Potential efficacy and mechanism of eight mild-natured and bitter-flavored TCMs based on gut microbiota: A review.

The mild-natured and bitter-flavored traditional Chinese medicines (MB-TCMs) are an important class of TCMs that have been widely used in clinical practice and recognized as safe long-term treatments for chronic diseases. However, as an important class of TCMs, the panorama of pharmacological effects and the mechanisms of MB-TCMs have not been systemically reviewed. Compelling studies have shown that gut microbiota can mediate the therapeutic activity of TCMs and help to elucidate the core principles of TCM medicinal theory. In this systematic review, we found that MB-TCMs commonly participated in the modulation of metabolic syndrome, intestinal inflammation, nervous system disease and cardiovascular system disease in association with promoting the growth of beneficial bacteria Bacteroides, Akkermansia, Lactobacillus, Bifidobacterium, Roseburia as well as inhibiting the proliferation of harmful bacteria Helicobacter, Enterococcus, Desulfovibrio and Escherichia-Shigella. These alterations, correspondingly, enhance the generation of protective metabolites, mainly including short-chain fatty acids (SCFAs), bile acid (BAs), 5-hydroxytryptamine (5-HT), indole and gamma-aminobutyric acid (GABA), and inhibit the generation of harmful metabolites, such as proinflammatory factors trimethylamine oxide (TAMO) and lipopolysaccharide (LPS), to further exert multiplicative effects for the maintenance of human health through several different signaling pathways. Altogether, this present review has attempted to comprehensively summarize the relationship between MB-TCMs and gut microbiota by establishing the TCMs-gut microbiota-metabolite-signaling pathway-diseases axis, which may provide new insight into the study of TCM medicinal theories and their clinical applications.

Comparative efficacy of Chinese patent medicines in patients with carotid atherosclerotic plaque: a Bayesian network meta- analysis.

BACKGROUND: Traditional Chinese patent medicines (TCPMs) have been widely used to treat carotid atherosclerotic plaque (CAP) in China. However, systematic evaluation of the clinical efficacy of TCPMs for CAP is still unknown, and the comparative efficacy of different TCPMs is unclear. OBJECTIVES: This study aims to compare and rank the effectiveness and safety of different TCPMs in treating CAP using a Bayesian network meta- analysis (NMA). METHODS: This NMA was performed according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) Extension Statement. Eight databases were searched from their inception to August 2023 for randomized controlled trials (RCTs). The articles regarding eligibility and extracted data were screened independently by two authors. The Cochrane Risk of Bias tool was used to evaluate quality and bias. The change of carotid artery intimal- medial thickness (IMT), carotid maximal plaque area, carotid atherosclerotic plaque Course score, serum lipid levels, CRP, and adverse events rate (AER) were used as outcomes. Data from each RCTs were first pooled using random- effect pairwise meta- analyses and illustrated as odds ratios (ORs) or standardized mean differences (SMDs) with 95% confidence interval (CI). NMAs were performed using Stata17.0 software and the GeMTC package of R software to evaluate the comparative effectiveness of TCPMs, and displayed as ORs or SMDs with 95% CI. A Bayesian hierarchical random- effects model was used to conduct NMAs using the Markov Chain Monte Carlo algorithm. The GRADE partially contextualised framework was applied for NMA result interpretation. RESULTS: NMA included 27 RCT trials with 4131 patients and nine types of TCPMs. Pairwise meta- analyses indicated that Conventional Western medicine (CWM) + TCPM was superior to CWM in reducing the IMT (SMD: - 1.26; 95% CI - 1.59 to - 0.93), the carotid maximal plaque area (SMD - 1.27; 95% CI - 1.71, - 0.82) and the carotid atherosclerotic plaque Course score (SMD - 0.72; 95% CI 95% CI - 1.20, - 0.25). NMAs demonstrated that CWM + Jiangzhiling pill (JZL) with SUCRA 70.6% exhibited the highest effective intervention for reducing IMT. CWM + SXBX (Shexiang baoxin pill) was superior to other TCPMs in reducing the carotid maximal plaque area (83.0%), the atherosclerotic plaque Course score (92.5%), TC (95.6%) and LDL (92.6%) levels. CWM + NXT (Naoxintong capsule), CWM + XS (Xiaoshuang granules/enteric capsule), and CWM + ZBT (Zhibitai) were superior to other CPMs in improving TG (90.1%), HDL (86.1%), and CRP (92.6%), respectively. No serious adverse events were reported. CONCLUSIONS: For CAP patients, CWM + XSBX was among the most effective in reducing carotid maximal plaque area, atherosclerotic plaque Course score, TC and LDL levels, and CWM + JZL was the most effective in reducing IMT. Overall, CWM + XSBX may be considered an effective intervention for the treatment of CAP. This study provides reference and evidence for the clinical optimization of TCPM selection in CAP treatment. More adequately powered, well- designed clinical trials to increase the quality of the available evidence are still needed in the future due to several limitations.

Traditional Chinese Medicine for the Common Cold: Evidence and Potential Mechanisms.

Traditional Chinese medicine (TCM) has a history of over 2000 years in treating infectious diseases, among which the clinical treatment of the common cold (colds) and influenza (flu) is the most widespread and well-established. It is difficult to tell the difference between a cold and the flu based on the symptoms alone. The flu vaccine protects against influenza, but there is no vaccine or specific medication to protect against the common cold. Due to the lack of a reliable scientific basis, TCM has not received sufficient attention in Western medicine. Therefore, we systematically evaluated the scientific evidence proving the efficacy of TCM intervention in treating colds for the first time by examining theoretical principles, clinical research, and pharmacological perspectives, as well as the mechanisms behind this efficacy. In TCM theory, there are four important external environmental factors that may cause a cold, which are called "cold, heat, dryness, and dampness". The scientific basis for this theory has been described and will help researchers to understand and recognize its importance. The results of the systematic review of high-quality randomized controlled clinical trials (RCTs) have shown that TCM is effective and safe for the treatment of colds. Therefore, TCM might be used as a complementary or alternative approach to cold treatment and management. Some clinical trials have demonstrated that TCM may have potential therapeutic effects in preventing colds and treating their sequelae. However, more high-quality, large-scale randomized controlled trials should be conducted in the future for further verification. Pharmacological studies have shown that active ingredients extracted from TCM for treating colds have antiviral, anti-inflammatory, immune-regulating, and anti-oxidative properties. We expect that this review will guide the optimization and rationalization of TCM clinical practice and scientific research in the treatment of colds.

Traditional Chinese medicines (TCMs) with varied meridians (Gui-Jing) differentially alleviate the adverse impact of Coptis chinensis on gut microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: The meridian (GuiJing) theory is a unique theory of traditional Chinese medicine (TCM) which has been guiding the clinical practice of TCM for thousands of years, but physiological foundation of TCM's meridian remains to be clarified. Recent investigations have marked gut microbiota as a key mediator for the pharmacological effects of various TCMs. However, most studies focus on the response of gut microbes to a single drug or formula, the interactive effects of different drugs on gut microbiota are scarcely investigated. AIM OF THE STUDY: In this work, we evaluated the co-regulatory effects of different TCMs on gut microbiota when they were individually combined with Coptis chinensis (HL), and assessed the relationship between gut microbiota and the GuiJing of TCMs. MATERIALS AND METHODS: Normal C57BL/6 mice were gavaged with HL extract for 14 days to disrupt the gut microbial community. Simultaneously, animals were treated with different TCMs which all possess antimicrobial activity but belong to different meridians. The gut microbiota was analyzed by full-length 16S rRNA gene amplicon sequencing to get a thorough bacterial profile at the species level. RESULTS: Administration of HL dramatically disrupted the gut microbiota and decreased the alpha diversity. Co-administration of different TCMs alleviated the adverse impact of HL on gut microbiota in a meridian-dependent manner. TCMs belonging to Shaoyin meridian moderately shifted the gut microbiota, while TCMs belonging to Taiyin and especially Jueyin meridians remarkably recovered the gut microbial community to the normal status. Decreased Firmicutes (Clostridia and Bacilli) and Actinobacteria (Bifidobacteriales) and increased Proteobacteria (Enterobacteriaceae) were main features of HL-induced gut dysbiosis. TCMs belonging to Shaoyin, Taiyin and Jueyin meridians gradually reversed the abundance of these bacteria to their normal levels. Simultaneously, the promoting effect of HL on beneficial bacteria such as Akkermansia muciniphila and Blautia coccoides was substantially preserved when co-administration of these TCMs, suggesting that co-treatment with these TCMs may reduce the toxicity of HL without deteriorating its beneficial effects. CONCLUSION: Combination of special TCMs may alleviate the adverse effect of HL on gut microbiota while preserving its beneficial actions. Gut microbiota may be a potential biological indicator of the meridian of TCMs.

Standards for Collection, Preservation, and Transportation of Fecal Samples in TCM Clinical Trials.

Background: Unlike chemical drugs with a single or a few kinds of active compounds, traditional Chinese medicines (TCMs)uses herbal formulas composed of numerous kinds of chemical constituents. Therefore, TCM clinical trials require unique and stricter standards for collecting, preserving, and transporting fecal samples than those used for chemical drugs. Unfortunately, there are no special standards for processing fecal samples in TCM clinical trials. Methods: We invited interdisciplinary experts within TCM clinical trials and gut microbiome research to help formulate this standard. After more than a year's in-depth discussion and amendments, we achieved a standard via expert interviews, literature research, questionnaire surveys, and public opinion solicitation. This standard has been reviewed and approved by the Standards Office of China of the Association of Chinese medicine. Results: We established a sample information processing method prior to TCM clinical sample collection, which is adapted to the unique features of TCM. The method formulates detailed processing requirements for TCM information in addition to the factors that may disturb the gut microbiome. We also constructed a set of methods for collecting, preserving, and transporting fecal samples that meet the characteristics of TCM. These methods formulate detailed operating specifications on the collection approaches, storage conditions, transportation requirements, and management of fecal samples. Conclusions: This standard guides the information processing prior to sample collection and the standard operating procedures for the collection, preservation, and transportation of fecal samples in TCM clinical trials, which also can be used as a reference by clinicians and researchers in modern medicines.

Gut microbiota specifically mediates the anti-hypercholesterolemic effect of berberine (BBR) and facilitates to predict BBR's cholesterol-decreasing efficacy in patients.

Introduction: Gut microbiota has been implicated in the pharmacological activities of many natural products. As an effective hypolipidemic agent, berberine (BBR)'s clinical application is greatly impeded by the obvious inter-individual response variation. To date, little evidence exists on the causality between gut microbes and its therapeutic effects, and the linkage of bacteria alterations to the inter-individual response variation. Objectives: This study aims to confirm the causal role of the gut microbiota in BBR's anti-hyperlipidemic effect and identify key bacteria that can predict its effectiveness. Methods: The correlation between gut microbiota and BBR's inter-individual response variation was studied in hyperlipidemic patients. The causal role of gut microbes in BBR's anti-hyperlipidemic effects was subsequently assessed by altered administration routes, co-treatment with antibiotics, fecal microbiota transplantation, and metagenomic analysis. Results: Three-month clinical study showed that BBR was effectively to decrease serum lipids but displayed an obvious response variation. The cholesterol-lowering but not triglyceride-decreasing effect of BBR was closely related to its modulation on gut microbiota. Interestingly, the baseline levels of Alistipes and Blautia could accurately predict its anti-hypercholesterolemic efficiency in the following treatment. Causality experiments in mice further confirmed that the gut microbiome is both necessary and sufficient to mediate the lipid-lowering effect of BBR. The absence of Blautia substantially abolished BBR's cholesterol-decreasing efficacy. Conclusion: The gut microbiota is necessary and sufficient for BBR's hyperlipidemia-ameliorating effect. The baseline composition of gut microbes can be an effective predictor for its pharmacotherapeutic efficacy, providing a novel way to achieve personalized therapy.

The effect of cold exposure on serum cholesterol is dependent upon ApoE.

BACKGROUND: Several lines of evidence indicate that cold stimulation may not only activate brown adipose tissue (BAT) and the white adipose tissue (WAT), but also regulate the lipid metabolism and influence the development of atherosclerosis. However, the study of cold exposure affecting cholesterol metabolism have opposite results in different experiments, and Apolipoprotein E (ApoE) may play an important role. There is still a lack of complete research to illustrate this problem. METHODS: In this study, we first analyzed and discussed the activation of interscapular brown adipose tissue (iBAT), inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) under cold exposure (4 °C) in male wild-type C57BL/6 J (WT) and ApoE-deficient mice (ApoE-/-) fed high-fat diet (HFD) for 4 weeks. Subsequently, we investigated the effect of cold exposure on blood lipid profiles in both models. We further explored whether cold exposure can reduce serum cholesterol. RESULTS: In both WT and ApoE-/- mice, cold exposure activates iBAT and iWAT, as well as hardly affects eWAT. In WT mice,4 weeks cold exposure (4 °C) reduces serum triglyceride by 28%, cholesterol by 30% and LDL-cholesterol by 63%. In ApoE-/- mice, cold stimulation decreases serum triglyceride by 59%, but increases cholesterol by 20% and LDL-cholesterol by 25%. CONCLUSIONS: Based on these findings, we conclude that cold exposure decreases serum cholesterol is dependent upon the existence of ApoE.

The Importance of Glycans of Viral and Host Proteins in Enveloped Virus Infection.

Animal viruses are parasites of animal cells that have characteristics such as heredity and replication. Viruses can be divided into non-enveloped and enveloped viruses if a lipid bilayer membrane surrounds them or not. All the membrane proteins of enveloped viruses that function in attachment to target cells or membrane fusion are modified by glycosylation. Glycosylation is one of the most common post-translational modifications of proteins and plays an important role in many biological behaviors, such as protein folding and stabilization, virus attachment to target cell receptors and inhibition of antibody neutralization. Glycans of the host receptors can also regulate the attachment of the viruses and then influence the virus entry. With the development of glycosylation research technology, the research and development of novel virus vaccines and antiviral drugs based on glycan have received increasing attention. Here, we review the effects of host glycans and viral proteins on biological behaviors of viruses, and the opportunities for prevention and treatment of viral infectious diseases.

Berberine, a potential prebiotic to indirectly promote Akkermansia growth through stimulating gut mucin secretion.

BACKGROUND: Akkermansia spp. plays important roles in maintenance of host health. Increasing evidence reveals that berberine (BBR) may exert its pharmacological effects via, at least partially, promotion of Akkermansia spp. However, how BBR stimulates Akkermansia remains largely unknown. PURPOSE: In this study, we investigated the mechanism underlying the Akkermansia-promoting effect of BBR. MATERIALS AND METHODS: The effect of BBR on Akkermansia was assessed in BBR-gavaged mice and direct incubation. The influence of BBR on intestinal mucin production was determined by alcian-blue staining and real-time PCR. The feces were analysis by gas chromatography-time-of-flight mass spectrometry (GC-TOF/MS) metabolomics. The role of polyamines in BBR-elicited mucin secretion and Akkermansia growth was evaluated by administration of difluoromethylornithine (DFMO) in mice. RESULTS: Gavage of BBR dose-dependently and time-dependently increased the abundance of Akkermansia in mice. However, it did not stimulate Akkermansia growth in direct incubation, suggesting that BBR may promote Akkermansia in a host-dependent way. Oral administration of BBR significantly increased the transcription of mucin-producing genes and mucin secretion in colon. Untargeted metabolomics analysis showed that BBR increased polyamines production in feces which are known to stimulate goblet cell proliferation and differentiation, but treatment with eukaryotic polyamine synthase inhibitor DFMO did not abolish the stimulating effect of BBR on mucin secretion and Akkermansia growth, indicating that the gut bacteria-derived but not the host-derived polyamines may involve in the BBR-promoted Akkermansia growth. CONCLUSIONS: Our results reveal that BBR is a promising prebiotic for Akkermansia, and it promotes Akkermansia growth via stimulating mucin secretion in colon.