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Ulcerative colitis (UC) has become a global epidemic, and the lack of an effective cure highlights the necessity and urgency to explore novel therapies. Sijunzi Decoction (SJZD), a classical Chinese herbal formula, has been comprehensively applied and clinically proven effective in treating UC; however, the pharmacological mechanism behind its therapeutic benefits is largely obscure. Here, we find that SJZD can restore microbiota homeostasis and intestinal barrier integrity in DSS-induced colitis. SJZD significantly alleviated the colonic tissue damage and improved the goblet cell count, MUC2 secretion, and tight junction protein expressions, which indicated enhanced intestinal barrier integrity. SJZD remarkedly suppressed the abundance of phylum Proteobacteria and genus Escherichia-Shigella, which are typical features of microbial dysbiosis. Escherichia-Shigella was negatively correlated with body weight and colon length, and positively correlated with disease activity index and IL-1[Formula: see text]. Furthermore, through gut microbiota depletion, we confirmed that SJZD exerted anti-inflammatory activities in a gut microbiota-dependent manner, and fecal microbiota transplantation (FMT) validated the mediating role of gut microbiota in the SJZD treatment of UC. Through gut microbiota, SJZD modulates the biosynthesis of bile acids (BAs), especially tauroursodeoxycholic acid (TUDCA), which has been identified as the signature BA during SJZD treatment. Cumulatively, our findings disclose that SJZD attenuates UC via orchestrating gut homeostasis in microbial modulation and intestinal barrier integrity, thus offering a promising alternative approach to the clinical management of UC.

Background: Metabolic diseases pose considerable burden on the healthcare system worldwide, indicating the significance of prevention and treatment. In constitution theory of traditional Chinese medicine, phlegm-dampness constitution (PDC) is the common basis of metabolic diseases. In clinical practice, Huatan Qushi (HTQS) decoction targeting on PDC can effectively improve metabolic indicators. However, its underlying biochemical mechanism still remains unclear. Methods: Eight PDC participants received HTQS decoction for three months. Their blood was collected at baseline and 1 and 3 months after intervention started. Related biomedical indicators were detected. High-throughput sequencing and RT-qPCR were used for validation. Due to the missing data, repeated measures with missing values in mixed models were used. Results: After 3-month treatment, HDL-C level increased (P

Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1, which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes.

The gut microbiota exists throughout the full life cycle of the human body, and it has been proven to have extensive impacts on health and disease. Accumulating evidence demonstrates that the interplay between gut microbiota and host epigenetics plays a multifaceted role in health maintenance and disease prevention. Intestinal microflora, along with their metabolites, could regulate multiple epigenetic pathways; e.g., DNA methylation, miRNA, or histone modification. Moreover, epigenetic factors can serve as mediators to coordinate gut microbiota within the host. Aiming to dissect this interplay mechanism, the present review summarizes the research profile of gut microbiota and epigenetics in detail, and further interprets the biofunctions of this interplay, especially the regulation of intestinal inflammation, the improvement of metabolic disturbances, and the inhibition of colitis events. This review provides new insights into the interplay of epigenetics and gut microbiota, and attempts to reveal the mysteries of health maintenance and disease prevention from this new perspective.

Traditional Chinese medicine (TCM) has guided health maintenance and disease treatment for thousands of years and has been widely used in many countries around the world. TCM regards each individual as unique so all corresponding therapeutic and preventive approaches in TCM are personalized. Personalized medicine, also referred to as precision medicine, is an emerging medical paradigm that points toward a new direction for future medical development. TCM constitution studies the holistic body condition, which is affected by both inborn and acquired factors. Body constitution lays the foundation for disease diagnosis, prevention and treatment. Different constitution types predispose individuals to different disease susceptibilities. Examining an individual’s unique body constitution can promote effective health management and benefit the application of personalized medicine significantly. This review will introduce and discuss the application of the TCM constitution for health maintenance and disease prevention. In last decade, a number of modern techniques have been employed in the constitution research to evaluate the health status of individuals. The TCM constitution reflects the current status and future trends of human health in four aspects, i.e., individual differences, life processes, psychological condition and adaptability to natural and social environments. This TCM constitution theory has already been applied in the Chinese public health management at different levels with promising outcome. The constitution theory and practice provide a new approach for health maintenance and disease prevention.

Introduction As a commonly used chemotherapeutic agent, fluorouracil (5-FU) has serious dose-limiting side effects. In this study, we evaluated the synergy between red American ginseng (RAG) and 5-FU on human colorectal cancer cells, and explored the potential mechanisms. Methods Ginsenoside contents of white American ginseng (WAG) and RAG were determined by HPLC. Cell proliferation was evaluated by MTS assay. Combination Index (CI) analysis was executed using CompuSyn software. Paraptotic events were observed after crystal violet staining. Cell cycle distribution, cyclin A expression and apoptotic induction were analyzed using flow cytometry. Results We observed the heat treatment remarkably increased levels of ginsenoside Rg3, 20R-Rg3, Rk1 and Rg5. When the combinations of 5-FU and RAG were applied, cell proliferation inhibition rates were notably increased, indicating that RAG significantly enhanced 5-FU’s effect. Additionally, CI analysis suggested that there was a synergistic action of 5-FU and RAG when combined. The cell cycle data indicated 5-FU induced S phase arrest, and the combination of 5-FU and RAG increased G1 phase. Further, the RAG’s ability to enhance the anti-cancer effects of 5-FU was linked to both paraptosis and apoptosis inductions. Conclusion RAG may have clinical utility to decrease the dosage of 5-FU in colorectal cancer therapeutics.

Oplopanax horridus, widely distributed in North America, is an herbal medicine traditionally used by Pacific indigenous peoples for various medical conditions. After oral ingestion, constituents in O. horridus extract (OhE) could be converted to their metabolites by the enteric microbiome before absorption. In this study, in order to mimic gut environment, the OhE was biotransformed using the enteric microbiome of healthy human subjects. For accurate and reliable data collection with optimized approaches in sample preparation and analytical conditions, ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry were used to characterize parent constituents and their metabolites. In the extract, 20 parent compounds were identified including polyynes, sesquiterpenes, monoterpeondids, phenylpropanoids and phenolic acids. After the biotransformation, a total of 78 metabolites were identified, of which 37 belonged to polyynes metabolites. The common biotransformation pathways are hydroxylation, acetylization, methylation and demethylation. Based on the pathway distributions, the metabolism signature of OhE has been explored. The metabolism pathways of OhE compounds are dependent on their structural classifications and hydrophilic/hydrophobic properties. In summary, with comprehensive analysis, we systematically investigated human microbiome-derived OhE metabolites. The enteric microbial metabolism signature provides novel information for future effective use of O. horridus.

Objective: To measure vascular endothelial function (VED) in obese/overweight people grouped according to the constitutional theory of traditional Chinese medicine (TCM). We wished to predict the risk of VED and cardiovascular diseases in obese/overweight populations. Methods: This was a cross-sectional study. Eighty-six obese/overweight volunteers from Beijing Chao-Yang Hospital were enrolled and divided into four groups based on body-constitution type: phlegm dampness (PD); phlegm dampness with blood stasis (PDBS); qi-deficiency (QD); balance (BA). Height, weight, waist circumference and hip circumference were measured, and percent body fat and reactive hyperemia index (RHI) calculated. Levels of vascular endothelial growth factor (VEGF), von Willebrand factor (vWF) and plasma endothelial-1 (ET-1) were detected by immunohistochemistry. Results: The RHI and vWF levels in the PDBS group were significantly lower than those in the BA group and QD group (P .05). These two indicators displayed no significant differences among BA, QD, and PD groups (P > .05). There was no significant difference among the four groups in level of ET-1 or VEGF (P > .05). Conclusion: Of the four indicators selected, the RHI and vWF displayed significant differences between the PDBS group and BA group, and between the PDBS group and QD group. Hence, in an obese/overweight population with different constitutional types, compared with BA and QD groups, a relatively higher risk of suffering from VED was detected in the PDBS group. Meanwhile, this study provides the experimental basis for confirming the feasibility of constitutional classification in obese/overweight population. Keywords: Obese/overweight, Constitution classification, Vascular endothelial dysfunction, Reactive hyperemia index

The XOD inhibitory effects of Plantaginis Semen, that is, the seeds of P. asiatisca, and its representative four single compounds, acteoside, 1H-indolo-3-carbaldehyde, isoacteoside, and myristic acid, were evaluated by electron transfer signal blocking activities (ETSBA), which is based on the electron transfer signal of XOD enzymatic reaction. The blocking activities were detected using an electrochemical biosensing method. Compared with control, significant effects were observed after the addition of P. asiatica extract, acteoside, and 1H-indolo-3-carbaldehyde (all p<0.05). The IC50 values of the extract and acteoside are 89.14 and 7.55 μg·mL−1, respectively. The IC20 values of the extract, acteoside, and 1H-indolo-3-carbaldehyde are 24.28, 3.88, and 16.16 μg·mL−1, respectively. Due to the relatively lower inhibitory potential of 1H-indolo-3-carbaldehyde, its IC50 was not obtained. In addition, isoacteoside and myristic acid did not show any XOD inhibitory effects. Our data demonstrated that the XOD inhibitory effects of the extract, acteoside, and 1H-indolo-3-carbaldehyde can be accurately evaluated by the ETSBA method. The results from this study indicated that Plantaginis Semen significantly inhibited XOD activities to reduce hyperuricemia and treat gout. The study also proves that measuring the electron transfer signal blocking activities is a simple, sensitive, and accurate method to evaluate the XOD inhibitory effects.

Background/Aims: Based on the theory of constitution in Traditional Chinese Medicine (TCM), the Chinese Han population has been classified into nine constitutions. Of these, Yang deficiency constitution mainly exhibit cold intolerance while Yin deficiency constitution mainly exhibit heat intolerance. Some studies have been carried out to explore the modern genetic and biological basis of such constitution classification, but more remains to be done. MicroRNA (miRNA) serves as post-transcriptional regulators of gene expression and may play a role in the classification process. Here, we examined miRNA expression profile of saliva to further improve the comprehensiveness of constitution classification. Methods: Saliva was collected from Chinese Han individuals with Yang deficiency, Yin deficiency and Balanced constitutions (n=5 each), and miRNA expression profile was determined using the Human miRNA OneArray®v7. Based on 1.5 Fold change, means log2|Ratio|≥0.585 and P-value< 0.05, differentially expressed miRNA was screened. Target genes were predicted using DIANA-TarBasev7.0 and analysis of KEGG pathway was carried out using DIANA-mirPathv.3. Results: We found that 81 and 98 differentially expressed miRNAs were screened in Yang deficiency and Yin deficiency constitution, respectively. Among them, 16 miRNAs were identical and the others were unique. In addition, the target genes that are regulated by the unique miRNAs were significantly enriched in 27 and 20 signaling pathways in Yang deficiency and Yin deficiency constitution, respectively. Thyroid hormone signaling pathway is present in both constitutions. These unique miRNAs that regulated target genes of thyroid hormone signaling pathway may be associated with cold intolerance or heat intolerance. Conclusion: The results of our study show that Yang deficiency and Yin deficiency constitutions exhibit systematic differences in miRNA expression profile. Moreover, the distinct characteristics of TCM constitution may be explained, in part, by differentially expressed miRNAs.

Oplopanax elatus (Nakai) Nakai, in the Araliaceae family, has been used in traditional Chinese medicine (TCM) to treat diseases as an adaptogen for thousands of years. This study established an ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) method to identify chemical components and biotransformation metabolites of root bark extract from O. elatus. A total of 18 compounds were characterized in O. elatus extract, and 62 metabolites by human intestinal microbiota were detected. Two polyynes, falcarindiol and oplopandiol were recognized as the main components of O. elatus, whose metabolites are further illustrated. Several metabolic pathways were proposed to generate the detected metabolites, including methylation, hydrogenation, demethylation, dehydroxylation, and hydroxylation. These findings indicated that intestinal microbiota might play an essential role in mediating the bioactivity of O. elatus.

Objective To assess the efficacy of Qingre Lishi Tuihuang therapy (QLTT) for acute icteric hepatitis B infection. Methods Eight electronic databases were searched from inception to December 2016 with no language restrictions for reports of randomized controlled trials evaluating the effect of QLTT treating acute icteric hepatitis B. Two researchers independently extracted detailed data and assessed methodological quality. Review Manager 5.3.0 software was used to analyze the data. Results A total of 13 randomized controlled trials involving 2238 participants were included in this review. The methodological quality was generally poor. The results indicated that supplemented Yinchenhao decoction combined with non-specific treatments was more effective in improving the cure rate (risk ratio = 1.80; 95% CI 1.21–2.68) and reducing the serum levels of total bilirubin (mean difference = −29.74; 95% CI −31.91 to −27.57) and aspartate aminotransferase. Other self-made prescriptions conforming to QLTT plus non-specific treatments had beneficial effect for acute icteric hepatitis B in curing this disease (risk ratio = 1.48; 95% CI 1.27–1.73), as well as for negative seroconversion of HBeAg (risk ratio = 1.39; 95% CI 1.11–1.74). Supplemented Yinchenhao decoction plus non-specific treatments was more effective than other self-made prescriptions conforming to QLTT in reducing serum total bilirubin level. Conclusion Qingre Lishi Tuihuang therapy appears to improve effect based on non-specific treatments for the treatment of acute icteric hepatitis B. However, it is premature to draw confirmative conclusions, owing to the poor methodological quality and high clinical heterogeneity of the included trials. Further well-designed clinical randomized controlled trials with large sample sizes should be undertaken.

The root of Asian ginseng (Panax ginseng C.A. Meyer) has been used for centuries in Oriental medicine to improve general well-being and to relieve various medical conditions. It is commonly understood that ginsenosides are responsible for the pharmacological activities of ginseng. Compared to the root of ginseng, studies on the berry are considerably limited. In this study, we evaluated the effects of polysaccharides from Asian ginseng berries on plasma lipid levels, chemically-induced enteric inflammation and neoplasm, and cancer chemoprevention in different experimental models. We tested two polysaccharide preparations: regular ginseng berry polysaccharide extract (GBPE) and ginseng berry polysaccharide portion (GBPP, removed MV [Formula: see text]). We first observed that both oral GBPE and oral GBPP significantly reduced plasma cholesterol and triglycerides levels in a dose-related manner in ob/ob mice, without obvious body weight changes. Then, in AOM/DSS-induced acute colitis mice, GBPE and GBPP significantly ameliorated the increased gut disease activity index and inhibited the reduction of the colon length. Further, the berry polysaccharides significantly suppressed chemically-induced pro-inflammatory cytokine levels. This is consistent with the observation that GBPE and GBPP attenuated tumorigenesis in mice by significantly and dose-dependently reducing tumor load. Finally, in vitro HCT-116 and HT-29 human colon cancer cells were used. While these berry preparations had better antiproliferation effects on the HCT-116 than the HT-29 cells, the GBPE had significantly stronger inhibitory effects than GBPP. The observed in vitro GBPE’s effect could contribute to the actions of its small-molecule non-polysaccharide compounds due to their direct antiproliferative activities. Results obtained from the present study suggest that ginseng berry polysaccharides may have a therapeutic role in the management of high lipid levels, enteric inflammation, and colon malignancies.

Objective To explore the possible correlation between traditional Chinese medicine (TCM) constitution and facial features in color images and to improve the accuracy of automated constitution classification. Methods Color images were taken of 5150 individuals of different professions. Automated face detection and key point positioning were performed on the collected images, which were then transformed into a standard size. The relationship between facial features and TCM constitution based on the red, green, blue (RGB) pixel and the local binary pattern (LBP) texture features was explored. Results The overall accuracy rate and robustness of TCM constitution classification based on RGB features were low. Classification results of the phlegm-dampness, damp-heat, blood stasis, and balance constitutions achieved high accuracy rates. Classification accuracy rate using the LBP texture feature was higher than that of the RGB feature, with the best accuracy observed for the balance constitution. Conclusion Application of computer image acquisition and processing of facial features may serve as an adjunct to the TCM diagnostic method of inspection.

Background: Ginseng is a commonly used herbal medicine in treating various medical conditions. Chronic gut inflammation is a recognized factor for the development of colorectal cancer (CRC). In this project, Asian ginseng berry polysaccharide preparations were used to assess their effects on CRC and related immune regulation mechanisms. Methods: Ginseng berry polysaccharide extract (GBPE) and purified ginseng berry polysaccharide portion (GBPP) were used to evaluate their activities on human HCT-116 and HT-29 CRC cell proliferation. Interleukin-8 secretion analysis was performed on HT-29 cells. Naive CD4 cell isolation and T-helper cell differentiation were performed and determined using flow cytometry for Th1 and Treg in addition to cell cycle and apoptotic investigation. Results: GBPE and GBPP significantly inhibited interleukin-8 secretion and cancer cell proliferation, inhibited CD4+IFN-γ+ cell (Th1) differentiation, and decreased CD4+FoxP3+ cell (Treg) differentiation. Compared to the GBPE, GBPP showed more potent antiinflammatory activities on the malignant cells. This is consistent with the observation that GBPP can also inhibit Th1-cell differentiation better, suggesting that it has an important role in antiinflammation, whereas Treg cells hinder the body's immune response against malignancies. Supported by cell cycle and apoptosis data, GBPE and GBPP, at various degrees, remarkably enhanced the anticancer activities of 5-fluorouracil. Conclusion: Data from this project suggested that Asian ginseng berry potentially has clinical utility in managing enteric inflammation and suppressing CRC through immunomodulation mechanisms. Keywords: Adaptive immune response, Colorectal cancer, 5-Fluorouracil, Ginseng berry polysaccharides, Inflammation

Inflammatory bowel disease (IBD) is a significant public health problem in the United States. Abdominal pain is a major complaint among individuals with IBD. Successful IBD management not only controls enteric inflammation, but also reduces abdominal discomfort. Recently, increased attention has been focused on alternative strategies for IBD management. HPLC/Q-TOF-MS analysis was employed to evaluate the intestinal microbiome's biotransformation of parent American ginseng compounds into their metabolites. Using a DSS mouse model, the effects of American ginseng microbial metabolites on chemically induced colitis was investigated with disease activity index and histological assessment. Expressions of inflammatory cytokines were determined using real-time PCR and ELISA. Abdominal pain was evaluated using the von Frey filament test. After the gut microbiome's biotransformation, the major metabolites were found to be the compound K and ginsenoside Rg3. Compared with the DSS animal group, American ginseng treatment significantly attenuated experimental colitis, as supported by the histological assessment. The enteric microbiome-derived metabolites of ginseng significantly attenuated the abdominal pain. American ginseng treatment significantly reduced gut inflammation, consistent with pro-inflammatory cytokine level changes. The gut microbial metabolite compound K showed significant anti-inflammatory effects even at low concentrations, compared to its parent ginsenoside Rb1. American ginseng intestinal microbial metabolites significantly reduced chemically-induced colitis and abdominal pain, as mediated by the inhibition of pro-inflammatory cytokine expression. Intestinal microbial metabolism plays a critical role in American ginseng mediated colitis management.

Ginsenoside Rb1, a major component of different ginseng species, can be bioconverted into compound K by gut microbiota, and the latter possess much stronger cancer chemopreventive potential. However, while the initiation and progression of colorectal cancer is closely associated with gut inflammation, to date, the effects of compound K on inflammation-linked cancer chemoprevention have not been reported. In the present study, liquid chromatography quadrupole time-of-flight mass spectrometry analysis was applied to evaluate the biotransformation of Rb1 in American ginseng by human enteric microflora. The in vitro inhibitory effects of Rb1 and compound K were compared using the HCT-116 and HT-19 human colorectal cancer cell lines by a MTS assay. Cell cycle and cell apoptosis were assayed using flow cytometry. Using ELISA, the anti-inflammatory effects of Rb1 and compound K were compared for their inhibition of interleukin-8 secretion in HT-29 cells, induced by lipopolysaccharide. The results revealed that compound K is the major intestinal microbiome metabolite of Rb1. When compared with Rb1, compound K had significantly stronger anti-proliferative effects in HCT-116 and HT-29 cell lines (P

Inflammatory bowel disease is a significant public health issue in America. This gut disease is also a risk factor for the initiation and development of colon cancer. As an anti-inflammatory botanical, American ginseng has been shown to play a role in suppressing colitis, reducing inflammation, and preventing cancer. However, the effects of ginseng on the enteric microbiome and on specific molecular profiles have yet to be explored. Using an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced gut inflammation and tumorigenesis mouse model, the effects of oral American ginseng (15 and 30 mg/kg/day) on colitis and colon cancer were determined. After the establishment of a 16S rRNA illumina library from fecal samples, MiSeq sequencing was carried out to reveal the microbial population. A metabolomic analysis was conducted to detect endogenous metabolite changes for potential biomarkers. The results showed that in the acute phase, chemically-induced colitis was significantly reduced by ginseng in a dose-dependent manner, which was supported by histology evaluation. In the chronic phase, obvious colon carcinogenesis was observed in the model group. Ginseng treatment significantly reduced colon tumor multiplicity, which was consistent with pro-inflammatory cytokine level changes. For the fecal microbial communities, greater colitis severity was negatively associated with alpha diversity. With beta diversity, AOM/DSS induced an obvious separation between the control and model groups; however, the plots of the ginseng treatment group were very close to those of the untreated control group. Chemically induced colitis and colon tumorigenesis were correlated with an augment of Bacteroidaceae and Porphyromonadaceae, while the proportion of these families was diminished by ginseng treatment. Our results suggest that the colon cancer preventive effects of ginseng are mediated through an enteric microbiome population-shift recovery and dysbiosis restoration. In both acute and chronic phases, serum metabolomic analysis showed that the plots of the model group were clearly separated from the normal control group, while ginseng treatment, especially in high-dose group, pushed the plots back towards the control group. Compared to model group, ginseng treatment appeared to restore the levels of the observed key endogenous metabolites including glutamine, 6-P-glucose, EPA and oleic acid, which were related to inflammatory responses and energy balance regulations. In summary, we used a platform combining metabolomic and microbiome data to interpret the efficacies of ginseng. With further verification, microbiome profiles and selective endogenous small molecules could be used as biomarkers to elucidate the effects of American ginseng on colitis-associated colon cancer. (This work was supported in part by the NIH/NCCAM grants AT004418 and AT005362). Citation Format: Chong-Zhi Wang, Haiqiang Yao, Jin-Yi Wan, Jinxiang Zeng, Clara Sava-Segal, Chun-Su Yuan. Gut microbiome and metabolomic profiling reveal preventive effects of American ginseng on inflammation-associated colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1248.