Alleviation of lipid metabolic dysfunction through regulation of intestinal bacteriophages and bacteria by green tea polyphenols in Ob/Ob mice.

Green tea polyphenols (GTP) have been shown to ameliorate lipid metabolic disorders by regulating intestinal bacteria. Given the significant role of intestinal bacteriophages in shaping the gut microbiota, this study investigates GTP's influence on gut bacteriophage-bacteria interactions and lipid metabolism using metagenomics and metabonomics. The research results indicated that GTP significantly reduced body weight, serum triglycerides, leptin, insulin resistance, interleukin-6, and TNF-α levels while increasing adiponectin in ob/ob mice fed high-fat diet, aiding intestinal repair. GTP improved gut health by decreasing Enterobacter, Siphoviridae and Enterobacteria_phage_sfv, increasing Bifidobacterium and intestinal metabolites SCFA and hippuric acid. Correlation analysis showed negative correlations between Enterobacter sp. 50,588,862 and Enterobacteria_phages, Shigella_phages with 4-hydroxyphenylpyruvate and hippuric acid. Bifidobacterium choerinum and Bifidobacterium sp. AGR2158 were positively correlated with fatty acids and bile acids. In conclusion, GTP reduced fat accumulation and inflammation, enhanced gut barrier function in obese mice, closely associated with changes in the gut bacteriophage community.

Quercetin Alleviates Insulin Resistance and Repairs Intestinal Barrier in db/db Mice by Modulating Gut Microbiota.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy individuals, and its disorder may affect health status and even results in metabolic diseases. Quercetin, a natural flavonoid, has been shown to have biological activities that can be used in the prevention and treatment of metabolic diseases. This study aimed to explore the mechanism of quercetin in alleviating T2DM based on gut microbiota. db/db mice were adopted as the model for T2DM in this study. After 10 weeks of administration, quercetin could significantly decrease the levels of body weight, fasting blood glucose (FBG), serum insulin (INS), the homeostasis model assessment of insulin resistance (HOMA-IR), monocyte chemoattractant protein-1 (MCP-1), D-lactic acid (D-LA), and lipopolysaccharide (LPS) in db/db mice. 16S rRNA gene sequencing and untargeted metabolomics analysis were performed to compare the differences of gut microbiota and metabolites among the groups. The results demonstrated that quercetin decreased the abundance of Proteobacteria, Bacteroides, Escherichia-Shigella and Escherichia_coli. Moreover, metabolomics analysis showed that the levels of L-Dopa and S-Adenosyl-L-methionine (SAM) were significantly increased, but 3-Methoxytyramine (3-MET), L-Aspartic acid, L-Glutamic acid, and Androstenedione were significantly decreased under quercetin intervention. Taken together, quercetin could exert its hypoglycemic effect, alleviate insulin resistance, repair the intestinal barrier, remodel the intestinal microbiota, and alter the metabolites of db/db mice.

Modulation of intestinal metabolites by calorie restriction and its association with gut microbiota in a xenograft model of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor, and its occurrence and development are closely related to dysbiosis of gut microbes. Previously, we found calorie restriction altered the composition of the microbial community in a colorectal cancer mouse model and inhibited in vivo growth of CRC cells. Here, we aim to further investigate alteration in the intestinal metabolites and explore the interplay between gut microbiota and intestinal metabolites upon calorie restriction. METHODS: Human colorectal cancer HCT116 cells were used to establish a colorectal cancer xenograft mouse model. The changes of intestinal metabolites in the ad libitum group and calorie restriction group were investigated through untargeted metabolomics analysis. The integrative analysis of gut microbiota and metabolites to elucidate the associations between gut microbiota and intestinal metabolites. RESULTS: Compared with the mice in the ad libitum group, mice upon calorie restriction exhibited downregulation of Isoleucyl-Valine, and upregulation of D-Proline, 1-Palmitoylphosphatidylcholine, and 4-Trimethylammoniobutanoic acid. Additionally, an integrative analysis of gut microbiota and metabolites revealed that Lactobacillus, Parabacteroides and rC4-4 genus were upregulated in the calorie restriction group and positively correlated with D-Proline, 4-Trimethylammoniobutanoic acid or 1-Palmitoylphosphatidylcholine, while negatively correlated with Isoleucyl-Valine. In contrast, the Nitrospirae and Deferribacteres phylum exhibited opposite trends. CONCLUSION: Calorie restriction affects the abundance of gut microbes such as Nitrospirae phylum and Lactobacillus genus in mouse model of colorectal cancer, leading to changes in the metabolites such as D-Proline、Isoleucyl-Valine, which contributes to the suppression of in vivo growth of CRC by calorie restriction.

Metabolic Insights into Caffeine's Anti-Adipogenic Effects: An Exploration through Intestinal Microbiota Modulation in Obesity.

Obesity, a chronic condition marked by the excessive accumulation of adipose tissue, not only affects individual well-being but also significantly inflates healthcare costs. The physiological excess of fat manifests as triglyceride (TG) deposition within adipose tissue, with white adipose tissue (WAT) expansion via adipocyte hyperplasia being a key adipogenesis mechanism. As efforts intensify to address this global health crisis, understanding the complex interplay of contributing factors becomes critical for effective public health interventions and improved patient outcomes. In this context, gut microbiota-derived metabolites play an important role in orchestrating obesity modulation. Microbial lipopolysaccharides (LPS), secondary bile acids (BA), short-chain fatty acids (SCFAs), and trimethylamine (TMA) are the main intestinal metabolites in dyslipidemic states. Emerging evidence highlights the microbiota's substantial role in influencing host metabolism and subsequent health outcomes, presenting new avenues for therapeutic strategies, including polyphenol-based manipulations of these microbial populations. Among various agents, caffeine emerges as a potent modulator of metabolic pathways, exhibiting anti-inflammatory, antioxidant, and obesity-mitigating properties. Notably, caffeine's anti-adipogenic potential, attributed to the downregulation of key adipogenesis regulators, has been established. Recent findings further indicate that caffeine's influence on obesity may be mediated through alterations in the gut microbiota and its metabolic byproducts. Therefore, the present review summarizes the anti-adipogenic effect of caffeine in modulating obesity through the intestinal microbiota and its metabolites.

Engineered probiotics introduced to improve intestinal microecology for the treatment of chronic diseases: present state and perspectives.

Purpose: Correcting intestinal microecological imbalance has become one of the core strategies to treat chronic diseases. Some traditional microecology-based therapies targeting intestine, such as prebiotic therapy, probiotic therapy and fecal microbiota transplantation therapy, have been used in the prevention and treatment of clinical chronic diseases, which still facing low safety and poor controllability problems. The development of synthetic biology technology has promoted the development of intestinal microecology-based therapeutics for chronic diseases, which exhibiting higher robustness and controllability, and become an important part of the next generation of microecological therapy. The purpose of this review is to summarize the application of synthetic biology in intestinal microecology-based therapeutics for chronic diseases. Methods: The available literatures were searched to find out experimental studies and relevant review articles on the application of synthetic biology in intestinal microecology-based therapeutics for chronic diseases from year 1990 to 2023. Results: Evidence proposed that synthetic biology has been applied in the intestinal microecology-based therapeutics for chronic diseases, covering metabolic diseases (e.g. diabetes, obesity, nonalcoholic fatty liver disease and phenylketonuria), digestive diseases (e.g. inflammatory bowel disease and colorectal cancer), and neurodegenerative diseases (e.g. Alzheimer's disease and Parkinson's disease). Conclusion: This review summarizes the application of synthetic biology in intestinal microecology-based therapeutics for major chronic diseases and discusses the opportunities and challenges in the above process, providing clinical possibilities of synthetic biology technology applied in microecological therapies.

Berberine improves DSS-induced colitis in mice by modulating the fecal-bacteria-related bile acid metabolism.

Ulcerative colitis (UC) has been confirmed as a disease with a high incidence and low cure rate worldwide. In severe cases, UC can develop into colon cancer. Modern research has confirmed that berberine (BBR) can treat UC by inhibiting the expressions of inflammatory factors. However, the contribution of gut microbiota and flora metabolites in treating UC with BBR remains unclear. In this study, the ameliorative effects of BBR on gut microbiota dysbiosis and flora metabolites were investigated in a dextran sodium sulfate (DSS)-induced UC rodent model. We found that BBR significantly improved the pathological phenotype, attenuated intestinal barrier disruption, and mitigated colonic inflammation in DSS mice. By 16 S rDNA sequencing, BBR alleviated gut microbiota dysbiosis in UC mice. Moreover, the gut microbiota depletion experiment confirmed that the therapeutic effect of BBR was inextricably correlated with the gut microbiota. Besides, the flora metabolites (e.g., short-chain fatty acids, bile acids, and 5-hydroxytryptamine) were studied using HPLC-MS. The results suggested that BBR ameliorated the bile acid imbalance induced by DSS in the liver and gut. Furthermore, BBR treatment repaired gut barrier damage. The above results revealed that BBR alleviated DSS-induced UC in mice by restoring the disturbed gut microbiota, elevating unconjugated and secondary bile acids in the gastrointestinal tract, and activating the FXR and TGR5 signal pathway. This study provides novel insights into the mechanism of BBR in treating UC.

Molecular Pathogenesis of Colitis-associated Colorectal Cancer: Immunity, Genetics, and Intestinal Microecology.

Patients with inflammatory bowel disease (IBD) have a high risk for colorectal cancer (CRC). This cancer type, which is strongly associated with chronic inflammation, is called colitis-associated CRC (CAC). Understanding the molecular pathogenesis of CAC is crucial to identify biomarkers necessary for early diagnosis and more effective treatment directions. The accumulation of immune cells and inflammatory factors, which constitute a complex chronic inflammatory environment in the intestinal mucosa, may cause oxidative stress or DNA damage to the epithelial cells, leading to CAC development and progression. An important feature of CAC is genetic instability, which includes chromosome instability, microsatellite instability, hypermethylation, and changes in noncoding RNAs. Furthermore, the intestinal microbiota and metabolites have a great impact on IBD and CAC. By clarifying immune, genetic, intestinal microecology, and other related pathogenesis, CAC may be more predictable and treatable.

This review summarizes the molecular pathogenesis of colitis-associated colorectal cancer (CAC) from the aspects of immunity, genetics, and intestinal microecology, and it points out the potential mechanisms worthy of further study. It highlights the complexity of the inflammation process to cancer and the dual effects of inflammatory mediators in order to provide inspiration for finding effective biomarkers or targets to make CAC more predictable and treatable.

Long-term simulated microgravity alters gut microbiota and metabolome in mice.

Spaceflight and microgravity has a significant impact on the immune, central nervous, bone, and muscle support and cardiovascular systems. However, limited studies are available on the adverse effects of long-term microgravity on the intestinal microbiota, metabolism, and its relationships. In this study, a ground-based simulated microgravity (SMG) mouse model was established to evaluate the impact of long-term microgravity on gut microbiota and metabolome. After 8 weeks of SMG, alterations of the intestinal microbiota and metabolites were detected using 16S rRNA sequencing and untargeted metabolomics. Compared to the control, no significant differences in α-diversity were observed at weeks 2, 4 and 8. Nevertheless, there were clear differences in community structures at different time points. The phylum Verrucomicrobia significantly declined from 2 to 8 weeks of SMG, yet the relative abundance of Actinobacteria and Deferribacteres expanded remarkably at weeks 8. SMG decreased the genus of Allobaculum and increased Bacteroides significantly throughout the period of 8 weeks. Besides, Genus Akkermansia, Gracilibacter, Prevotella, Odoribacter, Rothia, Sporosarcina, Gracilibacter, Clostridium, and Mucispirillum were identified as biomarkers for SMG group. Desulfovibrio_c21_c20, Akkermansia_muciniphila, and Ruminococcus_gnavus dropped at week 2, which tend to recover at week 4, except for Akkermansia_muciniphila. Bacteroides_uniformis and Faecalibacterium_prausnitzii declined significantly, while Ruminococcus_flavefaciens and Mucispirillum_schaedleri elevated at week 8. Furthermore, intestinal metabolome analysis showed that 129 were upregulated and 146 metabolites were downregulated in SMG. Long-term SMG most affected steroid hormone biosynthesis, tryptophan, cysteine, methionine, arginine, proline metabolism, and histidine metabolism. Correlated analysis suggested that the potential beneficial taxa Allobaculum, Akkermansia, and Faecalibacterium were negatively associated with tryptophan, histidine, arginine, and proline metabolism, but positively with steroid hormone biosynthesis. Yet Bacteroides, Lachnospiraceae_Clostridium, Rothia, Bilophila, and Coprococcus were positively correlated with arginine, proline, tryptophan, and histidine metabolism, while negatively associated with steroid hormone biosynthesis. These results suggest that Long-term SMG altered the community of intestinal microbiota, and then further disturbed intestinal metabolites and metabolic pathways, which have great potential to help understand and provide clues for revealing the mechanisms of long-term SMG involved diseases.

Myofibrillar protein-chlorogenic acid complexes ameliorate glucose metabolism via modulating gut microbiota in a type 2 diabetic rat model.

Growing evidence suggests that polyphenols could mitigate type 2 diabetes mellitus (T2DM). The glucose-regulatory effects of protein-bound polyphenols, however, have been rarely studied. In this study, macrogenomic and metabolomic analyses were applied to investigate the modulation of myofibrillar protein-chlorogenic acid (MP-CGA) complexes on T2DM rats from the gut microbiota perspective. Results showed that MP-CGA improved hyperglycemia and hyperlipidemia, decreased intestinal inflammation, and reduced intestinal barrier injury. MP-CGA reconstructed gut microbiota in T2DM rats, elevating the abundance of probiotics Bacteroides, Akkermansia, and Parabacteroides while suppressing opportunistic pathogens Enterococcus and Staphylococcus. MP-CGA significantly elevated the concentrations of intestinal metabolites like butyric acid that positively regulate T2DM and reduced the secondary bile acids contents. Therefore, MP-CGA modulated the gut microbiota and related metabolites to maintain stable blood glucose in T2DM rats, providing new insights into the application of protein-polyphenol complexes in foods.

Fu Brick Tea Manages HFD/STZ-Induced Type 2 Diabetes by Regulating the Gut Microbiota and Activating the IRS1/PI3K/Akt Signaling Pathway.

The antidiabetic effects of Fu brick tea aqueous extract (FTE) and its underlying molecular mechanism in type 2 diabetes mellitus (T2DM) mice were investigated. FTE treatment significantly relieved dyslipidemia, insulin resistance (IR), and hepatic oxidative stress caused by T2DM. FTE also ameliorated the T2DM-induced gut dysbiosis by decreasing the Firmicutes/Bacteroidota (F/B) ratio at the phylum level and promoting the proliferation of Bifidobacterium, Parabacteroides, and Roseburia at the genus level. Besides, FTE significantly improved colonic short-chain fatty acid levels of T2DM mice. Furthermore, the antidiabetic effects of FTE were proved to be mediated by the IRS1/PI3K/Akt and AMPK-mediated gluconeogenesis signaling pathways. Metabolomics analysis illustrated that FTE recovered the levels of 28 metabolites associated with T2DM to the levels of normal mice. Taken together, these findings suggest that FTE can alleviate T2DM by reshaping the gut microbiota, activating the IRS1/PI3K/Akt pathway, and regulating intestinal metabolites.

Mechanisms Underlying the Interaction Between Chronic Neurological Disorders and Microbial Metabolites via Tea Polyphenols Therapeutics.

The number of hydroxyl groups and existence of characteristic structural groups in tea polyphenols (TP) make them have antioxidant activity, which gives TP anti-inflammatory effects, toward protecting the intestinal flora and brain neurons. Host-associated microbial metabolites are emerging as dominant modifiers of the central nervous system. As yet, the investigations on host-microbiota crosstalking remain challenging, studies focusing on metabolites such as serotonin, short-chain fatty acids, and others have pinpointed multiple actionable signaling pathways relevant to host health. However, there are still complexities and apparent limitations inherent in transforming complex human diseases to corresponding animal models. Here, we choose to discuss several intestinal metabolites with research value, as crucial areas for assessing TP-mediated chronic brain diseases interactions with microbial.

Alterations of gut microbiota diversity, composition and metabonomics in testosterone-induced benign prostatic hyperplasia rats.

BACKGROUND: Studies had shown many diseases affect the stability of human microbiota, but how this relates to benign prostatic hyperplasia (BPH) has not been well understood. Hence, this study aimed to investigate the regulation of BPH on gut microbiota composition and metabonomics. METHODS: We analyzed gut samples from rats with BPH and healthy control rats, the gut microbiota composition and metabonomics were detected by 16S rDNA sequencing and liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: High-throughput sequencing results showed that gut microbiota beta-diversity increased (P < 0.01) in the BPH group vs. control group. Muribaculaceae (P < 0.01), Turicibacteraceae (P < 0.05), Turicibacter (P < 0.01) and Coprococcus (P < 0.01) were significantly decreased in the BPH group, whereas that of Mollicutes (P < 0.05) and Prevotella (P < 0.05) were significantly increased compared with the control group. Despite profound interindividual variability, the levels of several predominant genera were different. In addition, there were no statistically significant differences in several bacteria. BPH group vs. control group: Firmicutes (52.30% vs. 57.29%, P > 0.05), Bacteroidetes (46.54% vs. 41.64%, P > 0.05), Clostridia (50.89% vs. 54.66%, P > 0.05), Ruminococcaceae (25.67% vs. 20.56%, P > 0.05). LC-MS/MS of intestinal contents revealed that differential metabolites were mainly involved in cellular processes, environmental information processing, metabolism and organismal systems. The most important pathways were global and overview maps, lipid metabolism, amino acid metabolism, digestive system and endocrine system. Through enrichment analysis, we found that the differential metabolites were significantly enriched in metabolic pathways, steroid hormone biosynthesis, ovarian steroidogenesis, biosynthesis of unsaturated fatty acids and bile secretion. Pearson correlation analysis (R = 0.94) showed that there was a strong correlation between Prevotellaceae, Corynebacteriaceae, Turicibacteraceae, Bifidobacteriaceae and differential metabolites. CONCLUSION: Our findings suggested an association between the gut microbiota and BPH, but the causal relationship between the two groups is unclear. Thus, further studies are warranted to elucidate the potential mechanisms and causal relationships between BPH and gut microbiota.

Dietary α-Linolenic Acid-Rich Flaxseed Oil Ameliorates High-Fat Diet-Induced Atherosclerosis via Gut Microbiota-Inflammation-Artery Axis in ApoE -/- Mice.

Atherosclerosis (AS) is closely associated with abnormally chronic low-grade inflammation and gut dysbiosis. Flaxseed oil (FO) rich in omega-3 polyunsaturated fatty acids (PUFAs), which are mainly composed of alpha-linolenic acid (ALA, 18:3 omega-3), has been demonstrated to exhibit pleiotropic benefits in chronic metabolic diseases. However, the impact of dietary ALA-rich FO on AS and its associated underlying mechanisms remain poorly understood. Thus, the present study was designed as two phases to investigate the effects in atherosclerotic Apolipoprotein E (ApoE)-/- mice. In the initial portion, the ApoE -/- mice were randomly allocated to three groups: control group (CON), model group (MOD), and FO-fed model group (MOD/FO) and were treated for 12 weeks. The second phase used antibiotic (AB)-treated ApoE -/- mice were divided into two groups: AB-treated model group (AB/MOD) and FO-fed AB-treated model group (AB/FO). In the results, the dietary ALA-rich FO administration ameliorated atherosclerotic lesion, as well as the parameters of AS (body weights (BWs) and the total bile acids (TBA). Chronic systemic/vascular inflammatory cytokines and in situ macrophages (Mψs) were reduced with FO intervention. In addition, the FO improved the gut integrity and permeability by decreasing the plasma lipopolysaccharide (LPS). Moreover, gut dysbiosis and metabolites [short-chain fatty acids (SCFAs) and bile acids (BAs)] in AS were modulated after FO treatment. Intriguingly, during an AB-treated condition, a significantly weakened amelioration of FO-treated on AS proposed that the intestinal microbiota contributed to the FO effects. A correlation analysis showed close relationships among gut bacteria, metabolites, and inflammation. Collectively, these results suggested that the dietary ALA-rich FO ameliorated the AS in ApoE -/- mice via the gut microbiota-inflammation-artery axis.

Small molecules, big effects: microbial metabolites in intestinal immunity.

The mammalian intestine is host to a vast number of microbial organisms. The immune system must balance tolerance with innate and adaptive defense mechanisms to maintain homeostasis with the microbial community. Interestingly, microbial metabolites have been shown to play a role in shaping the host immune response, thus assisting with adaptations that have significant implications for human health and disease. New investigations have uncovered roles for metabolites in modulating almost every aspect of the immune system. In this minireview, we survey these recent findings, which taken together reveal nuanced interactions that we are just beginning to understand.

Preparative isolation and purification of urolithins from the intestinal metabolites of pomegranate ellagitannins by high-speed counter-current chromatography.

Urolithins were separated from the intestinal metabolites of pomegranate ellagitannins by high-speed counter current chromatography in two steps using two solvent systems composed of n-hexane-ethyl acetate-methanol-acetic acid-water (2.5:2:0.25:5, v/v/v/v/v) and n-hexane-ethyl acetate-methanol-acetic acid-water (2.5:0. 8:0.25:5, v/v/v/v/v) for the first time. Each injection of 100mg extract yielded 21mg of pure urolithin A and 10mg of pure urolithin B. High-performance liquid chromatography analyses revealed that the purity of urolithin A and urolihtin B was over 98.5%. The structures of urolithin A and urolitihn B were identified by high resolution-MS, NMR and single crystal x-ray analysis. Urolithins reduced the oxidative stress status in colon cancer by decreasing the intracellular ROS and malondialdehyde levels, and increasing SOD activity in H2O2 treated Caco-2 cells.