucosal barrier repaired by FA. This study is the first to suggest that FA as a potential modulator can more effectively regulate the inflammatory status and gut microbiota to repair the intestinal barrier damage caused by colitis.

Chinese integrated guideline on the management of gastric precancerous conditions and lesions.

The standardized diagnosis and management of gastric precancerous conditions and lesions are important to prevent gastric cancer. This guideline, created by 5 traditional Chinese medicine and Western medicine associations, based on the current morbidity and diagnosis and treatment of gastric precancerous conditions and lesions, provides specific key points and strategies for diagnosis and treatment in the following five aspects: definition and epidemiology, diagnosis and stage, surveillance, treatment and efficacy evaluation. It is hoped that these aspects, assessed by integrating Western medicine and traditional Chinese medicine and involving multidisciplinary participation, will play a guiding role in clinical diagnosis and treatment and achieve effective secondary prevention of gastric cancer.

Herbal Medicine Hewei Jiangni Decoction Is Noninferior to Oral Omeprazole for the Treatment of Nonerosive Gastroesophageal Reflux Disease: A Randomized, Double-Blind, and Double-Dummy Controlled Trail.

Objectives: Conventional approaches for patients with nonerosive gastroesophageal reflux disease (NERD) were not satisfactory. This study aimed to evaluate the effectiveness and mechanisms of Chinese herbal medicine Hewei Jiangni Decoction (HWJND) as a novel and promising regimen for NERD. Methods: A total of 128 patients with NERD were randomly assigned to the Treatment group and Control group. The patients from the Treatment group were administered HWJND (81 g) plus dummy omeprazole (20 mg) daily for 8 weeks, and the others were given dummy HWJND granules (81 g) plus omeprazole (20 mg). The clinical efficacy was assessed using the gastroesophageal reflux disease questionnaire (GERD-Q) scale, patient reported outcomes (PRO) scale, and short form health survey 36 (SF-36) scale at week 4. Moreover, its pharmacological and molecular mechanisms were elucidated based on network pharmacology and molecular docking. Results: Due to case shedding and other reasons, 109 patients, including 56 in the Treatment group and 53 in the Control group completed this study. Our results showed that HWJND significantly improved heartburn, regurgitation, epigastric pain, nausea, and sleep disturbance, which led to a significant reduction of GERD-Q scores in NERD patients. In addition, PRO scores of NERD patients with HWJND administration were improved, and sufficient relief of physical role, body pain, general health, social function, and mental health on the SF-36 scale was also observed in patients after HWJND treatment. We further showed that the curative effect of HWJND was close to that of omeprazole, except for the better improvement of general health and social function. What's more, the main active ingredients of HWJND included quercetin, beta-sitosterol, naringenin, baicalein, and kaempferol were retrieved, and the protective effects of HWJND against NERD may be closely related to targets such as TNF, IL6, IL1B, MMP9, CXCL8, and EGFR, which were mainly enriched in IL-17 signaling pathway and TNF signaling pathway. Conclusion: Our findings demonstrate that HWJND is noninferior to oral omeprazole for the treatment of patients with NERD, plays a therapeutic role through multiple targets and diverse pathways, and holds promise for complementary and alternative therapy for the treatment of NERD. This trial is registered with http://www.chictr.org.cn, Chinese Clinical Trials Registry [ChiCTR2200055960].

Qingchang Wenzhong Decoction Alleviates DSS-Induced Inflammatory Bowel Disease by Inhibiting M1 Macrophage Polarization In Vitro and In Vivo.

Background: An imbalance of macrophage M1/M2 polarization significantly influences the pathogenesis of inflammatory bowel disease. Qingchang Wenzhong decoction (QCWZD) has a proven therapeutic effect on patients with inflammatory bowel disease (IBD) and can significantly inhibit the inflammatory response in mice with colitis. However, its effect on macrophages during IBD treatment remains nebulous. Aim of the Study. Explore the mechanism underlying QCWZD effects in a dextran sulfate sodium (DSS)-induced colitis mouse model in vivo and RAW264.7 cell in vitro by observing macrophage polarization dynamics. Methods: The main active components of QCWZD were determined using high-performance liquid chromatography. Surface marker expression on M1-type macrophages was analyzed using flow cytometry and immunofluorescence. The effect on inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) released by M1 type macrophages was determined using ELSA and RT-PCR. The expression of key proteins in the JAK2/STAT3 signaling pathway was analyzed using western blotting. QCWZD cytotoxicity in macrophages was measured using CCK8 and Annexin V-FITC/PI assays. Results: The main active components of QCWZD were berberine chloride, coptisine chloride, epiberberine chloride, gallic acid, ginsenoside Rg1, ginsenoside Rb1, indigo, indirubin, notoginsenoside R1, palmatine chloride, and 6-curcumin. QCWZD markedly alleviated DSS-induced colitis in mice, as revealed by the rescued weight loss and disease activity index, attenuated the colonic shortening and mucosal injury associated with the inhibition of M1 macrophage polarization and expression of related cytokines, such as IL-6 and TNF-α, in vivo and in vitro. Furthermore, QCWZD decreased the iNOS, JAK2, and STAT3 levels in vivo and in vitro, regulating the JAK2/STAT3 signaling pathway. Conclusion: QCWZD administration improves intestinal inflammation by inhibiting M1 macrophage polarization. The JAK2/STAT3 signaling pathway may mediate the effects of QCWZD on M1 macrophage polarization in colitis treatment. This study presents a novel macrophage-mediated therapeutic strategy for the treatment of IBD.

Protective Effects and Mechanisms of Yinchen Linggui Zhugan Decoction in HFD-Induced Nonalcoholic Fatty Liver Disease Rats Based on Network Pharmacology and Experimental Verification.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, characterized by excessive accumulation of hepatocyte fat. However, there is no exact and effective pharmacotherapy for NAFLD. Yinchen linggui zhugan decoction (YLZD) has been widely used to treat NAFLD. Nevertheless, its pharmacological and molecular mechanisms have not been clearly elucidated. This study was carried out to investigate the active components of YLZD and explore its potential mechanisms for treating NAFLD by network pharmacology and experimental verification. The results showed that a total of 120 active components of YLZD and 365 targets were retrieved through databases, and the main active ingredients of YLZD consisted of chlorogenic acid, emodin, aloe-emodin, rhein, and geniposide. KEGG enrichment analysis revealed fundamental roles of TNF, PI3K/AKT, HIF-1α, and insulin resistance signaling pathways in the treatment of NAFLD by YLZD. Moreover, our experimental verification results showed that YLZD improved the liver pathological and cholesterol level, and reduced the expressions of TNF-α, IL-1ß, IL-6, NF-κB, CCL2, and CXCL10 in NAFLD rats, which all belonged to TNF signaling pathway. The molecular docking confirmed the correlation between the four core components (chlorogenic acid, emodin, rhein, and geniposide) and key factors (TNF-α, IL-6, and NF-κB) in TNF signaling pathway. In conclusion, the present study systematically clarified the protective mechanisms of YLZD against NAFLD through targeting the TNF signaling pathway, and provided new ideas for the drug research of this disease.

Network Pharmacology Analysis of Hewei Jiangni Granule for Gastroesophageal Reflux Disease and Experimental Verification of Its Anti-Neurogenic Inflammation Mechanism.

Purpose: Proton pump inhibitors, as the first-line drugs for treating gastroesophageal reflux disease (GERD), are unable to completely relieve patients' symptoms and patients are prone to recurrence after prolonged drug withdrawal. Thus, it is crucial to find herbal medicines as a complementary and alternative treatment. Hewei Jiangni granule (HWJNG) is a classical Chinese medicinal formula with clinical therapeutic effects on GERD, but its pharmacological mechanism of action remains unclear. This study aimed to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy. Methods: A network pharmacology approach was applied to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy. The active ingredients of HWJNG, as well as therapeutic targets of GERD were acquired from specialized databases. The "herb-ingredient-gene-target" network for HWJNG in GERD treatment was built. The protein-protein interaction (PPI) network was constructed to screen the core coincident targets. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The core targets and signaling pathways associated with the anti-neurogenic inflammatory effect were partially verified via experiments in vivo at molecular level. Results: In total, 179 chemical ingredients in HWJNG and 298 intersection targets between GERD and HWJNG were selected from databases. A large proportion of core targets and top signaling pathways were involved in neurogenic inflammation. HWJNG significantly alleviated pathological injuries of esophagus and reversed dilated intracellular spaces. Additionally, HWJNG markedly inhibited the excessive release of inflammatory cytokines such as interleukin (IL)-1ß, IL-6, tumor necrosis factor receptor (TNF-a), as well as regulated stimulation sensors including transient receptor potential vanilloid type 1 (TRPV1) and its related neuroinflammatory mediators in GERD mice. Conclusion: HWJNG is a promising therapeutic strategy for GERD treatment via regulation of multiple targets and pathways, its effects in alleviating neurogenic inflammation are especially acknowledged.

Investigation of the Active Ingredients and Mechanism of Hudi Enteric-Coated Capsules in DSS-Induced Ulcerative Colitis Mice Based on Network Pharmacology and Experimental Verification.

BACKGROUND: Hudi enteric-coated capsule (HDC) is a Chinese medicine prescribed to treat ulcerative colitis (UC). However, its anti-inflammatory active ingredients and mechanisms remain unknown. This study aimed to investigate the active components of HDC and explore its potential mechanisms against UC by integrating network pharmacology and experimental verification. METHODS: A DSS-induced colitis murine model was established to validate the efficacy of HDC by detecting disease activity index (DAI) and histopathological changes. Network pharmacological analysis was performed to identify the active compounds and core targets of HDC for the treatment of UC. The main compounds in HDC were identified by high-performance liquid chromatography. The relative expressions of HDC's core targets were also determined in vivo. Finally, molecular docking was applied to model the interaction between HDC and target proteins. RESULTS: In an in vivo experiment, HDC, especially the middle-dose HDC, effectively reduced clinical symptoms of UC, including weight loss, bloody stool, and colon shortening. Besides, the severity of colitis was considerably suppressed by HDC as evidenced by reduced DAI scores. A total of 118 active compounds and 69 candidate targets from HDC closely related to UC progression were identified via network pharmacology. Enrichment analysis revealed that the key targets of HDC correlated with the expressions of PTGS2, TNF-α, IL-6, and IL-1ß. Meanwhile, these cytokines were enriched in various biological processes through the IL-17/JAK2/STAT3 signaling pathway. The middle-dose HDC contributed more to ameliorating DSS-induced colitis through this signaling pathway than other dosages. Nine components binding to JAK2, STAT3, IL-17 and IL-6 were identified by molecular docking, confirming again the inhibition effects of HDC on the IL-17/JAK2/STAT3 signaling pathway. CONCLUSION: The HDC treatment, particularly the middle-dose, exerted an anti-UC effect in a multi-component, multi-target, and multi-mechanism manner, especially inhibiting the IL-17/JAK2/STAT3 signaling pathway to downregulate the secretion of proinflammatory cytokines.

Efficacy and safety of the Chinese herbal formula Hewei Jiangni recipe for NERD with cold-heat complex syndrome: study protocol for a double-blinded randomized controlled trial.

BACKGROUND: Proton pump inhibitor (PPI) is effective for the treatment of nonerosive gastroesophageal reflux (NERD), but long-term use of PPI is prone to have complications and recurrence after withdrawal. Traditional Chinese medicine (TCM) can relieve the symptoms of reflux and improve the quality of life. The purpose of this study is to evaluate the safety and efficacy of Hewei Jiangni recipe (HWJNR) in the treatment of NERD with cold-heat complex syndrome, and clarify the mechanism of HWJNR on NERD based on the correlation analysis of intestinal flora and metabolites. METHODS: This is a single-center, randomized controlled, double-blind, placebo-controlled clinical trial in which 72 eligible participants with NERD and TCM syndrome of intermingled heat and cold will be randomly allocated in the ratio of 1:1 to two groups: TCM group and western medicine group. The TCM group will receive HWJNR with omeprazole enteric-coated tablets placebo, while the western medicine group will receive omeprazole enteric-coated tablets with HWJNR placebo. Each group will be treated for 8 weeks. The primary outcome is the score of gastroesophageal reflux disease (GERD) health-related quality of life questionnaire (GERD-Q). Secondary outcomes include SF-36 quality of life scale (SF-36), patient-reported outcomes (PRO) self-rating scale score, syndrome score of TCM, and adverse events. Mechanistic outcome is the correlation analysis of intestinal flora and metabolites from healthy individuals and NERD participants before and after the treatment respectively. DISCUSSION: The goal of this trial is to investigate the efficacy and safety of HWJNR in the treatment of NERD with cold-heat complex syndrome, and to study the composition structure and metabolite expression profile of intestinal flora in patients with NERD through 16SrRNA sequencing and metabolomic correlation analysis of fecal flora, which makes us identify the dominant links of treatment and reveal the potential mechanism of HWJNR. ChiCTR2000041225 . Registered on 22 December 2020.

Tongxie Anchang Decoction Relieves Visceral Hypersensitivity in Diarrhea-Predominant Irritable Bowel Syndrome Rats by Regulating the NGF/TrkA Signaling Pathway.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease characterized by visceral hypersensitivity-related abdominal pain, in which diarrhea-predominant IBS (IBS-D) is the main subtype and has a high clinical incidence. Tongxie Anchang Decoction (TXACD) has been proved to significantly improve abdominal pain in patients with IBS-D, but its underlying therapeutic mechanism still remains unclear. In the present study, IBS-D model rats were induced by neonatal maternal separation (NMS) combined with restraint stress (RS). The therapeutic effect of TXACD was evaluated by fecal characteristics and abdominal withdrawal reflex (AWR) scores. After 14 days of intragastric administration, the colonic tissues of rats were collected to detect the protein and gene level of the NGF, TrkA, and TRPV1 using Western blotting and real-time polymerase chain reaction, respectively, and detect mast cells infiltration using toluidine blue staining. The abdominal aorta blood centrifuged was collected for detecting serum levels of SP, 5-HT, and CGRP with ELISA. The results revealed that TXACD could significantly improve visceral hypersensitivity in IBS-D rats, reflected in the decrease of AWR score and the serum levels of SP, 5-HT, and CGRP. In addition, TXACD treatment could alleviate mast cells infiltration. Moreover, the expression levels of the NGF, TrkA, and TRPV1 were repressed by TXACD. The findings of the present study indicated that the therapeutic effect of TXACD on visceral hypersensitivity might be closely related to the downregulation of the NGF/TrkA signaling pathway, the reversal of TRPV1 expression and mast cells infiltration, and the decreased release of neuroendocrine factors SP, 5-HT, and CGRP.

Serum metabolic profiling of traditional Chinese medicine syndromes in patients with diarrhea-predominant irritable bowel syndrome.

OBJECTIVE: The clinical symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D) can be effectively improved by traditional Chinese medicine (TCM) treatment, based on the usage of specific therapies for different TCM syndromes. However, in the stage of diagnosis, the standard criteria for the classification of TCM syndrome were still deficient. Through serum metabolic profiling, this study aimed to explore potential biomarkers in IBS-D patients with different TCM syndromes, which can assist in diagnosis of the disease. METHODS: Serum samples were collected from healthy controls (30 cases), IBS-D patients with Liver-Stagnation and Spleen-Deficiency syndrome (LSSD, 30 cases), Yang Deficiency of Spleen and Kidney syndrome (YDSK, 11 cases) and Damp Abundance due to Spleen-Deficiency syndrome (DASD, 22 cases). Serum metabolic profiling was conducted by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential biomarkers were screened by orthogonal partial least square-discriminate analysis, while metabolic pathways undergoing alterations were identified by pathway enrichment analysis in MetaboAnalyst 4.0. RESULTS: Overall, 34 potential biomarkers were identified in LSSD group, 36 in YDSK group and 31 in DASD group. And the 13 metabolites shared by three groups were determined as the potential biomarkers of IBS-D. Glycerophospholipid metabolism was disturbed significantly in IBS-D patients, which may play a role in IBS-D through inflammation. What's more, three TCM syndromes have the specific potential biomarkers in glycerophospholipid metabolism. CONCLUSION: The serum metabolomics revealed that different TCM syndrome types in IBS-D may have different metabolic patterns during disease progression and glycerophospholipid metabolism was one of the pathways, whose metabolism was disturbed differently among three TCM syndromes in IBS-D. Therefore, the specific potential biomarkers in glycerophospholipid metabolism of three TCM syndromes in IBS-D can serve as the objective indicators, which can facilitate the TCM-syndrome objective classification of IBS-D.

Systematic assessment of environmental factors for gastroesophageal reflux disease: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Side effects of long-term acid suppression have increased the scholars' interest in nonpharmacologic intervention. AIMS: We summarized an umbrella review of the association between environmental factors and gastroesophageal reflux disease (GERD) and assessed their credibility. METHODS: We appraised systematic reviews and meta-analyses. For each meta-analysis, we considered the effect size, 95% confidence interval, the heterogeneity, small-study effects, P-value for excess significance and largest study significant, then we graded the evidence according to Assessment of Multiple Systematic Reviews and the GRADE assessment. RESULTS: 23 publications met the inclusion criteria (13 meta-analyses and 10 systematic reviews), which evaluated 24 environmental factors. Among observational studies, we identified 7 risk factors: overweight/obesity [GERD/erosive esophagitis (EE)/GERD symptom], central adiposity [EE], smoking [GERD], alcohol [GERD/EE/non-erosive reflux disease (NERD)], NSAID [GERD], coffee [EE], Helicobacter pylori eradication [EE], and 1 protective factor: physical activity [GERD], this was based on a suggestive evidence of credibility. Across intervention studies, we identified 1 risk factor-Helicobacter pylori eradication [GERD] and 1 protective factor-breathing exercises [GERD], evidence for both was low grade. CONCLUSIONS: We found varying levels of evidence for different environmental factors of GERD. None of them was proven to be convincing or highly recommended.

Network Pharmacology Identifies the Mechanisms of Action of Tongxie Anchang Decoction in the Treatment of Irritable Bowel Syndrome with Diarrhea Predominant.

AIM: This study aims to uncover the pharmacological mechanism of Tongxie Anchang Decoction (TXACD), a new and effective traditional Chinese medicine (TCM) prescription, for treating irritable bowel syndrome with diarrhea predominant (IBS-D) using network pharmacology. METHODS: The active compounds and putative targets of TXACD were retrieved from TCMSP database and published literature; related target genes of IBS-D were retrieved from GeneCards; PPI network of the common target hub gene was constructed by STRING. Furthermore, these hub genes were analyzed using gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. RESULTS: A total of 54 active compounds and 639 targets were identified through a database search. The compound-target network was constructed, and the key compounds were screened out according to the degree. By using the PPI and GO and KEGG enrichment analyses, the pharmacological mechanism network of TXACD in the treatment of IBS-D was constructed. CONCLUSIONS: This study revealed the possible mechanisms by which TXACD treatment alleviated IBS-D involvement in the modulation of multiple targets and multiple pathways, including the immune regulation, inflammatory response, and oxidative stress. These findings provide novel insights into the regulatory role of TXACD in the prevention and treatment of IBS-D and hold promise for herb-based complementary and alternative therapy.

Study on the clinical mechanism of Tong-Xie-An-Chang Decoction in the treatment of diarrheal irritable bowel syndrome based on single-cell sequencing technology.

BACKGROUND: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a kind of functional gastrointestinal disorder with obscure pathogenesis, and exploration about differential gene expression and cell heterogeneity of T lymphocytes in peripheral blood in IBS-D patients still remains unknown. Clinicians tend to use symptomatic treatment, but the efficacy is unstable and symptoms are prone to relapse. Traditional Chinese Medicine (TCM) is used frequently in IBS-D with stable and lower adverse effects. Tong-Xie-An-Chang Decoction (TXACD) has been proven to be effective in the treatment of IBS-D. However, the underlying therapeutic mechanism remains unclear. This trial aims to evaluate the clinical efficacy and safety of TXACD in IBS-D and elucidate the gene-level mechanism of IBS-D and therapeutic targets of TXACD based on single-cell sequencing technology. METHODS/DESIGN: This is a randomized controlled, double-blind, double-simulation clinical trial in which 72 eligible participants with IBS-D and TCM syndrome of liver depression and spleen deficiency will be randomly allocated in the ratio of 1:1 to two groups: the experimental group and the control group. The experimental group receives Tong-Xie-An-Chang Decoction (TXACD) and Pinaverium bromide tablets placebo; the control group receives pinaverium bromide tablets and TXACD placebo. Each group will be treated for 4 weeks. The primary outcome: the rate of IBS-Symptom Severity Score (IBS-SSS). The secondary outcomes: TCM syndrome score, adequate relief and IBS-Quality of Life Questionnaire (IBS-QOL). Mechanistic outcome is the single-cell sequencing profiling of the T lymphocytes in peripheral blood from IBS-D participants before and after the treatment and healthy individuals. DISCUSSION: This trial will prove the efficacy and safety of TXACD with high-quality evidence and provide a comprehensive perspective on the molecular mechanism of IBS-D by single-cell sequencing profiling, which makes us pinpoint specific biomarkers of IBS-D and therapeutic targets of TXACD.

Clinical efficacy of Qi Di laxative decoction in the treatment of functional constipation: A protocol for systematic review and meta-analysis.

BACKGROUND: Functional constipation (FC) is a common gastrointestinal disorder characterized by slow bowel movement and defecation difficulties, significantly impacting patients' quality of life and exerting heavy financial burden to whole society. However, more than 50% FC patients are not completely satisfied with current therapies and alternative therapies are urgently required. Increasing evidences have demonstrated that traditional Chinese medicine has a good therapeutic effect on FC, which is well known for its multitarget and multimode effects on diverse diseases as well as less side effects. Furthermore, studies proved that Qi Di Laxative Decoction was an effective treatment for FC. Its safety and effectiveness should be verified by further studies. METHODS: We will search the following electronic databases for randomized controlled trials to evaluate the clinical efficacy of Qi Di Laxative Decoction in treating FC: Wanfang and Pubmed Database, China National Knowledge Infrastructure Database, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and Excerpta Medica database. Each database will be searched from inception to November 2020. The entire process will include study selection, data extraction, risk of bias assessment, and meta-analyses. RESULTS: This proposed study will evaluate the clinical efficacy of Qi Di Laxative Decoction for patients with FC. The outcomes will include changes in FC relief and adverse effect. CONCLUSION: This proposed systematic review will evaluate the existing evidence on the clinical efficacy of Qi Di Laxative Decoction in treating FC. DISSEMINATION AND ETHICS: The results of this review will be disseminated through peer-reviewed publication. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/M2ESR.

Clinical evaluation of traditional Chinese medicine on mild active ulcerative colitis: A multi-center, randomized, double-blind, controlled trial.

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by a relapsing-remitting course owing to recurrent intestinal inflammation. UC often has symptoms such as intermittent rectal bleeding, diarrhea, and abdominal pain. As the precise etiology of UC has not completely clarified, UC has become a public health challenge worldwide. According to an epidemiological survey, there were about 350,000 new cases of IBD in China from 2005 to 2014. By 2025, the number of IBD patients in China will reach 1.5 million. Traditional Chinese medicine (TCM) has been widely used to treat UC in China, however, it is still challenging to systematically determine the efficacy of in UC. Therefore, this trial aims to evaluate the clinical efficacy and safety of CHM in the treatment of mild active UC patients. METHODS: A multi-center, double-blinding, double-dummy, active-controlled, randomized trial will be established. A total of 240 patients in 6 centers with mild active UC (Mayo score is 3-5 points) and TCM syndrome of damp-heat stasis blocking and spleen-qi deficiency will be randomly allocated in the ratio of 1:1 to 2 groups: the experimental group and the control group. The experimental group will receive Hudi enteric-coated capsules (HEC) and enteric-coated mesalazine tablets placebo; the control group will receive enteric-coated mesalazine tablets and HEC placebo. Each group will be treated for 8 weeks. The primary therapeutic outcome: the rate of clinical efficacy and clinical remission at 8 weeks of treatment (last survey point) according to the modified Mayo score. The secondary outcomes: individual symptom score, TCM syndrome score, endoscopic response rate, mucosal healing rate, and quality of life scale score. Outcomes will be assessed at baseline and the end of the trial. Besides, intestinal mucosa, stools and blood biopsies from the mild active UC patients before and after treatment will be collected to reveal the underlying mechanisms. DISCUSSION: The results of this trial will provide compelling evidence of the efficacy and safety of HEC for treatment of mild active UC and preliminarily show the potential mechanism of how HEC acts. Finally, it will widen treatment options for patients with mild active UC.

Epigastric pain syndrome: What can traditional Chinese medicine do? A randomized controlled trial of Biling Weitong Granules.

BACKGROUND: Recent research suggests that although prokinetic agents, acid suppressors, and radical treatment for Helicobacter pylori infection may be effective in patients with functional dyspepsia (FD), a large proportion of patients still fail to respond to these treatments or may suffer from severe adverse reactions. Many traditional Chinese medicinal herbs can regulate the status of the entire body and have special advantages in the treatment of functional diseases. The present study was designed to verify the efficacy of Biling Weitong Granules (BLWTG), a traditional Chinese medicinal herbal compound formula, in alleviating epigastric pain syndrome (EPS) in FD patients, in an attempt to provide an effective prescription for the clinical treatment of this disease. AIM: To evaluate the clinical efficacy and safety of BLWTG in treating EPS in patients with FD. METHODS: In this multicenter, stratified, randomized, double-blind, placebo-controlled, parallel group clinical trial, eligible patients were randomized into the BLWTG and placebo groups who were treated for 6 wk. Efficacy indicators including the severity and frequency of EPS and the time to pain resolution and safety indicators including adverse events were observed and compared. RESULTS: The baseline demographic data and clinical characteristics, such as epigastric pain symptoms, pain intensity, and frequency of attacks, were matched between the two groups before randomization. After 6 wk of treatment and after the center effect was eliminated, the epigastric pain was significantly improved in 28.33% and 85.59% of the patients in the placebo and BLWTG groups, respectively (P < 0.05). At 6 wk, the resolution rate of epigastric pain was 15% and 69.49% in the placebo and BLWTG groups, respectively (P < 0.05). The differences of total FD clinical score between these two groups were significant (P < 0.05) at 2, 4, and 6 wk (P < 0.05). The scores of each item and the total score in the Functional Digestive Disorders Quality of Life Questionnaire showed significant differences between the two groups at 6 wk after both the center and interaction effects were eliminated (P < 0.05). There was no significant difference in the incidence of adverse events between the two groups, and no serious adverse event was noted during the observation. CONCLUSION: Compared with placebo, BLWTG markedly improved EPS in FD patients without causing serious adverse reactions.

Indigo Naturalis Alleviates Dextran Sulfate Sodium-Induced Colitis in Rats via Altering Gut Microbiota.

Ulcerative colitis is a gastrointestinal disorder intricately associated with intestinal dysbiosis, but effective treatments are currently limited. Indigo naturalis, a traditional Chinese medicine derived from indigo plants, has been widely used in the treatment of ulcerative colitis. However, the specific mechanisms have not yet been identified. Accordingly, in this study, we evaluated the effects and mechanisms of indigo naturalis on dextran sulfate sodium (DSS)-induced colitis in rats. Our results showed that indigo naturalis potently alleviated DSS-induced colitis in rats, and reversed DSS-induced intestinal dysbiosis using bacterial 16S rRNA amplicon sequencing. The protective effects of indigo naturalis were gut microbiota dependent, as demonstrated by antibiotic treatments and fecal microbiota transplantation. Depletion of the gut microbiota through a combination of antibiotic treatments blocked the anti-inflammatory effect of indigo naturalis on the DSS-induced colitis, and the recipients of the gut microbiota from indigo naturalis-treated rats displayed a significantly attenuated intestinal inflammation, which was actively responsive to therapeutic interventions with indigo naturalis. Notably, supplement with indigo naturalis greatly increased the levels of feces butyrate, which was positively correlated with the relative abundances of Ruminococcus_1 and Butyricicoccus. We further showed that indigo naturalis-dependent attenuation of colitis was associated with elevated expression of short-chain fatty acid-associated receptors GPR41 and GPR43. Collectively, these results suggested that indigo naturalis alleviates DSS-induced colitis in rats through a mechanism of the microbiota-butyrate axis, particularly alterations in Ruminococcus_1 and Butyricicoccus abundances, and target-specific microbial species may have unique therapeutic promise for ulcerative colitis.