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Metabolic disorders are an increasing concern in the industrialized world. Current research has shown a direct link between the composition of the gut microbiota and the pathogenesis of obesity and diabetes. In only a few weeks, an obesity-inducing diet can lead to increased gut permeability and microbial dysbiosis, which contributes to chronic inflammation in the gut and adipose tissues, and to the development of insulin resistance. In this review, we examine the interplay between gut inflammation, insulin resistance, and the gut microbiota, and discuss how some probiotic species can be used to modulate gut homeostasis. We focus primarily on Faecalibacterium prausnitzii, a highly abundant butyrate-producing bacterium that has been proposed both as a biomarker for the development of different gut pathologies and as a potential treatment due to its production of anti-inflammatory metabolites.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is one of the most common chronic functional gastrointestinal diseases with limited treatments. Gut microbiota play an important role in chronic gastrointestinal diseases. In traditional Chinese medicine (TCM), Spleen–Yang deficiency (SYD) is one of the root causes of IBS-D. Fuzi-Lizhong pill (FLZP) is well known for its powerful capacity for treating SYD and has a good clinical effect on IBS-D. However, the mechanism of FLZP on the gut microbiota of IBS-D has not been fully clarified. Our present study aimed to reveal the mechanism of FLZP regulating gut microbiota of IBS-D. The body mass, CCK, MTL, and Bristol fecal character score were used to verify the establishment of the IBS-D model. IL-6, TNF, IL-1β, and IFN-γ were crucial targets screened by network pharmacology and preliminarily verified by ELISA. Eighteen gut microbiota were important for the treatment of IBS-D with FLZP. Bacteroidetes, Blautia, Turicibacter, and Ruminococcus_torques_group were the crucial gut microbiota that FLZP inhibits persistent systemic inflammation in the IBS-D model. Lactobacillus is the crucial gut microbiota that FLZP renovates intestinal immune barrier in the IBS-D model. In summary, FLZP can affect bacterial diversity and community structures in the host and regulate inflammation and immune system to treat IBS-D.

Objective: Diabetic kidney disease (DKD) has become the major cause of end-stage renal disease (ESRD) associated with the progression of renal fibrosis. As gut microbiota dysbiosis is closely related to renal damage and fibrosis, we investigated the role of gut microbiota and microbiota-related serum metabolites in DKD progression in this study.Methods: Fecal and serum samples obtained from predialysis DKD patients from January 2017 to December 2019 were detected using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry, respectively. Forty-one predialysis patients were divided into two groups according to their estimated glomerular filtration rate (eGFR): the DKD non-ESRD group (eGFR ≥ 15 ml/min/1.73 m2) (n = 22), and the DKD ESRD group (eGFR < 15 ml/min/1.73 m2) (n = 19). The metabolic pathways related to differential serum metabolites were obtained by the KEGG pathway analysis. Differences between the two groups relative to gut microbiota profiles and serum metabolites were investigated, and associations between gut microbiota and metabolite concentrations were assessed. Correlations between clinical indicators and both microbiota-related metabolites and gut microbiota were calculated by Spearman rank correlation coefficient and visualized by heatmap.Results: Eleven different intestinal floras and 239 different serum metabolites were identified between the two groups. Of 239 serum metabolites, 192 related to the 11 different intestinal flora were mainly enriched in six metabolic pathways, among which, phenylalanine and tryptophan metabolic pathways were most associated with DKD progression. Four microbiota-related metabolites in the phenylalanine metabolic pathway [hippuric acid (HA), L-(−)-3-phenylactic acid, trans-3-hydroxy-cinnamate, and dihydro-3-coumaric acid] and indole-3 acetic acid (IAA) in the tryptophan metabolic pathway positively correlated with DKD progression, whereas L-tryptophan in the tryptophan metabolic pathway had a negative correlation. Intestinal flora g_Abiotrophia and g_norank_f_Peptococcaceae were positively correlated with the increase in renal function indicators and serum metabolite HA. G_Lachnospiraceae_NC2004_Group was negatively correlated with the increase in renal function indicators and serum metabolites [L-(−)-3-phenyllactic acid and IAA].Conclusions: This study highlights the interaction among gut microbiota, serum metabolites, and clinical indicators in predialysis DKD patients, and provides new insights into the role of gut microbiota and microbiota-related serum metabolites that were enriched in the phenylalanine and tryptophan metabolic pathways, which correlated with the progression of DKD.

Inflammatory bowel disease (IBD) is characterized by chronic pathology associated with extensive intestinal microbial dysregulation and intestinal inflammation. Thus, efforts are underway to manipulate the gut microbiome to improve inflammatory pathology. Gegen Qinlian decoction (GQD), a traditional Chinese medicine prescription, has been widely utilized for treating diarrhea and ulcerative colitis (UC) for thousands of years. However, the underlying mechanism of its efficacy and whether its protective effect against colitis is mediated by the gut microbiota are poorly understood. In the present study, our data demonstrated that modified GQD (MGQD) administration significantly improved the pathological phenotypes and colonic inflammation challenged by DSS in mice, which were specifically manifested as reduced loss of body weight, shortening of colon length, DAI score, histological score and suppressed inflammatory response. 16S rRNA sequencing and targeted metabonomics analysis showed that MQGD altered the diversity and community landscape of the intestinal microbiota and the metabolic profiles. In particular, MQGD significantly boosted the abundance of the intestinal microbiota producing short-chain fatty acids (SCFAs), which are causally associated with promoting the development of Treg cells and suppressing the differentiation of pro-inflammatory Th17 cells. More importantly, transferring fecal microbiota from MGQD-treated or healthy controls exhibited equivalent alleviative effects on colitis mice. However, this protective effect could not be replicated in experiments of mice with depleted intestinal microbes through broad-spectrum antibiotic cocktails (ABX), further supporting the importance of SCFA-producing gut microbiota in the beneficial role of MGQD. In general, MGQD therapy has the potential to remodel the intestinal microbiome and reestablish immune homeostasis to ameliorate DSS-induced colitis.

Accumulating evidences suggested an association between gut microbiome dysbiosis and impaired glycemic control. Ginsenoside Rb1 (Rb1) is a biologically active substance of ginseng, which serves anti-diabetic effects. However, its working mechanism especially interaction with gut microbes remains elusive in detail. In this study, we investigated the impact of Rb1 oral supplementation on high fat diet (HFD) induced obesity mice, and explored its mechanism in regulating blood glucose. The results showed that higher liver weight and lower cecum weight were observed in HFD fed mice, which was maintained by Rb1 administration. In addition, Rb1 ameliorated HFD induced blood lipid abnormality and improved insulin sensitivity. Several mRNA expressions in the liver were measured by quantitative real-time PCR, of which UCP2, Nr1H4, and Fiaf were reversed by Rb1 treatment. 16S rRNA sequencing analysis indicated that Rb1 significantly altered gut microbiota composition and increased the abundance of mucin-degrading bacterium Akkermansia spp. compared to HFD mice. As suggested via functional prediction, amino acid metabolism was modulated by Rb1 supplementation. Subsequent serum amino acids investigation indicated that several diabetes associated amino acids, like branched-chain amino acids, tryptophan and alanine, were altered in company with Rb1 supplementation. Moreover, correlation analysis firstly implied that the circulation level of alanine was related to Akkermansia spp.. In summary, Rb1 supplementation improved HFD induced insulin resistance in mice, and was associated with profound changes in microbial composition and amino acid metabolism.

Gut microbiota plays important roles in several metabolic processes, such as appetite and food intake and absorption of nutrients from the gut. It is also of great importance in the maintenance of the health of the host. However, much remains unknown about the functional mechanisms of human gut microbiota itself. Here, we report the identification of one anticancer gut bacterial strain AD16, which exhibited potent suppressive effects on a broad range of solid and blood malignancies. The secondary metabolites of the strain were isolated and characterized by a bioactivity-guided isolation strategy. Five new compounds, streptonaphthalenes A and B (1-2), pestaloficins F and G (3-4), and eudesmanetetraiol A (5), together with nine previously known compounds, were isolated from the effective fractions of AD16. Structures of the new compounds were established by 1D and 2D NMR and MS analysis, and the absolute configurations were determined by the CD method. The analysis of network pharmacology suggested that 3, 2, and 13 could be the key components for the anti-NSCLC activity of AD16. In addition to the PI3K–Akt signaling pathway, the proteoglycans in cancer pathway could be involved in the anti-NSCLC action of AD16.

Liver diseases have been a common challenge for people all over the world, which threatens the quality of life and safety of hundreds of millions of patients. China is a major country with liver diseases. Metabolic associated fatty liver disease, hepatitis B virus and alcoholic liver disease are the three most common liver diseases in our country, and the number of patients with liver cancer is increasing. Therefore, finding effective drugs to treat liver disease has become an urgent task. Chinese medicine (CM) has the advantages of low cost, high safety, and various biological activities, which is an important factor for the prevention and treatment of liver diseases. This review systematically summarizes the potential of CM in the treatment of liver diseases, showing that CM can alleviate liver diseases by regulating lipid metabolism, bile acid metabolism, immune function, and gut microbiota, as well as exerting anti-liver injury, anti-oxidation, and anti-hepatitis virus effects. Among them, Keap1/Nrf2, TGF-β/SMADS, p38 MAPK, NF-κB/IκBα, NF-κB-NLRP3, PI3K/Akt, TLR4-MyD88-NF-κB and IL-6/STAT3 signaling pathways are mainly involved. In conclusion, CM is very likely to be a potential candidate for liver disease treatment based on modern phytochemistry, pharmacology, and genomeproteomics, which needs more clinical trials to further clarify its importance in the treatment of liver diseases.

Objectives:Polygonatum kingianum is a medicinal herb used in various traditional Chinese medicine formulations. The polysaccharide fraction of P. kingianum can reduce insulin resistance and restore the gut microbiota in a rat model of aberrant lipid metabolism by down regulating miR-122. The aim of this study was to further elucidate the effect of P. kingianum on lipid metabolism, and the roles of specific miRNAs and the gut microbiota.Key findings:P. kingianum administration significantly altered the abundance of 29 gut microbes and 27 differentially expressed miRNAs (DEMs). Several aberrantly expressed miRNAs closely related to lipid metabolism were identified, of which some were associated with specific gut microbiota. MiR-484 in particular was identified as the core factor involved in the therapeutic effects of P. kingianum. We hypothesize that the miR-484-Bacteroides/Roseburia axis acts as an important bridge hub that connects the entire miRNA-gut microbiota network. In addition, we observed that Parabacteroides and Bacillus correlated significantly with several miRNAs, including miR-484, miR-122-5p, miR-184 and miR-378b.Summary:P. kingianum alleviates lipid metabolism disorder by targeting the network of key miRNAs and the gut microbiota.

Triple-negative breast cancer (TNBC) has been acknowledged as an aggressive disease with worst prognosis, which requires endeavor to develop novel therapeutic agents. Bruceae fructus oil (BO), a vegetable oil derived from the fruit of Brucea javanica (L.) Merr., is an approved marketable drug for the treatment of cancer in China for several decades. Despite that the anti–breast cancer activity of several quassinoids derived from B. javanica has been found, it was the first time that the potential of BO against TNBC was revealed. Although BO had no cytotoxicity on TNBC cell lines in vitro, the oral administration of BO exhibited a gut microbiota–dependent tumor suppression without toxicity on the non-targeted organs in vivo. By metagenomics and untargeted metabolomics, it was found that BO not only altered the composition and amino acid metabolism function of gut microbiota but also regulated the host’s amino acid profile, which was in accordance with the metabolism alternation in gut microbiota. Moreover, the activity of mTOR in tumor was promoted by BO treatment as indicated by the phosphorylation of 4E-binding protein 1 (4E-BP1) and ribosomal protein S6, and hyper-autophagy was consequently restrained. By contrast, the failure of tumor suppression by BO under pseudo germ-free (PGF) condition came with indistinctive changes in autophagy and mTOR activity, implying the critical role of the gut microbiota in BO’s anticancer activity. The present study highlighted a promising application of BO against breast cancer with novel efficacy and safety.

Ulcerative colitis (UC) is considered an immune disease, which is related to the dysbiosis of intestinal microbiota and disorders of the host immune system and metabolism. Sophora flavescens Aiton has been used for the clinical treatment of UC in China and East Asia for thousands of years. It has many traditional prescriptions and modern preparations, and its curative effects are definite. We are the first to report that the flavonoids in Sophora flavescens (S. flavescens) Aiton EtOAc extract (SFE) could potentially attenuate the dextran sodium sulfate–induced UC in mice, which changed the current understanding of considering alkaloids as the only anti-UC pharmacological substances of S. flavescens Aiton. Based on the 16S rRNA gene sequencing and metabolomic analysis, it was found that the anti-UC effects of SFE were due to the regulation of gut microbiota, reversing the abnormal metabolisms, and regulation of the short-chain fatty acids synthesis. Notably, according to the interaction networks of specific bacteria and “bacteria and metabolites” co-expression network, the SFE could enrich the abundance of the commensal bacterium Lactobacillus, Roseburia, norank_f__Muribaculaceae, Anaerotruncus, Candidatus_Saccharimona, and Parasutterella, which are proposed as potentially beneficial bacteria, thereby playing vital roles in the treatment of UC.

Diabetes mellitus (DM) and its complications pose a major public health threat which is approaching epidemic proportions globally. Current drug options may not provide good efficacy and even cause serious adverse effects. Seeking safe and effective agents for DM treatment has been an area of intensive interest. As a healing system originating in Tibet, Traditional Tibetan Medicine (TTM) has been widely used by Tibetan people for the prevention and treatment of DM and its complications for hundreds of years. Tibetan Materia Medica (TMM) including the flower of Edgeworthia gardneri (Wall.) Meisn., Phyllanthi Fructus, Chebulae Fructus, Huidouba, and Berberidis Cortex are most frequently used and studied. These TMMs possess hypoglycemic, anti-insulin resistant, anti-glycation, lipid lowering, anti-inflammatory, and anti-oxidative effects. The underlying mechanisms of these actions may be related to their α-glucosidase inhibitory, insulin signaling promoting, PPARs-activating, gut microbiota modulation, islet β cell-preserving, and TNF-α signaling suppressive properties. This review presents a comprehensive overview of the mode and mechanisms of action of various active constituents, extracts, preparations, and formulas from TMM. The dynamic beneficial effects of the products prepared from TMM for the management of DM and its complications are summarized. These TMMs are valuable materia medica which have the potential to be developed as safe and effective anti-DM agents.

The present study aimed to determine if metformin exerts anti-inflammatory and mucus-protective effects via the gut microbiota. Metformin has extensive benefits including anti-inflammatory effects. Previous studies showed that metformin changed the gut microbiota composition and increases the number of goblet cells. Intestinal dysbiosis and goblet cell depletion are important features of ulcerative colitis (UC). The underlying mechanism and whether metformin can improve the mucus barrier in UC remain unclear. Metformin (400 mg/kg/day) was administered to mice with dextran sulfate sodium (DSS)-induced UC for 2 wk to investigate the effects of metformin on the intestinal mucus barrier. The gut microbiota was depleted, using antibiotics, to explore its role in the mucus-protecting effects of metformin. Akkermansia muciniphila (A. muciniphila), which was enriched in metformin-treated mice, was administered to mice to investigate the effects of the bacteria on UC and the mucus barrier. Metformin attenuated DSS-induced UC in mice, as evidenced by the alleviation of diarrhea, hematochezia, and the decrease in body weight. The expression of mucin2, a prominent mucus barrier protein, was increased in the metformin-treated group compared to the DSS-treated group. Furthermore, fecal 16S rRNA analysis showed that metformin treatment changed the gut microbiota composition by increasing the relative abundance of Lactobacillus and Akkermansia species while decreasing Erysipelatoclostridium at the genus level. Antibiotic treatment partly abolished the anti-inflammatory and mucus-protecting effects of metformin. Administration of A. muciniphila alleviated the colonic inflammation and mucus barrier disruption. Metformin alleviated DSS-induced UC in mice and protected against cell damage via affecting the gut microbiota, thereby providing a new mechanism for the therapeutic effect of metformin in patients with UC. This study also provides evidence that A. muciniphila as a probiotic has potential benefits for UC.

The first-line treatment for colorectal cancer (CRC) is 5-fluorouracil (5-FU). However, the efficacy of this treatment is sometimes limited owing to chemoresistance as well as treatment-associated intestinal mucositis and other adverse events. Growing evidence suggests that certain phytochemicals have therapeutic and cancer-preventing properties. Further, the synergistic interactions between many such plant-derived products and chemotherapeutic drugs have been linked to improved therapeutic efficacy. Polysaccharides extracted from Albuca bracteata (Thunb.) J.C.Manning and Goldblatt (ABP) have been reported to exhibit anti-oxidant, anti-inflammatory, and anti-tumor properties. In this study, murine CRC cells (CT26) and a murine model of CRC were used to examine the anti-tumor properties of ABP and explore the mechanism underlying the synergistic interactions between ABP and 5-FU. Our results revealed that ABP could inhibit tumor cell proliferation, invasion, and migratory activity in vitro and inhibited tumor progression in vivo by suppressing β-catenin signaling. Additionally, treatment with a combination of ABP and 5-FU resulted in better outcomes than treatment with either agent alone. Moreover, this combination therapy resulted in the specific enrichment of Ruminococcus, Anaerostipes, and Oscillospira in the intestinal microbiota and increased fecal short-chain fatty acid (SCFA) levels (acetic acid, propionic acid, and butyric acid). The improvement in the intestinal microbiota and the increase in beneficial SCFAs contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Together, these data suggest that ABP exhibits anti-neoplastic activity and can effectively enhance the efficacy of 5-FU in CRC treatment. Therefore, further research on the application of ABP in the development of novel anti-tumor drugs and adjuvant compounds is warranted and could improve the outcomes of CRC patients.

The gastrointestinal and respiratory systems are colonized by a complex ecosystem of microorganisms called the microbiota. These microorganisms co-evolved over millions of years with the host, creating a symbiotic relationship that is fundamental for promoting host homeostasis by producing bioactive metabolites and antimicrobial molecules, and regulating the immune and inflammatory responses. Imbalance in the abundance, diversity, and function of the gut microbiota (known as dysbiosis) have been shown to increase host susceptibility to infections in the lungs, suggesting crosstalk between these organs. This crosstalk is now referred to as the gut-lung axis. Hence, the use of probiotics, prebiotics, and synbiotics for modulation of gut microbiota has been studied based on their effectiveness in reducing the duration and severity of respiratory tract infections, mainly owing to their effects on preventing pathogen colonization and modulating the immune system. This review discusses the role and responses of probiotics, prebiotics, and synbiotics in the gut-lung axis in the face of lung infections.

Colorectal cancer (CRC) is a complex condition with heterogeneous aetiology, caused by a combination of various environmental, genetic, and epigenetic factors. The presence of a homeostatic gut microbiota is critical to maintaining host homeostasis and determines the delicate boundary between health and disease. The gut microbiota has been identified as a key environmental player in the pathogenesis of CRC. Perturbations of the gut microbiota structure (loss of equilibrium and homeostasis) are associated with several intestinal diseases including cancer. Such dysbiosis encompasses the loss of beneficial microorganisms, outgrowth of pathogens and pathobionts and a general loss of local microbiota diversity and richness. Notably, several mechanisms have recently been identified how bacteria induce cellular transformation and promote tumour progression. In particular, the formation of biofilms, the production of toxic metabolites or the secretion of genotoxins that lead to DNA damage in intestinal epithelial cells are newly discovered processes by which the microbiota can initiate tumour formation. The gut microbiota has also been implicated in the metabolism of therapeutic drugs (conventional chemotherapy) as well as in the modulation of radiotherapy responses and targeted immunotherapy. These new findings suggest that the efficacy of a given therapy depends on the composition of the host’s gut microbiota and may therefore vary from patient to patient. In this review we discuss the role of host-microbiota interactions in cancer with a focus on CRC pathogenesis. Additionally, we show how gut bacteria can be exploited in current therapies and how mechanisms directed by microbiota, such as immune cell boost, probiotics and oncolytic bacteria, can be applied in the development of novel therapies.

Alcoholic liver disease (ALD) is one of the leading causes of morbidity among adults with alcohol use disorder (AUD) worldwide. Its clinical course ranges from steatosis to alcoholic hepatitis, progressing to more severe forms of liver damage, such as cirrhosis and hepatocellular carcinoma. The pathogenesis of ALD is complex and diverse elements are involved in its development, including environmental factors, genetic predisposition, the immune response, and the gut-liver axis interaction. Chronic alcohol consumption induces changes in gut microbiota that are associated with a loss of intestinal barrier function and inflammatory responses which reinforce a liver damage progression triggered by alcohol. Alcohol metabolites such as acetaldehyde, lipid peroxidation-derived aldehyde malondialdehyde (MDA), and protein-adducts act as liver-damaging hepatotoxins and potentiate systemic inflammation. Additionally, ethanol causes direct damage to the central nervous system (CNS) by crossing the blood-brain barrier (BBB), provoking oxidative stress contributing to neuroinflammation. Overall, these processes have been associated with susceptibility to depression, anxiety, and alcohol craving in ALD. Recent evidence has shown that probiotics can reverse alcohol-induced changes of the microbiota and prevent ALD progression by restoring gut microbial composition. However, the impact of probiotics on alcohol consumption behavior has been less explored. Probiotics have been used to treat various conditions by restoring microbiota and decreasing systemic and CNS inflammation. The results of some studies suggest that probiotics might improve mental function in Alzheimer’s, autism spectrum disorder, and attenuated morphine analgesic tolerance. In this sense, it has been observed that gut microbiota composition alterations, as well as its modulation using probiotics, elicit changes in neurotransmitter signals in the brain, especially in the dopamine reward circuit. Consequently, it is not difficult to imagine that a probiotics-based complementary treatment to ALD might reduce disease progression mediated by lower alcohol consumption. This review aims to present an update of the pathophysiologic mechanism underlying the microbiota-gut-liver-brain axis in ALD, as well as to provide evidence supporting probiotic use as a complementary therapy to address alcohol consumption disorder and its consequences on liver damage.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by complex immune dysregulation and closely related to the gut microbiome. The present study investigated the microbiome-mediated effect of Sihocheonggan-Tang (SHCGT) on AD-like symptoms induced by 2,4-dinitrochlorobenzene (DNCB) in BALB/c mice. DNCB was applied regularly to the ear and dorsal skin of BALB/c mice, and SHCGT was administered orally daily for 2 weeks. The composition of the gut microbiota was analyzed using 16S rRNA sequencing, and the effect of gut microbiome-derived metabolites, specifically short-chain fatty acids (SCFAs), was evaluated in tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-treated HaCaT cells. SHCGT alleviated DNCB-induced symptoms of AD and the immune response to AD by decreasing the plasma immunoglobulin E level and splenic interleukin-4, interleukin-10, TNF-α, and IFN-γ levels. The gut microbiome composition and the damaged gut epithelial barrier in mice with AD were also significantly altered by SHCGT, and the reduced SCFA levels therein were elevated. We found that SFCAs directly inhibited the mRNA expression of IL-6 and ICAM-1 in TNF-α- and INF-γ-treated HaCaT cells. The finding that SHCGT regulates the gut microbiome and improves DNCB-induced AD in mice suggests that this herbal medicine has therapeutic potential in patients with AD.

Obesity, generally characterized by excessive lipid accumulation, is a metabolic threat worldwide due to its rapid growth in global prevalence. Ginsenosides are crucial components derived from natural plants that can confer metabolic benefits for obese patients. Considering the low bioavailability and degradable properties of ginsenosides in vivo, it should be admitted that the mechanism of ginsenosides on anti-obesity contribution is still obscure. Recently, studies have indicated that ginsenoside intervention has beneficial metabolic effects on obesity and its complications because it allows for the correction of gut microbiota dysbiosis and regulates the secretion of related endogenous metabolites. In this review, we summarize the role of gut microbiota in the pathogenetic process of obesity, and explore the mechanism of ginsenosides for ameliorating obesity, which can modulate the composition of gut microbiota by improving the metabolism of intestinal endogenous substances and alleviating the level of inflammation. Ginsenosides are expected to become a promising anti-obesity medical intervention in the foreseeable clinical settings.

Altered gut microbiota and a damaged colon mucosal barrier have been implicated in the development of colon cancer. Astragalus mongholicus Bunge-Curcuma aromatica Salisb. (ACE) is a common herbal drug pair that widely used clinically to treat cancer. However, whether the anti-cancer effect of ACE is related to gut microbiota remains unclear yet. We standardized ACE and investigated the effects of ACE on tumour suppression and analyze the related mechanisms on gut microbiota in CT26 colon cancer-bearing mice in the present study. Firstly, four flavonoids (calycosin-7-glucoside, ononin, calycosin, formononetin) and three astragalosides (astragaloside A, astragaloside II, astragaloside I) riched in Astragalus mongholicus Bunge, three curcumins (bisdemethoxycurcumin, demethoxycurcumin, curcumin) and four essential oils (curdione, curzerene, germacrone and β-elemene) from Curcuma aromatica Salisb., in concentrations from 0.08 to 2.07 mg/g, were examined in ACE. Then the results in vivo studies indicated that ACE inhibited solid tumours, liver and spleen metastases of colon cancer while simultaneously reducing pathological tissue damage. Additionally, ACE regulated gut microbiota dysbiosis and the short chain fatty acid content in the gut, repaired intestinal barrier damage. ACE treatment suppressed the overgrowth of conditional pathogenic gut bacteria, including Escherichia-Shigella, Streptococcus and Enterococcus, while the probiotic gut microbiota like Lactobacillus, Roseburia, Prevotellaceae_UCG-001 and Mucispirillum were increased. More interestingly, the content level of SCFAs such as propionic acid and butyric acid was increased after ACE administration, which further mediates intestinal SDF-1/CXCR4 signalling pathway to repair the integrity of the intestinal barrier, decrease Cyclin D1 and C-myc expressions, eventually suppress the tumor the growth and metastasis of colon cancer. To sum up, the present study demonstrated that ACE could efficiently suppress colon cancer progression through gut microbiota modification, which may provide a new explanation of the mechanism of ACE against colon cancer.

This study investigated the gut microbiota and short chain fatty acids (SCFAs) characteristics of subjects with obesity from Xinjiang in northwestern China, a region with a multiethnic culture and characteristic lifestyle, and to explore the potential microbes that respond to a 12-wk medication of orlistat and ezetimibe with a randomized controlled open-label trial manner. The gut microbiota profile of patients with overweight and obesity with dyslipidemia in Xinjiang was distinctive and characterized by enrichment of Lactobacillus and the reduction of the diversity and the depletion of Actinobacteria, Bacteroides, Bifidobacterium, and Bacteroides fragilis. Prevotella-type, Gemmiger-type, and Escherichia/Shigella-type were the gut microbial patterns of the Xinjiang population. However, the fecal SCFAs levels and enterotypes were similar between healthy individuals and patients. These results indicated that the contribution of the gut microbiota to obesity was highly dependent on geography and dietary habits. Waist circumference, total triglyceride (TG), and fasting blood glucose (FBG) were significantly decreased after orlistat therapy, whereas TG, total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) were significantly decreased by ezetimibe. Overall, the gut microbiota and their SCFAs metabolites were relatively stable after treatment with the two drugs, with alteration of some low-abundant bacteria, i.e., significantly increased Proteobacteria and decreased Alloprevotella after orlistat, and increased Fusobacteria and Fusobacterium after ezetimibe therapy. These results indicated that intestinal malabsorption of dietary fat and cholesterol caused by orlistat and ezetimibe had a limited effect on the overall gut microbial community and their metabolites. Nevertheless, significant correlations between several core microbes that responded to the medications and biochemical data were found; in particular, Actinomyces and Bacteroides were positively correlated with FBG after orlistat intervention, while Clostridium XVIII and Lachnospiracea incertae sedis were negatively correlated with TC and LDL-C after ezetimibe intervention, thus indicating their roles in improving glucolipid metabolism in obesity by acting as potential microbial targets.

Panax notoginseng (PN) is a traditional herbal medicine containing several active compounds such as saponins and ginsenosides with many therapeutic applications including anti-obesity activity. Fermentation by lactic acid bacteria has the potential to metabolize ginsenosides to more active forms. This study examined whether fermentation has any benefits on the protective effects of a PN extract against obesity using a high-fat diet (HFD)-fed mouse model. PN was fermented with Lactobacillus plantarum which exhibited high β-glucosidase activity. Upon fermentation, the PN extract exhibited an altered ginsenoside profile, a dramatic increase in the lactate level. Treatment of the HFD group with fermented PN (FPN), but not PN, decreased both the food and calorie intake significantly, which was consistent with the more potent suppressing effects of FPN than PN on the signaling pathways involved in appetite and energy intake. The PN treatment also modulated the gut microbial composition. The PN and FPN treatment groups showed clear differences in the population of gut microbiota. The relative abundance of Bacteroidetes, Erysipelotrichaceae, Coprococus, and Dehalobacterium were significantly higher in the FPN group then the normal, HFD, and XEN groups. Furthermore, the relative abundances of Akkermansia, Dehalobacterium, Erysipeliotrichaceae and parpabacteroides were significantly higher in the FPN group than the PN group, but the relative abundances of Allobaculum, Erysipelotrichi and Erysipelotrichale were significantly lower. The relative abundance of Bacteroides and Lactococcus was significantly higher and lower, respectively in the PN and FPN groups than the HFD group. In conclusion, the altered ginsenoside and organic acid’s profile, and altered gut microbial composition are believed to be the major factors contributing to the anti-obesity properties of FPN.

Obesity is a chronic metabolic disease caused by genetic and environmental factors that has become a serious global health problem. There is evidence that gut microbiota is closely related to the occurrence and development of obesity. Erchen Decoction (ECD), a traditional Chinese medicine, has been widely used for clinical treatment and basic research of obesity and related metabolic diseases in recent years. It can significantly improve insulin resistance (IR) and lipid metabolism disorders. However, there is no microbiological study on its metabolic regulation. In this study, we investigated the effects of ECD on obesity, especially lipid metabolism and the composition and function of gut microbiota in Zucker diabetic fatty (ZDF) rats, and explored the correlation between the biomarkers of gut microbiota and metabolite and host phenotype. The results showed that ECD could reduce body weight, improve IR and lipid metabolism, and reduce the concentration of free fatty acids (FFA) released from white adipose tissue (WAT) due to excessive lipolysis by interfering with the insulin receptor substrate 1 (IRS1)/protein kinase B (AKT)/protein kinase A (PKA)/hormone-sensitive triglyceride lipase (HSL) signaling pathway in ZDF rats. Additionally, ECD gradually adjusted the overall structure of changed gut microbiota, reversed the relative abundance of six genera, and changed the function of gut microbiota by reducing the content of propionic acid, a metabolite of gut microbiota, in ZDF rats. A potentially close relationship between biomarkers, especially Prevotella, Blautia, and Holdemania, propionic acid and host phenotypes were demonstrated through correlation analysis. The results suggested that the beneficial effects of ECD on obesity, especially lipid metabolism disorders, are related to the regulation of gut microbiota in ZDF rats. This provides a basis for further research on the mechanism and clinical application of ECD to improve obesity via gut microbiota.

Metformin is a widely prescribed medication for the treatment of type 2 diabetes mellitus (T2DM). It possesses effective roles in various disorders, including cancer, dyslipidemia, and obesity. However, the underlying mechanisms of metformin's multiple benefits are not fully understood. Herein, a mass spectrometry-based untargeted metabolomics approach was used to investigate the metabolic changes associated with the administration of a single dose of metformin in the plasma of 26 healthy subjects at five-time points; pre-dose, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-dose. A total of 111 metabolites involved in various biochemical processes were perturbed, with branched-chain amino acid (BCAA) being the most significantly altered pathway. Additionally, the Pearson similarity test revealed that 63 metabolites showed a change in their levels dependent on metformin level. Out of these 63, the level of 36 metabolites was significantly altered by metformin. Significantly altered metformin-dependent metabolites, including hydroxymethyl uracil, propionic acid, glycerophospholipids, and eicosanoids, pointed to fundamental biochemical processes such as lipid network signaling, energy homeostasis, DNA lesion repair mechanisms, and gut microbiota functions that could be linked to the multiple beneficial roles of metformin. Thus, the distinctive metabolic pattern linked to metformin administration can be used as a metabolic signature to predict the potential effect and mechanism of actions of new chemical entities during drug development.

Metabolic syndrome (MetS) is a pathological state of many abnormal metabolic sections. These abnormalities are closely related to diabetes, heart pathologies and other vascular diseases. Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine formula that has been used as a therapy for Alzheimer’s disease. DSS has rarely been reported in the application of MetS and its mechanism of how it improves gut microbia dysbiosis and hepatic lipid homeostasis. In this study, three extracts of DSS were obtained using water, 50% methanol in water and methanol as extracting solvents. Their chemical substances were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass (UPLC-Q/TOF-MS). Pharmacodynamic effect of the extracts were evaluated by comparison of biochemical factors, 16S rRNA sequencing test for gut microbiota analysis, as well as metabonomic and transcriptomic assessments on liver tissues from fructose-fed rats. This study aimed at investigating DSS’s mechanism of regulating blood lipid, anti-inflammation and reducing blood glucose. The results showed that the 50% methanol extract (HME) was more effective. It was worth noting that hydroxysteroid 17β-dehydrogenase 13 (HSD17β13) as a critical element of increasing blood lipid biomarker-triglyceride (TG), was decreased markedly by DSS. The influence from upgraded hydroxysteroid 17β-dehydrogenase 7 (HSD17β7) may be stronger than that from downgraded Lactobacillus in the aspect of regulating back blood lipid biomarker-total cholesterol (TC). The differential down-regulation of tumornecrosis factor alpha (TNF-α) and the significant up-regulation of Akkermansia showed the effective effect of anti-inflammation by DSS. The declining glycine and alanine induced the lowering glucose and lactate. It demonstrated that DSS slowed down the reaction of gluconeogenesis to reduce the blood glucose. The results demonstrated that DSS improved pathological symptoms of MetS and some special biochemical factors in three aspects by better regulating intestinal floras and improving hepatic gene expressions and metabolites.

Atherosclerosis (AS), especially atherosclerotic cardiovascular diseases (ASCVDs), and metabolic diseases (such as diabetes, obesity, dyslipidemia, and nonalcoholic fatty liver disease) are major public health issues worldwide that seriously threaten human health. Exploring effective natural product-based drugs is a promising strategy for the treatment of AS and metabolic diseases. Berberine (BBR), an important isoquinoline alkaloid found in various medicinal plants, has been shown to have multiple pharmacological effects and therapeutic applications. In view of its low bioavailability, increasing evidence indicates that the gut microbiota may serve as a target for the multifunctional effects of BBR. Under the pathological conditions of AS and metabolic diseases, BBR improves intestinal barrier function and reduces inflammation induced by gut microbiota-derived lipopolysaccharide (LPS). Moreover, BBR reverses or induces structural and compositional alterations in the gut microbiota and regulates gut microbe-dependent metabolites as well as related downstream pathways; this improves glucose and lipid metabolism and energy homeostasis. These findings at least partly explain the effect of BBR on AS and metabolic diseases. In this review, we elaborate on the research progress of BBR and its mechanisms of action in the treatment of AS and metabolic diseases from the perspective of gut microbiota, to reveal the potential contribution of gut microbiota to the multifunctional biological effects of BBR.

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. The symptoms of COVID-19 range from mild flu-like symptoms, including cough and fever, to life threatening complications. There are still quite a number of patients with COVID-19 showed enteric symptoms including nausea, vomiting, and diarrhea. The gastrointestinal tract may be one of the target organs of SARS-CoV-2. Angiotensin converting enzyme 2 (ACE2) is the main receptor of SARS-CoV-2 virus, which is significantly expressed in intestinal cells. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Intestinal flora imbalance and endotoxemia may accelerate the progression of COVID-19. Many herbs have demonstrated properties relevant to the treatment of COVID-19, by supporting organs and systems of the body affected by the virus. Herbs can restore the structure of the intestinal flora, which may further modulate the immune function after SARS-CoV-2 infection. Regulation of intestinal flora by herbal medicine may be helpful for the treatment and recovery of the disease. Understanding the role of herbs that regulate intestinal flora in fighting respiratory virus infections and maintaining intestinal flora balance can provide new ideas for preventing and treating COVID-19.

In this study, we investigated the therapeutic effects and mechanism of atractylodin (ATL) on dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. We found that atractylodin could significantly reverse the effects of DSS-induced ulcerative colitis, such as weight loss, disease activity index score; shorten the colon length, and reverse the pathological changes in the colon of mice. Atractylodin could inhibit the activation of colonic macrophages by inhibiting the MAPK pathway and alleviate intestinal inflammation in the mouse model of ulcerative colitis. Moreover, it could protect the intestinal barrier by inhibiting the decrease of the tight junction proteins, ZO-1, occludin, and MUC2. Additionally, atractylodin could decrease the abundance of harmful bacteria and increase that of beneficial bacteria in the intestinal tract of mice, effectively improving the intestinal microecology. In an LPS-induced macrophage model, atractylodin could inhibit the MAPK pathway and expression of the inflammatory factors of macrophages. Atractylodin could also inhibit the production of lactate, which is the end product of glycolysis; inhibit the activity of GAPDH, which is an important rate-limiting enzyme in glycolysis; inhibit the malonylation of GAPDH, and, thus, inhibit the translation of TNF-α. Therefore, ours is the first study to highlight the potential of atractylodin in the treatment of ulcerative colitis and reveal its possible mechanism.

Ganoderma lucidum (Lingzhi) polysaccharide peptide (GL-pp) is a component of the globally acknowledged traditional Chinese medicine Ganoderma lucidum; Ganoderma lucidum is known for its sedative, hypnotic, immune regulatory, antitumor, and other pharmacological effects. In recent years, sleep disorders have been linked to many diseases and human body disorders, including cancer. Some experimental studies in mice found that sleep fragmentation could promote tumor development and progression. However, effects on GL-pp on tumor metastasis under circumstances of sleep disorders have rarely been studied. Thus, in this study, we used mice with sleep fragmentation (SF) bearing B16-F10-luc-G5 melanoma tumors to investigate the effect of SF on melanoma metastasis. Furthermore, we investigated the antitumor and antimetastatic effects of GL-pp (80 mg/kg) in mice suffering from SF and bearing B16-F10-luc-G5. Then, whole proteomics was used to analyze the differences in protein expression in the lung tissue between SF mice bearing B16-F10-luc-G5 with and without GL-pp administration. High-throughput pyrosequencing of 16S rRNA was also used to analyze the impact of GL-pp on the gut microbiota composition in SF mice bearing B16-F10-luc-G5. Last, the effects of GL-pp on macrophage polarization and TNF-α serum levels were detected. Collectively, we found that SF significantly facilitated the B16-F10-luc-G5 melanoma tumor metastasis in mice, while GL-pp significantly reduced B16-F10-luc-G5 melanoma tumor metastasis under the condition of SF, in which proteomics and gut microbiota had been changed greatly.

Cholesterol gallstone (CG) disease has relationships with several metabolic abnormalities. Astragalus polysaccharides (APS) have been shown to have multiple benefits against metabolic disorders. We attempted to uncover the effect and mechanism of action of APS on diet-induced CG formation in mice. Animals were fed a chow diet or lithogenic diet (LD) with or without APS supplementation. The effect of APS on CG formation was evaluated. The level of individual bile acids (BAs) in gallbladder bile and ileum were measured by liquid chromatography-tandem mass spectrometry. Real-time reverse transcription-quantitative polymerase chain reaction and western blotting were used to assess expression of the genes involved in BA metabolism and the enterohepatic circulation. Cecal contents were collected to characterize microbiota profiles. APS ameliorated LD-induced CG formation in mice. APS reduced the level of total cholesterol, bile acid hydrophobicity index and cholesterol saturation index in gallbladder bile. The protective effect of APS might result from reduced absorption of cholic acid in the intestine and increased hepatic BA synthesis. APS relieved the LD-induced activation of the intestinal farnesoid X receptor and decreased ileal expression of fibroblast growth factor 15. In the liver, expression of cytochrome P450 (Cyp) enzyme Cyp7a1 and Cyp7b1 was increased, whereas expression of adenosine triphosphate-binding cassette (Abc) transporters Abcg5 and Abcg8 was decreased by APS. APS improved the diversity of the gut microbiota and increased the relative abundance of the Bacteroidetes phylum. APS had demonstratable benefits against CG disease, which might be associated with enhanced BA synthesis and improved gut microbiota. Our results suggest that APS may be a potential strategy for the prevention of CG disease.

Hepatic fibrosis (HF) is a typical consequence in the development of multiple chronic liver diseases, which is intimately related to the composition and metabolic status of gut microbiota. A myriad of evidence has indicated that traditional Chinese medicine can treat HF by regulating gut microbiota. Yinchen Wuling powder (YCWLP) is a famous traditional Chinese medicine prescription, which has been used to relieve liver diseases for thousands of years. YCWLP has demonstrated protective function on HF, but its effect on the alterations of gut microbiota is still unclear, and its explicit therapeutic mechanism also needs to be further elucidated. In this study, 16S rRNA gene sequencing and fecal metabolomics analysis were combined to investigate the influence of YCWLP on gut microbiota in HF rats and the interactions between gut microbiota and host metabolism. The results showed that YCWLP treatment significantly improved the disorder of multiple organ indices, HF-related cytokines and plasma LPS induced by HF. Masson’s trichrome stainings also showed that YCWLP treatment could significantly alleviate the severity of HF in rats. Additionally, YCWLP could reverse the significant changes in the abundance of certain genera closely related to HF phenotype, including Barnesiella [Ruminococcus] and Christensenella. Meanwhile, YCWLP significantly increased the abundance of Bifidobacterium, Coprococcus and Anaerostipes, which are closely related to butyrate production. Metabolomics and Spearman’s correlation analysis showed that YCWLP could regulate the disorder of arginine biosynthesis, sphingolipid metabolism and alanine, aspartate and glutamate metabolism in HF rats, and these regulations were intimately related to Barnesiella, [Ruminococcus], Christensenella, Coprococcus and Anaerostipes. By explaining the biological significance of the above results, we concluded that YCWLP might ameliorate HF by regulating the imbalance of gut microbiota, increasing the abundance of butyrate-producing bacteria to reduce ammonia production, promote ammonia degradation, and regulate pro-inflammatory cytokines and immune function.

Background: Clinical trials have proven that indigo naturalis is a candidate drug for treating ulcerative colitis (UC), but its therapeutic mechanism is still unclear.Purpose: This study aimed to evaluate the protective effect and mechanism of indigo naturalis to treat mice with dextran sulfate sodium (DSS)-induced UC.Methods: DSS-induced UC mice were treated with indigo naturalis (200 mg/kg), indigo (4.76 mg/kg), and indirubin (0.78 mg/kg) for 1 week. The anti-UC mechanism of indigo naturalis was studied by pathological section, inflammatory factor, western blot, and 16S rRNA sequencing.Results: According to body weight change, disease activity index, and colon length, indigo naturalis had the strongest anti DSS-induced UC effect, followed by indirubin and indigo. Pathological section showed that indigo naturalis, indigo, and indirubin could reduce the infiltration of inflammatory cells, increase the secretion of intestinal mucus, and repair the intestinal mucosa. Indigo naturalis, indigo, and indirubin could reduce IL-1β,IL-6, and TNF-α by inhibiting TLR4/MyD88/NF-κB signal transduction. Indigo naturalis and indigo could also reduce IgA and IgG both in serum and colon tissue. In addition, indigo naturalis, indigo, and indirubin could adjust the gut microbiota structure of DSS-induced UC mice, reducing the ratio of Firmicutes/Bacteroidetes and increasing the abundance of probiotics.Conclusion: Indigo and indirubin are one of the main anti-UC components of indigo naturalis. INN could regulate intestinal flora, reduce inflammation, repair intestinal mucosa, and improve the physiological status of DSS-induced UC mice and its anti-UC mechanism may be involved in inhibiting TLR4/MyD88/NF-κB signal transduction.

Our previous studies have shown that chlorogenic acid (CGA) could significantly improve acute and chronic liver injury through antioxidant and anti-inflammatory activities. However, its effect on non-alcoholic fatty liver disease (NAFLD) are not entirely clear. This study aims to explore the effect of CGA on NAFLD induced by high-fat diet (HFD) and whether it regulates the gut microbiota and Glucagon-like peptide-1 (GLP-1). NAFLD mice were established by HFD and treated with or without CGA. Serum transaminase, fasting blood glucose (FBG), blood lipids, insulin, GLP-1 and lipopolysaccharide (LPS) were detected. Liver histology was evaluated with Hematoxylin-eosin staining. Toll like receptor 4 (TLR4) signaling pathway was analyzed with western blot and inflammatory cytokines were detected with real-time PCR. The content of gut microbiota were determined with real-time PCR of the bacterial 16S rRNA gene. Expressions of intestine tight junctional protein were examined with immunohistochemistry. CGA could alleviate HFD-induced hepatic steatosis and inflammation, reduce serum transaminase, FBG and blood lipids, increase insulin sensitivity. CGA also could reverse HFD-induced activation of TLR4 signaling pathway and expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver. Meanwhile, CGA increased the content of Bifidobacterium and reduced the content of Escherichia coli in feces. Furthermore, CGA could increase the expression of tight junction proteins Occludin and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, CGA could the level of LPS and increased the level of GLP-1 in portal vein. These results indicated that CGA protected against HFD-induced hepatic steatosis and inflammation probably through its anti-inflammatory effects associated with regulation of gut microbiota and an increase of GLP-1 secretion and thus could be used as a potential drug for prevention and treatment of NAFLD.

Background: Emerging evidence implicates the dysregulated kynurenine pathway (KP), an immune-inflammatory pathway, in the pathophysiology of mood disorders (MD), including depression and bipolar disorder characterized by a low-grade chronic pro-inflammatory state. The metabolites of the KP, an important part of the microbiota-gut-brain axis, serve as immune system modulators linking the gut microbiota (GM) with the host central nervous system.Aim: This bibliometric analysis aimed to provide a first glimpse into the KP in MD, with a focus on GM research in this field, to guide future research and promote the development of this field.Methods: Publications relating to the KP in MD between the years 2000 and 2020 were retrieved from the Scopus and Web of Science Core Collection (WoSCC), and analyzed in CiteSpace (5.7 R5W), biblioshiny (using R-Studio), and VOSviewer (1.6.16).Results: In total, 1,064 and 948 documents were extracted from the Scopus and WoSCC databases, respectively. The publications have shown rapid growth since 2006, partly owing to the largest research hotspot appearing since then, “quinolinic acid.” All the top five most relevant journals were in the neuropsychiatry field, such as Brain Behavior and Immunity. The United States and Innsbruck Medical University were the most influential country and institute, respectively. Journal co-citation analysis showed a strong tendency toward co-citation of research in the psychiatry field. Reference co-citation analysis revealed that the top four most important research focuses were “kynurenine pathway,” “psychoneuroimmunology,” “indoleamine 2,3-dioxygenase,” and “proinflammatory cytokines,” and the most recent focus was “gut-brain axis,” thus indicating the role of the KP in bridging the GM and the host immune system, and together reflecting the field’s research foundations. Overlap analysis between the thematic map of keywords and the keyword burst analysis revealed that the topics “Alzheimer’s disease,” “prefrontal cortex,” and “acid,” were research frontiers.Conclusion: This comprehensive bibliometric study provides an updated perspective on research associated with the KP in MD, with a focus on the current status of GM research in this field. This perspective may benefit researchers in choosing suitable journals and collaborators, and aid in the further understanding of the field’s hotspots and frontiers, thus facilitating future research.

Cardiovascular disease is the main cause of death worldwide, and traditional cardiovascular risk factors cannot fully explain the occurrence of the disease. In recent years, the relationship between gut microbiota and its metabolites and cardiovascular disease has been a hot study topic. The changes in gut microbiota and its metabolites are related to the occurrence and development of atherosclerosis, myocardial infarction, heart failure, and hypertension. The mechanisms by which gut microbiota and its metabolites influence cardiovascular disease have been reported, although not comprehensively. Additionally, following ingestion, flavonoids are decomposed into phenolic acids that are more easily absorbed by the body after being processed by enzymes produced by intestinal microorganisms, which increases flavonoid bioavailability and activity, consequently affecting the onset of cardiovascular disease. However, flavonoids can also inhibit the growth of harmful microorganisms, promote the proliferation of beneficial microorganisms, and maintain the balance of gut microbiota. Hence, it is important to study the relationship between gut microbiota and flavonoids to elucidate the protective effects of flavonoids in cardiovascular diseases. This article will review the role and mechanism of gut microbiota and its metabolites in the occurrence and development of atherosclerosis, myocardial infarction, heart failure, and hypertension. It also discusses the potential value of flavonoids in the prevention and treatment of cardiovascular disease following their transformation through gut microbiota metabolism.

Glucosamine (GlcN) is used as a supplement for arthritis and joint pain and has been proved to have effects on inflammation, cancer, and cardiovascular diseases. However, there are limited studies on the regulatory mechanism of GlcN against glucose and lipid metabolism disorder. In this study, we treated high-fat diet (HFD)-induced diabetic mice with GlcN (1 mg/ml, in drinking water) for five months. The results show that GlcN significantly reduced the fasting blood glucose of HFD-fed mice and improved glucose tolerance. The feces of intestinal contents in mice were analyzed using 16s rDNA sequencing. It was indicated that GlcN reversed the imbalanced gut microbiota in HFD-fed mice. Based on the PICRUSt assay, the signaling pathways of glucolipid metabolism and biosynthesis were changed in mice with HFD feeding. By quantitative real-time PCR (qPCR) and hematoxylin and eosin (H&E) staining, it was demonstrated that GlcN not only inhibited the inflammatory responses of colon and white adipose tissues, but also improved the intestinal barrier damage of HFD-fed mice. Finally, the correlation analysis suggests the most significantly changed intestinal bacteria were positively or negatively related to the occurrence of inflammation in the colon and fat tissues of HFD-fed mice. In summary, our studies provide a theoretical basis for the potential application of GlcN to glucolipid metabolism disorder through the regulation of gut microbiota.

SARS-CoV-2, primarily considered a respiratory virus, is increasingly recognized as having gastrointestinal aspects based on its presence in the gastrointestinal (GI) tract and feces. SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 (ACE-2), a critical member of the renin-angiotensin-aldosterone system (RAAS) involved in the regulation of blood pressure and fluid system. In addition to the systemic endocrine functions, RAAS components are also involved in intracrine and organ-specific local functions. The angiotensin-converting enzyme 2 (ACE-2) is a key component of RAAS and a receptor for SARS-CoV-2. It is expressed in many tissues with gastrointestinal (GI) tract ACE-2 levels far exceeding those in the respiratory tract. SARS-CoV-2 binding to its receptor results in a deficiency of ACE-2 activity in endocrine, intracrine, and local lung and GI tract ACE-2. The local ACE-2 has different organ-specific functions, including hypertension-independent activities; dysregulations of these functions may contribute to multiorgan COVID-19 pathology, its severity, long-term effects, and mortality. We review supporting evidence from this standpoint. Notably, COVID-19 comorbidities involving hypertension, obesity, heart disease, kidney disease, and diabetes are associated with gastrointestinal problems and display ACE-2 deficits. While RAAS inhibitors target both endocrine and intracrine ACE-2 activity, the deficit of the local ACE-2 activity in the lungs and more so in the gut have not been targeted. Consequently, the therapeutic approach to COVID-19 should be carefully reconsidered. Ongoing clinical trials testing oral probiotic bound ACE-2 delivery are promising.

Morphine abuse is a global public health problem. Increasing evidence has shown that gut microbiota dysbiosis plays an important role in several central nervous system diseases. However, whether there is an association between gut microbiota and morphine dependence remains unclear. In this study, the effects of isorhynchophylline on morphine dependence were evaluated based on the microbiota-gut-brain axis (MGBA). The results showed that isorhynchophylline could reverse the changes in alpha and beta diversity, composition, and richness of the intestinal flora occurring in morphine-dependent zebrafish, as well as the morphine-induced changes in the expression of MGBA-related genes in BV2 cells and the brain and intestine of zebrafish. Based on the results, we then used antibiotics to evaluate whether disrupting the gut microbiota would affect morphine addiction in zebrafish. The results showed that the antibiotic-induced intestinal floral imbalance changed the behavior of morphine-dependent zebrafish, the characteristics of the zebrafish intestinal flora, and the expression of MGBA-related genes in the zebrafish brain and intestine. Importantly, we also show that, following antibiotic administration, the ameliorative effects of isorhynchophylline on morphine addiction were lost. Together, our results indicate that the gut microbiota interacts with the brain, and dysbiosis of the intestinal flora may affect the efficacy of isorhynchophylline in the body. Our findings provide a novel framework for understanding the mechanisms of morphine addiction through the MGBA and may provide new therapeutic strategies for the use of Chinese medicines in the prevention of drug addiction.

Hyperlipidemia is a chronic disorder that is difficult to cure and usually treated with long-term lipid-reducing drugs. Recent trends have led to the use of diet therapies or food-derived strategies in the treatment of such long-term diseases. The Chinese rice wine (huangjiu) contains a wide range of bioactive peptides that are produced during the multi-species fermentation process. To clarify the regulation effects of lipid metabolism and gut microbiota by huangjiu bioactive peptides, three huangjiu peptides were isolated, purified and characterized by hyper-filtration, macroporous resin, gel filtration separation and structural identification. Meanwhile, a mouse model of high-fat diet-induced hyperlipidemia was established to study the effects of huangjiu peptides on serum biomarker, hepatic metabolism and gut microbiota dysbiosis. Experimental results showed that huangjiu peptides T1 and T2 (HpT1, HpT2) treatment alleviated the increase in serum total cholesterol, triglyceride, low-density lipoprotein cholesterol levels and aberrant hepatic lipid accumulation in the high-fat diet-induced hyperlipidemia mice. Furthermore, HpT2 and HpT1 restored the α-diversity and structure of gut microbial community after hyperlipidemia-induced microbiota disturbance compared with simvastatin and HpT3. The administration of HpT2 and HpT1 regulated the microbiota-mediated gut ecology through alterations of characteristic taxa including Lactobacillus, Ileibacterium, Faecalibaculum and Alloprevotella by linear discriminant analysis effect size analysis. Collectively, our results offer new insights into the abilities of food-derived peptides on alleviation of high-fat diet-induced hyperlipidemia, hepatic steatosis and gut dysbiosis in mice.

Oxalate is an ionic form of a potentially toxic oxalic acid that is formed in the human body from a combination of food sources and their absorption in the gastrointestinal tract (approximately 30%), as well as the endogenous synthesis of glyoxylate (40%) and ascorbic acid (30%) (Jonassen et al., 2005; Robijn et al., 2011). The balance of oxalate in the human body is achieved due to its renal (up to 90%) and intestinal (10%) excretion (Robijn et al., 2011; Huang et al., 2020). Loss of kidney function decreases renal oxalate clearance and increases plasma oxalic acid (POx) concentration, according to the progression of chronic kidney disease (CKD) stages (Robijn et al., 2011; Perinpam et al., 2017). The accumulation of oxalate may be associated with oxidative stress, inflammation (Khan, 2014; Ermer et al., 2016; Dominguez-Gutierrez et al., 2018; Korol et al., 2021) and a high risk of cardiovascular disease (CVD) (Liu et al., 2014; Fan X et al., 2017; Arafa et al., 2020; Demikhov et al., 2020) in patients with kidney stones. However, although impaired oxalate homeostasis is a well-known occurrence in patients with end-stage renal disease (ESRD), a high POx concentration has never been considered a trigger for oxidative stress, systemic inflammation, and CVD risk in these patients. In this opinion article, based on the published data and results of our clinical studies, we outlined the possible contribution of oxalate to oxidative stress, chronic inflammation, and CVD risk in patients with ESRD. Gut Microbiota Disruption Causes Hyperoxalemia in Patients With ESRD Given that oxalate is mainly excreted by the kidneys, dialysis seems to be the main approach for oxalate removal in patients with ESRD (Ermer et al., 2017; Perinpam et al., 2017). Nevertheless, despite a homogeneous patient population and a standardized dialysis regimen, the intraindividual predialysis POx concentration level varies from 1.8 mg/L (20 µmol/L) to 5.4 mg/L (60 µmol/L) in different studies (Ermer et al., 2017; Perinpam et al., 2017; Korol et al., 2021). Considering the marginal dependence of oxalate homeostasis on its dietary intake (Mitchell et al., 2019; Kumar et al., 2021) and limited renal excretion in patients with ESRD, it remains unclear why they have significant differences in POx concentration under the same treatment conditions. We hypothesized that in patients with anuria/kidney failure, the gut plays a much more significant role in oxalate handling than in healthy participants. Both paracellular and transcellular intestinal oxalate transport disruption and less functional activity of oxalate-degrading bacteria (ODB) in fecal microbiota might be the main factors affecting oxalate homeostasis in patients on dialysis. The gastrointestinal tract plays a complex role in oxalate metabolism via intestinal oxalate transport and the ability of ODB to degrade oxalate (Hatch and Freel, 2008; Robijn et al., 2011; Huang et al., 2020; Ticinesi et al., 2020). Oxalate is absorbed from all parts of the gastrointestinal tract through paracellular (predominantly passive) and active transcellular mechanisms (Robijn et al., 2011; Ticinesi et al., 2020). The relative contribution of these two transport mechanisms varies with the intestinal segment and its condition (Hatch and Freel, 2008; Robijn et al., 2011; Whittamore and Hatch, 2017). Paracellular transport depends on the residence time of the chyme in the small intestine and the degree of calcium ionization (Hatch and Freel, 2008; Robijn et al., 2011; Whittamore and Hatch, 2017). The active transcellular oxalate flux is derived from anion exchange proteins belonging to the multifunctional SLC26 gene family. One of the gene family members, Slc26a6, is expressed at high levels in the intestine and proximal renal tubules and plays a major role in controlling systemic oxalate metabolism (Whittamore and Hatch, 2017). Oxalobacter formigenes produce a small protein that directly induces oxalate transport via the oxalate transporter SLC26A6–dependent mechanism in intestinal Caco-2 cells (Arvans et al., 2017). Among oxalate transporters, many factors are involved in determining oxalate absorption and secretion in the gut in patients with ESRD: 1) dietary restriction; 2) high uremic toxin concentration; 3) malabsorption; 4) low blood concentrations of calcium, magnesium, and fiber that may affect the oxalate absorption; 5) use of antibiotics, phosphate binders, or other medications that can influence the quantitative and qualitative composition of gut microbiota; and 6) oxalate-degrading activity (ODA) of gut microbiota (Robijn et al., 2011; Mitchell et al., 2019; Ticinesi et al., 2020). Gut microbiota is a critical factor affecting intestinal oxalate metabolism and kidney stone formation (Stepanova et al., 2018; Chen et al., 2019; Ticinesi et al., 2020). O. formigenes degrade oxalate in the intestine and stimulate its endogenous secretion (Hatch et al., 2006; Arvans et al., 2017). However, the absence of intestinal O. formigenes colonization may not be the only cause for kidney stones, and a diversity of gut ODB (e.g., Lactobacillus spp., Bifidobacterium spp., Bacillus spp., E. faecalis, N. albigula) were identified (Gomathi et al., 2014; Barnett et al., 2016; Miller et al., 2019; Stepanova et al., 2021). Since the gut microbiota in patients on dialysis is characterized by increased Enterobacteriaceae and low colonization of Bifidobacterium and Lactobacillus species compared with normal controls (Hu et al., 2020; Ren et al., 2020), the low abundance of ODB in gut microbiota may play a significant role in oxalate homeostasis in patients with ESRD. Indeed, we previously demonstrated that the ODB number in patients on dialysis was significantly lower than in healthy volunteers (Stepanova et al., 2020a; Stepanova et al., 2021). However, when we separately evaluated the ODB number and their total ODA in fecal microbiota in patients on dialysis, we got surprising results. The ODB number was associated neither with their total ODA in fecal microbiota nor urinary oxalate (UOx) excretion and POx concentration. According to the results, only total fecal ODA was associated with urine and plasma oxalate levels: the lower the ODA in the fecal microbiota, the higher the POx concentration and the lower the UOx excretion. Thus, total ODA in the fecal microbiota rather than the ODB number resulted in elevation of plasma and urine oxalate concentrations in patients with ESRD.

The disruption of gut microbes is associated with diabetic cardiomyopathy, but the mechanism by which gut microbes affect cardiac damage remains unclear. We explored gut microbes and branched-chain amino acid (BCAA) metabolite catabolism in diabetic cardiomyopathy mice and investigated the cardioprotective effect of pyridostigmine. The experiments were conducted using a model of diabetic cardiomyopathy induced by a high-fat diet + streptozotocin in C57BL/6 mice. The results of high-throughput sequencing showed that diabetic cardiomyopathy mice exhibited decreased gut microbial diversity, altered abundance of the diabetes-related microbes, and increased abundance of the BCAA-producing microbes Clostridiales and Lachnospiraceae. In addition, diabetes downregulated tight junction proteins (ZO-1, occludin, and claudin-1) and increased intestinal permeability to impair the intestinal barrier. These impairments were accompanied by reduction in vagal activity that manifested as increased acetylcholinesterase levels, decreased acetylcholine levels, and heart rate variability, which eventually led to cardiac damage. Pyridostigmine enhanced vagal activity, restored gut microbiota homeostasis, decreased BCAA-producing microbe abundance, and improved the intestinal barrier to reduce circulating BCAA levels. Pyridostigmine also upregulated BCAT2 and PP2Cm and downregulated p-BCKDHA/BCKDHA and BCKDK to improve cardiac BCAA catabolism. Moreover, pyridostigmine alleviated abnormal mitochondrial structure; increased ATP production; decreased reactive oxygen species and mitochondria-related apoptosis; and attenuated cardiac dysfunction, hypertrophy, and fibrosis in diabetic cardiomyopathy mice. In conclusion, the gut microbiota, BCAA catabolism, and vagal activity were impaired in diabetic cardiomyopathy mice but were improved by pyridostigmine. These results provide novel insights for the development of a therapeutic strategy for diabetes-induced cardiac damage that targets gut microbes and BCAA catabolism.

Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease, which usually manifests as abdominal pain, diarrhea and hematochezia. The disease often recurs and is difficult to cure. At present, the pathogenesis is not clear, but it is believed that the disease is caused by a complex interaction among immunity, heredity, environment and intestinal microflora disorders. MicroRNA (miRNA) is endogenous single-stranded non-coding RNA of 17–25 nucleotides (nts). They target the 3'Untranslated Region of a target gene and inhibit or degrade the target gene according to the extent of complementary bases. As important gene expression regulators, miRNAs are involved in regulating the expression of most human genes, and play an important role in the pathogenesis of many autoimmune diseases including UC. Studies in recent years have illustrated that abnormal expression of miRNA occurs very early in disease pathogenesis. Moreover, this abnormal expression is highly related to disease activity of UC and colitis-associated cancer, and involves virtually all key UC-related mechanisms, such as immunity and intestinal microbiota dysregulation. Recently, it was discovered that miRNA is highly stable outside the cell in the form of microvesicles, exosomes or apoptotic vesicles, which raises the possibility that miRNA may serve as a novel diagnostic marker for UC. In this review, we summarize the biosynthetic pathway and the function of miRNA, and summarize the usefulness of miRNA for diagnosis, monitoring and prognosis of UC. Then, we described four types of miRNAs involved in regulating the mechanisms of UC occurrence and development: 1) miRNAs are involved in regulating immune cells; 2) affect the intestinal epithelial cells barrier; 3) regulate the homeostasis between gut microbiota and the host; and 4) participate in the formation of tumor in UC. Altogether, we aim to emphasize the close relationship between miRNA and UC as well as to propose that the field has value for developing potential biomarkers as well as therapeutic targets for UC.

There is increasing evidence that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are associated with Crohn's disease (CD), but the specific mechanism by which F. nucleatum promotes CD development is unclear. Here, we first examined the abundance of F. nucleatum and its effects on CD disease activity and explored whether F. nucleatum aggravated intestinal inflammation and promoted intestinal mucosal barrier damage in vitro and in vivo. Our data showed that F. nucleatum was enriched in 41.21% of CD tissues from patients and was correlated with the clinical course, clinical activity, and refractory behavior of CD (P < 0.05). In addition, we found that F. nucleatum infection is involved in activating the endoplasmic reticulum stress (ERS) pathway during CD development to promote intestinal mucosal barrier destruction. Mechanistically, F. nucleatum targeted caspase activation and recruitment domain 3 (CARD3) to activate the ERS pathway and promote F. nucleatum-mediated mucosal barrier damage in vivo and in vitro. Thus, F. nucleatum coordinates a molecular network involving CARD3 and ERS to control the CD process. Measuring and targeting F. nucleatum and its associated pathways will provide valuable insight into the prevention and treatment of CD.

Background: Emerging evidence suggests that gut microbiota plays a vital role in the occurrence of multiple endocrine disorders including polycystic ovary syndrome (PCOS). Shaoyao-Gancao Decoction (SGD), a classical Chinese prescription, has been widely used in the treatment of PCOS for decades. In previous studies, we found that SGD treatment could effectively reduce ovarian inflammation in PCOS rats. However, whether the anti-inflammation effect of SGD involves the regulation of the gut microbiota remains elusive.Methods: Letrozole-induced PCOS rat models were established, and the therapeutic effects of SGD were evaluated. Specifically, body weight, serum hormone concentrations, estrus phase and ovary histopathology were assessed. Then the structure of gut microbiota was determined by 16s rRNA sequencing. Additionally, the serum levels of pro-inflammatory cytokines and LPS were measured by ELISA kits. The key gene and protein expressions of TLR4/NF-κB signaling pathway were detected by quantitative real-time PCR and western blot.Results: SGD could effectively reduce body weight, regulate estrous cycles and ameliorate hyperandrogenism in PCOS rats. In addition, SGD treatment decreased releases of pro-inflammatory cytokines, enhanced the expressions of tight junction (occludin and claudin1), and then prevented a translocation of LPS into bloodstream. SGD could significantly reduce the ratio of Firmicutes to Bacteroidetes, decrease the abundance of LPS-producing pathogens Proteobateria and enrich the abundance of Butyricicoccus, Coprococcus, Akkermansia Blautia and Bacteroides in PCOS rats. Furthermore, SGD blunted the key gene and protein expressions of TLR4/NF-κB signaling pathway both in vivo and in LPS-induced RAW264.7 cells.Conclusion: SGD administration could ameliorate the inflammatory response in PCOS rats by remodeling gut microbiome structure, protecting gut barrier, and suppressing TLR4/NF-κB signaling pathway.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease impairing the gastrointestinal tract, and its incidence and prevalence have been increasing over time worldwide. IBD greatly reduces peoples' quality of life and results in several life-threatening complications, including polyp, toxic colonic dilatation, intestinal perforation, gastrointestinal bleeding, and cancerization. The current therapies for IBD mainly include drugs for noncritical patients and operation for critical patients. However, continuous use of these drugs causes serious side effects and increased drug resistance, and the demand of effective and affordable drugs with minimal side effects for IBD sufferers is urgent. Natural-derived polysaccharides are becoming a research hotspot for their therapeutic effects on IBD. This study focuses on the research progress of various natural polysaccharides from plants, seaweeds, and mushrooms for the treatment of IBD during recent 20 years. Regulation of oxidative stress, inflammatory status, gut microbiota, and immune system and protection of the intestinal epithelial barrier function are the underlying mechanisms for the natural-derived polysaccharides to treat IBD. The excellent efficacy and safety of polysaccharides make them promising candidates for IBD therapy.

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1β, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.