Therapeutic Effects of Valeriana jatamansi on Ulcerative Colitis: Insights into Mechanisms of Action through Metabolomics and Microbiome Analysis.

Ulcerative colitis (UC), belonging to inflammatory bowel disease (IBD), is a chronic and relapsing inflammatory disorder of the gastrointestinal tract, which has not been completely cured in patients so far. Valeriana jatamansi is a Chinese medicine used clinically to treat "diarrhea," which is closely related to UC. This study was to elucidate the therapeutic effects of V. jatamansi extract (VJE) on dextran sodium sulfate (DSS)-induced UC in mice and its underlying mechanism. In this work, VJE effectively ameliorates the symptoms and histopathological scores and reduces the production of inflammatory factors in UC mice. The colon untargeted metabolomics analysis and 16S rDNA sequencing showed remarkable differences in colon metabolite profiles and intestinal microbiome composition between the control and DSS groups, and VJE intervention can reduce these differences. Thirty-two biomarkers were found and modulated the primary pathways including pyrimidine metabolism, arginine biosynthesis, and glutathione metabolism. Meanwhile, twelve significant taxa of gut microbiota were found. Moreover, there is a close relationship between endogenous metabolites and intestinal flora. These findings suggested that VJE ameliorates UC by inhibiting inflammatory factors, recovering intestinal maladjustment, and regulating the interaction between intestinal microbiota and host metabolites. Therefore, the intervention of V. jatamansi is a potential therapeutic treatment for UC.

Gut microbiota, bile acids, and nature compounds.

Natural compounds (NPs) have historically made a major contribution to pharmacotherapy in various diseases and drug discovery. In the past decades, studies on gut microbiota have shown that the efficacy of NPs can be affected by the interactions between gut microbiota and NPs. On one hand, gut microbiota can metabolize NPs. On the other hand, NPs can influence the metabolism and composition of gut microbiota. Among gut microbiota metabolites, bile acids (BAs) have attracted widespread attention due to their effects on the body homeostasis and the development of diseases. Studies have also confirmed that NPs can regulate the metabolism of BAs and ultimately regulate the physiological function of the body and disease progresses. In this review, we comprehensively summarize the interactions among NPs, gut microbiota, and BAs. In addition, we also discuss the role of microbial BAs metabolism in understanding the toxicity and efficacy of NPs. Furthermore, we present personal insights into the future research directions of NPs and BAs.

Correction: Cui, H., et al. BA-12 Inhibits Angiogenesis via Glutathione Metabolism Activation. Int. J. Mol. Sci. 2019, 20, 4062.

The authors wish to make the following corrections to this paper [...].

Gut microbiota, a new frontier to understand traditional Chinese medicines.

As an important component of complementary and alternative medicines, traditional Chinese medicines (TCM) are gaining more and more attentions around the world because of the powerful therapeutic effects and less side effects. However, there are still some doubts about TCM because of the questionable TCM theories and unclear biological active compounds. In recent years, gut microbiota has emerged as an important frontier to understand the development and progress of diseases. Together with this trend, an increasing number of studies have indicated that drug molecules can interact with gut microbiota after oral administration. In this context, more and more studies pertaining to TCM have paid attention to gut microbiota and have yield rich information for understanding TCM. After oral administration, TCM can interact with gut microbiota: (1) TCM can modulate the composition of gut microbiota; (2) TCM can modulate the metabolism of gut microbiota; (3) gut microbiota can transform TCM compounds. During the interactions, two types of metabolites can be produced: gut microbiota metabolites (of food and host origin) and gut microbiota transformed TCM compounds. In this review, we summarized the interactions between TCM and gut microbiota, and the pharmacological effects and features of metabolites produced during interactions between TCM and gut microbiota. Then, focusing on gut microbiota and metabolites, we summarized the aspects in which gut microbiota has facilitated our understanding of TCM. At the end of this review, the outlooks for further research of TCM and gut microbiota were also discussed.

Natural medicines for the treatment of fatigue: Bioactive components, pharmacology, and mechanisms.

It is a common phenomenon that people are in a sub-health condition and facing "unexplained fatigue", which seriously affects their health, work efficiency and quality of life. Meanwhile, fatigue is also a common symptom of many serious diseases such as HIV/AIDS, cancer, and schizophrenia. However, there are still no official recommendations for the treatment of various forms of fatigue. Some traditional natural medicines are often used as health care products, such as ginseng, Cordyceps militaris (L.ex Fr.Link) and Rhodiola rosea L., and these have been reported to have specific anti-fatigue effects with small toxic and side effects and rich pharmacological activities. It may be promising treatment strategy for sub-health. In this review, we first outline the generation of fatigue. Furthermore, we put emphasis on the anti-fatigue mechanism, bioactive components, and clinic trials of natural medicines, which will contribute to the development of potential anti-fatigue agents and open up novel treatments for sub-health.

Gut microbial modulation in the treatment of chemotherapy-induced diarrhea with Shenzhu Capsule.

BACKGROUND: Gut microbiota plays a crucial role in the treatment of gastrointestinal (GI) diseases such as chemotherapy-induced diarrhea (CID). Shenzhu Capsule (SZC) is a Chinese herbal formula, which is composed of Renshen (rhizomes of Panax ginseng C. A. Mey.) and Baizhu (rhizomes of Atractylodes macrocephala Koidz.). Many Chinese traditional anti-diarrheal formulae that contain Renshen and Baizhu are capable of effectively alleviating CID. However, the efficacy in vivo and potential mechanism of SZC (the form of compatibility of Renshen and Baizhu) in the treatment of CID had not been elucidated. Here, this study aimed to investigate whether SZC exhibited the anti-diarrheal activity, and whether gut microbiota was involved in the therapeutic effect of SZC on CID. METHODS: High performance liquid chromatography (HPLC), gas chromatography-mass spectrometer (GC-MS) and infrared spectroscopy (IR) analyses were used to characterize the extracted components in SZC. The mice were orally administrated with SZC in a preventive mode on the first 2 days of this experiment, and then intraperitoneally injected with 5-FU (40 mg/kg/d) for 6 days. SZC treatment lasted until the 3rd day after the end of 5-FU chemotherapy. We investigated the effects of SZC on body weights, diarrhea, thymus/spleen indexes, colonic tissues, and gut microbiota. Colonic histology was examined by hematoxylin-eosin (HE) staining. 16S rDNA Amplicon Sequencing was used to analyze the gut microbial structure from fecal samples. RESULTS: SZC significantly increased the body weights and thymus/spleen indexes, alleviated diarrhea, and reversed histopathological changes of colons. In addition, gut microbiota analysis revealed that the overall structure of gut microbiota in CID mice was disturbed, but reversed to the normal state after SZC treatment. At genus level, SZC significantly inhibited the growth of some potential pathogens associated with diarrhea, such as Clostridiumm, Bacteroides, Parabacteroides, Alloprevotella, Acinetobacter and Pseudomonas. CONCLUSIONS: In our study, these data illustrated that SZC inhibited the growth of many potential pathogens during the alleviation of CID. Gut microbial modulation was associated with the anti-diarrheal activity of SZC.

BA-12 Inhibits Angiogenesis via Glutathione Metabolism Activation.

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional Prunella vulgaris plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and Caenorhabditis elegans. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.

Oral hydroxysafflor yellow A reduces obesity in mice by modulating the gut microbiota and serum metabolism.

Given the high and increasing prevalence of obesity, the safe and effective treatment of obesity would be beneficial. Here, we examined whether oral hydroxysafflor yellow A (HSYA), an active compound from the dried florets of Carthamus tinctorius L., can reduce high-fat (HF) diet-induced obesity in C57BL/6 J mice. Our results showed that the average body weight of HF group treated by HSYA was significantly lower than that of the HF group (P < 0.01). HSYA also reduced fat accumulation, ameliorated insulin resistance, restored glucose homeostasis, reduced inflammation, enhanced intestinal integrity, and increased short-chain fatty acids (SCFAs) production in HF diet-fed mice. Sequencing of 16S rRNA genes in fecal samples demonstrated that HSYA reversed HF diet induced gut microbiota dysbiosis. Particularly, HSYA increased the relative abundances of genera Akkermansia and Romboutsia, as well as SCFAs-producing bacteria, including genera Butyricimonas and Alloprevotella, whereas it decreased the phyla Firmicutes/Bacteroidetes ratio of HF diet-fed mice. Additionally, serum metabolomics analysis revealed that HSYA increased lysophosphatidylcholines (lysoPCs), L-carnitine and sphingomyelin, and decreased phosphatidylcholines in mice fed a HF diet, as compared to HF group. These changed metabolites were mainly linked with the pathways of glycerophospholipid metabolism and sphingolipid metabolism. Spearman's correlation analysis further revealed that Firmicutes was positively while Bacteroidetes and Akkermansia were negatively correlated with body weight, fasting serum glucose and insulin. Moreover, Akkermansia and Butyricimonas had positive correlations with lysoPCs, suggestive of the role of gut microbiota in serum metabolites. Our findings suggest HSYA may be a potential therapeutic drug for obesity and the gut microbiota may be potential territory for targeting of HSYA.

[Influence of metal ions on stability of 2,3,5,4'-tetrahydroxy stilbene-2-O-ß-D-glucoside contained in Polygoni Multiflori Radix].

Decoction is one of the most commonly used dosage forms of traditional Chinese medicine. The stability of chemical constituents in decoction is closely related to the clinical efficacy and safety. There were few reports about the influence of metal ions in the stability of chemical constituents in traditional Chinese medicine. However, there is no evidence that metal ions in decoction water need to be controlled. In this study, 2,3,5,4'-tetrahydroxy stilbene-2-O-ß-D-glucoside (THSG), one of the main constituents in Polygoni Multiflori Radix was studied. Ordinary tap water, deionized water, and water containing different metal ions were used to investigate and compare the influence on THSG. The results showed that after storage in a dark place at the room temperature for 10 days, the degradation of THSG was 7% in deionized water, while undetectable in tap water. The content of THSG could be decreased by different kinds of metal ions, and the effect was concentration-dependent. Moreover, Fe3+ and Fe2+ showed the greatest influence at the same concentration; and our study has shown that THSG decreased more than 98% in Fe and Fe2+ solutions at 500 ppm concentration. In the same time we found out p-hydroxybenzaldehyde (molecular weight: 122.036 7) and 2,3,5-trihydroxybenzaldehyde-2-O-glycoside (molecular weight: 316.079 4) were the main degradation products of THSG in tap water and water containing Cu2+, Ca2+, Zn2+, Mg2+ and Al3+. The product of THSG dimer with a water molecule was found in water containing Fe3+ and Fe2+. The above results showed that the metal ions in water could significantly influence the stability of THSG in water, indicating that the clinical efficacy and safety of decoction would be affected if the metal ions in water were not under control. It's suggested that deionized water should be used in the preparation of decoction containing Polygoni Multiflori Radix in the clinic to avoid degradation of THSG. Meanwhile, decoction prepared by tap water should be taken by patients in a short time. Our investigation provides important information and reference about the influence of metal ions on the stability of decoctions in other traditional Chinese medicine that have unstable groups such as hydroxyls and unsaturated bonds, etc.

[Influence of specification on chemical composition of dissolution and hepatocytes toxicity of Polygonum multiflorum].

According to different toxicities of various aqueous extracts of Polygonum multiflorum on hepatocyte, the impacts of chemical composition on the safety of P. multiforum was studied. In this study, 8 main chemical compositions in aqueous extracts of P. multiflorum were determined by the established HPLC method; at the same time, the inhibition ratios of different aqueous extracts of P. multiflorum on L02 cell were determined. Afterwards, the potential compounds related to the toxicity of P. multiforum were tentatively found through a multiple correlation analysis. The results showed that P. multiforum with different chemical compositions exhibited great differences in dissolution. The hepatocyte toxicity of P. multiflorum powder was much greater than P. multiflorum lumps. In addition, three constituents closely related to toxicity of P. multiflorum were found by multiple correlation analysis. The study revealed that chemical composition of P. multiflorum is closely related to the hepatotoxicity, and the hepatotoxicity of P. multiflorum powder is greater than that of other dosage forms. This study indicates that P. multiflorum with different chemical compositions show varying toxicity, which therefore shall be given high attention.

[Uniformity of Coptidis Rhizoma decoction pieces dispensing based on effective constituent equivalence].

Traditional Chinese medicine (TCM) dispensing is the final step of TCM used for clinical treatment, the stability of TCM dispensing is the guarantee of good clinical effect. Establishment of effect-constituent equivalence for Chinese herbal pieces based on clinical efficacy, can not only guarantee the stability of TCM dispensing, but also relate to the precision of clinical effect. This study chose Coptidis Rhizoma as the model, established effect-constituent equivalence of Coptidis Rhizoma, based on the effect-constituent index already established by our research group, and taking into consideration of homogeneity of clinical dosage and compliance of decoction, the uniformity of dispensing for different specification of Coptidis Rhizoma decoction pieces was studied. This research model was then applied to guide the specification-optimization of Coptidis Rhizoma and its clinical dispensing. The result indicated, effective constituent equivalence could reflect the fluctuation of specification, dosage and decoction to the fluctuation of efficacy; Optimized Coptidis Rhizoma decoction pieces had the characteristic of high homogeneity as for clinical dispensing, good compliance as for decoction, and high effective constituent equivalence. In conclusion, effective constituent equivalence could improve relevance of methods of TCM dispensing control to clinical effect. Preparated Superior-standard Decoction Pieces based on effective constituent equivalence was featured by good quality and a good practice of adjustable dosage, which could promote the development of TCM decoction pieces toward precision medicine.

Quality fluctuation detection of an herbal injection based on biological fingerprint combined with chemical fingerprint.

Herbal injection is one of the most important preparations of traditional Chinese medicine. More than 130 types of herbal injections are used clinically for 400 million patients annually with total sales of over four billion US dollars per year. However, the current quality control (QC) methods relying mainly on chemical fingerprints (CF) can hardly ensure quality and safety of the herbal injections with complex chemical composition and have resulted in an increase in serious adverse drug reactions. In this study, a comprehensive approach for the QC of a controversial herbal injection Shuang-Huang-Lian lyophilized powder (SHL) was established based on the quality fluctuation detection by a combination of CF and biological fingerprint (BF). High-performance liquid chromatography and the impedance-based xCELLigence system were applied to establish the CF and BF, respectively. In addition, multivariate analysis was performed to evaluate the discriminant ability of the two methods. The results showed that being subjected to environmental influence like oxygen/air, high temperature, and extreme illumination could lead to quality fluctuation of SHL. The combination of chemical and biological fingerprint method is a more powerful tool for the QC of SHL because it can clearly discriminate different groups of abnormal samples. This method can be used for the detection of quality fluctuation of SHL and can provide reference for the quality control of other herbal injections.

Repairing gut barrier by traditional Chinese medicine: roles of gut microbiota.

Gut barrier is not only part of the digestive organ but also an important immunological organ for the hosts. The disruption of gut barrier can lead to various diseases such as obesity and colitis. In recent years, traditional Chinese medicine (TCM) has gained much attention for its rich clinical experiences enriched in thousands of years. After orally taken, TCM can interplay with gut microbiota. On one hand, TCM can modulate the composition and function of gut microbiota. On the other hand, gut microbiota can transform TCM compounds. The gut microbiota metabolites produced during the actions of these interplays exert noticeable pharmacological effects on the host especially gut barrier. Recently, a large number of studies have investigated the repairing and fortifying effects of TCM on gut barriers from the perspective of gut microbiota and its metabolites. However, no review has summarized the mechanism behand this beneficiary effects of TCM. In this review, we first briefly introduce the unique structure and specific function of gut barrier. Then, we summarize the interactions and relationship amidst gut microbiota, gut microbiota metabolites and TCM. Further, we summarize the regulative effects and mechanisms of TCM on gut barrier including physical barrier, chemical barrier, immunological barrier, and microbial barrier. At last, we discuss the effects of TCM on diseases that are associated gut barrier destruction such as ulcerative colitis and type 2 diabetes. Our review can provide insights into TCM, gut barrier and gut microbiota.

Fuzi lizhong pills alter microbial community compositions and metabolite profiles in ulcerative colitis rat with spleen-kidney yang deficiency syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic inflammatory bowel condition that is frequently related with Spleen-Kidney Yang Deficiency Syndrome (SKYD) in Chinese medicine. Fuzi Lizhong Pill (FLZP), a traditional medicine for SKYD, has been utilized in China for generations, although the exact mechanism by which it treats UC is unknown. AIM OF THE STUDY: The goal of this study is to further understand FLZP's therapeutic mechanism in SKYD-associated UC. MATERIALS AND METHODS: To investigate the impact of FLZP on SKYD-associated UC, we used a comprehensive method that included serum metabolomics and gut microbiota profiling. The chemical composition of FLZP was determined using mass spectrometry. UC rats with SKYD were induced and treated with FLZP. Serum metabolomics and 16S rRNA microbial community analysis were used to evaluate FLZP's effects on endogenous metabolites and gut microbiota, respectively. Correlation analysis investigated the association between metabolites and intestinal flora. A metabolic pathway analysis was undertaken to discover putative FLZP action mechanisms. RESULTS: FLZP contains 109 components, including liquiritin (584.8176 µg/g), benzoylaconine (16.3087 µg/g), benzoylhypaconine (31.9583), and hypaconitine (8.1160 µg/g). FLZP predominantly regulated seven metabolites and eight metabolic pathways involved in amino acid and nucleotide metabolism, with an emphasis on energy metabolism and gastrointestinal digestion. FLZP also influenced intestinal flora variety, increasing probiotic abundance while decreasing pathogenic bacteria prevalence. An integrated investigation identified associations between changes in certain gut flora and energy metabolism, specifically the tricarboxylic acid (TCA) cycle. CONCLUSIONS: FLZP successfully cures UC in SKYD rats by regulating amino acid and energy metabolism. Its positive effects may include altering microbiota composition and metabolite profiles in UC rats with SKYD. These findings shed light on FLZP's mode of action and its implications for UC management.

Atractylodes macrocephala Koidz. volatile oil relieves acute ulcerative colitis via regulating gut microbiota and gut microbiota metabolism.

Background: Atractylodes macrocephala Koidz. (AM) is a functional food with strong ant-colitis activity. AM volatile oil (AVO) is the main active ingredient of AM. However, no study has investigated the improvement effect of AVO on ulcerative colitis (UC) and the bioactivity mechanism also remains unknown. Here, we investigated whether AVO has ameliorative activity on acute colitis mice and its mechanism from the perspective of gut microbiota. Methods: Acute UC was induced in C57BL/6 mice by dextran sulfate sodium and treated with the AVO. Body weight, colon length, colon tissue pathology, and so on were assessed. The gut microbiota composition was profiled using 16s rRNA sequencing and global metabolomic profiling of the feces was performed. The results showed that AVO can alleviate bloody diarrhea, colon damage, and colon inflammation in colitis mice. In addition, AVO decreased potentially harmful bacteria (Turicibacter, Parasutterella, and Erysipelatoclostridium) and enriched potentially beneficial bacteria (Enterorhabdus, Parvibacter, and Akkermansia). Metabolomics disclosed that AVO altered gut microbiota metabolism by regulating 56 gut microbiota metabolites involved in 102 KEGG pathways. Among these KEGG pathways, many metabolism pathways play an important role in maintaining intestine homeostasis, such as amino acid metabolism (especially tryptophan metabolism), bile acids metabolism, and retinol metabolism. Conclusion: In conclusion, our study indicated that AVO can be expected as novel prebiotics to treat ulcerative colitis, and modulating the composition and metabolism of gut microbiota may be its pharmacological mechanism.

Interactions between gut microbiota and polyphenols: A mechanistic and metabolomic review.

BACKGROUND: Polyphenols are a class of naturally sourced compounds with widespread distribution and an extensive array of bioactivities. However, due to their complex constituents and weak absorption, a convincing explanation for their remarkable bioactivity remains elusive for a long time. In recent years, interaction with gut microbiota is hypothesized to be a reasonable explanation of the potential mechanisms for natural compounds especially polyphenols. OBJECTIVES: This review aims to present a persuasive explanation for the contradiction between the limited bioavailability and the remarkable bioactivities of polyphenols by examining their interactions with gut microbiota. METHODS: We assessed literatures published before April 10, 2023, from several databases, including Scopus, PubMed, Google Scholar, and Web of Science. The keywords used include "polyphenols", "gut microbiota", "short-chain fatty acids", "bile acids", "trimethylamine N-oxide", "lipopolysaccharides" "tryptophan", "dopamine", "intestinal barrier", "central nervous system", "lung", "anthocyanin", "proanthocyanidin", "baicalein", "caffeic acid", "curcumin", "epigallocatechin-3-gallate", "ferulic acid", "genistein", "kaempferol", "luteolin", "myricetin", "naringenin", "procyanidins", "protocatechuic acid", "pterostilbene", "quercetin", "resveratrol", etc. RESULTS: The review first demonstrates that polyphenols significantly alter gut microbiota diversity (α- and ß-diversity) and the abundance of specific microorganisms. Polyphenols either promote or inhibit microorganisms, with various factors influencing their effects, such as dosage, treatment duration, and chemical structure of polyphenols. Furthermore, the review reveals that polyphenols regulate several gut microbiota metabolites, including short-chain fatty acids, dopamine, trimethylamine N-oxide, bile acids, and lipopolysaccharides. Polyphenols affect these metabolites by altering gut microbiota composition, modifying microbial enzyme activity, and other potential mechanisms. The changed microbial metabolites induced by polyphenols subsequently trigger host responses in various ways, such as acting as intestinal acid-base homeostasis regulators and activating on specific target receptors. Additionally, polyphenols are transformed into microbial derivatives by gut microbiota and these polyphenols' microbial derivatives have many potential advantages (e.g., increased bioactivity, improved absorption). Lastly, the review shows polyphenols maintain intestinal barrier, central nervous system, and lung function homeostasis by regulating gut microbiota. CONCLUSION: The interaction between polyphenols and gut microbiota provides a credible explanation for the exceptional bioactivities of polyphenols. This review aids our understanding of the underlying mechanisms behind the bioactivity of polyphenols.

An UPLC-MS/MS method for targeted analysis of microbial and host tryptophan metabolism after administration of polysaccharides from Atractylodes macrocephala Koidz. in ulcerative colitis mice.

Botanic polysaccharides can be metabolized by gut microbiota into short-chain fatty acids (SCFAs) to exert extensive bioactivities, yet targeted analysis of the effect of botanic polysaccharides on other gut microbial metabolites is scarcely seen. Tryptophan metabolites such as indole and indole derivatives play import roles in health and disease development. Using polysaccharides from Atractylodes macrocephala Koidz. (AMP) in treating ulcerative colitis as the example, we checked the effects of AMP on tryptophan metabolites. After examination of pharmacological effects of AMP, we established an ultra-performance liquid chromatography coupled with mass spectrometry/mass spectrometry (UPLC-MS/MS) method to simultaneously determinate the levels of 30 tryptophan metabolites and used the method to determine the levels of these metabolites in feces and plasma. The detection results showed that 12 metabolites in feces can be detected, and 17 metabolites can be detected in plasma samples. In addition, we found out that total levels of aryl hydrocarbon receptor ligands were decreased in colitis model whereas AMP treatment can increase the levels of total ligands in both feces and plasma. The results indicated that the therapeutical effect of AMP on colitis was associated with modulation of fecal and host tryptophan metabolism. This study provides new insight into the molecular mechanisms of polysaccharides that the beneficial effects of polysaccharides can be achieved by modulating microbial tryptophan metabolism in addition to SCFAs.

Ameliorative effect of Aconite aqueous extract on diarrhea is associated with modulation of the gut microbiota and bile acid metabolism.

Introduction: Aconite is a form of traditional Chinese medicine (TCM) that has been widely used to treat diarrhea for thousands of years. However, it is not clear whether the anti-diarrhea role of aconite aqueous extract (AA) is associated with regulation of the gut microbiota or with bile acid (BA) metabolism. This study aimed to confirm whether AA exerts its anti-diarrhea effects by regulating the gut microbiota and BA metabolism. Methods: The therapeutic effect of AA in a mouse model of diarrhea was measured based on analysis of body weight, fecal water content, diarrhea scores, intestinal propulsion rate, colonic pathology, and colonic immunohistochemistry. In addition, 16S rRNA high-throughput sequencing was conducted to analyze the effect of AA on the gut microbiota, and targeted metabolomics was employed to analyze the effect of AA on metabolism of BAs. Results: The results showed that treatment with AA reduced fecal water content and diarrhea scores, inhibited intestinal propulsion rate and pathological changes in the colon, and increased AQP3 and AQP4 content in the colon. In addition, AA was found to be capable of regulating the gut microbiota. Effects included increasing its richness (according to the ACE and Chao1 indices); altering the gut microbiota community structure (PCA, PCoA, and NMDS); increasing the relative abundance of norank_f_Muribaculaceae, Ruminococcus, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, and norank_f_norank_o_Clostridia_UCG-014; and decreasing the relative abundance of Escherichia-Shigella, unclassified_f_Ruminococcaceae, Ruminococcus_torques_group, and Parasutterella. More importantly, AA significantly increased fecal TCA (a primary BA) and DCA, LCA, GDCA, dehydro-LCA, and 12-keto-LCA (secondary BAs), thus restoring BA homeostasis. Moreover, AA increased the ratios of DCA/CA, DCA/TCA, and LCA/CDCA and decreased the ratios of TLCA/LCA, GLCA/LCA, and TUDCA/UDCA. Conclusion: The anti-diarrhea effect of AA was associated with restoration of the gut microbiota and BA metabolism-related homeostasis. The results of this study provide insights into the application of AA and the treatment of diarrhea.

Anti-obesity and Gut Microbiota Modulation Effect of Astragalus Polysaccharides Combined with Berberine on High-Fat Diet-Fed Obese Mice.

OBJECTIVE: To investigate whether astragalus polysaccharides (APS) combined with berberine (BBR) can reduce high-fat diet (HFD)-induced obesity in mice. METHODS: Except for normal mice, 32 HFD-induced obese mice were randomized into HFD, APS (1,000 mg/kg APS), BBR (200 mg/kg BBR), and APS plus BBR (1,000 mg/kg APS plus 200 mg/kg BBR) groups, respectively. After 6-week treatment (once daily by gavage), the obesity phenotype and pharmacodynamic effects were evaluated by histopathological examination of epididymal fat, liver, and colon using hematoxylin-eosin staining and serum biochemical analyses by an automated chemistry analyzer. The feces were collected at the 12 th week, and taxonomic and functional profiles of gut microbiota were analyzed by 16S ribosomal ribonucleic acid (16S rRNA) sequencing. RESULTS: Compared with HFD group, the average body weight of APS plus BBR group was decreased (P<0.01), accompanied with the reduced fat accumulation, enhanced colonic integrity, insulin sensitivity and glucose homeostasis (P<0.05 or P<0.01). Importantly, APS combined with BBR treatment was more effective than APS or BBR alone in improving HFD-induced insulin resistance (P<0.05 or P<0.01). 16S rRNA sequence-based analysis of fecal samples demonstrated that APS combined with BBR treatment exhibited a better impact on HFD-induced gut microbiota dysbiosis, exclusively via the enriched abundances of Bacteroides, which corresponded to the large increase of predicted bacterial genes involved in carbohydrate metabolism. CONCLUSION: APS combined with BBR may synergistically reduce obesity and modulate the gut microbiota in HFD-fed mice.

Chronic cold environment regulates rheumatoid arthritis through modulation of gut microbiota-derived bile acids.

The pathologies of many diseases are influenced by environmental temperature. As early as the classical Roman age, people believed that exposure to cold weather was bad for rheumatoid arthritis (RA). However, there is no direct evidence supporting this notion, and the molecular mechanisms of the effects of chronic cold exposure on RA remain unknown. Here, in a temperature-conditioned environment, we found that chronic cold exposure aggravates collagen-induced arthritis (CIA) by increasing ankle swelling, bone erosion, and cytokine levels in rats. Furthermore, in chronic cold-exposed CIA rats, gut microbiota dysbiosis was identified, including a decrease in the differential relative abundance of the families Lachnospiraceae and Ruminococcaceae. We also found that an antibiotic cocktail suppressed arthritis severity under cold conditions. Notably, the fecal microbiota transplantation (FMT) results showed that transplantation of cold-adapted microbiota partly recapitulated the microbiota signature in the respective donor rats and phenocopied the cold-induced effects on CIA rats. In addition, cold exposure disturbed bile acid profiles, in particular decreasing gut microbiota-derived taurohyodeoxycholic acid (THDCA) levels. The perturbation of bile acids was also associated with activation of the TGR5-cAMP-PKA axis and NLRP3 inflammasome. Oral THDCA supplementation mitigated the arthritis exacerbation induced by chronic cold exposure. Our findings identify an important role of aberrant gut microbiota-derived bile acids in cold exposure-related RA, highlighting potential opportunities to treat cold-related RA by manipulating the gut microbiota and/or supplementing with THDCA.