Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway.

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as ß-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

Gut bacteria alleviate smoking-related NASH by degrading gut nicotine.

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.

Gut firmicutes: Relationship with dietary fiber and role in host homeostasis.

Firmicutes and Bacteroidetes are the predominant bacterial phyla colonizing the healthy human gut. Accumulating evidence suggests that dietary fiber plays a crucial role in host health, yet most studies have focused on how the dietary fiber affects health through gut Bacteroides. More recently, gut Firmicutes have been found to possess many genes responsible for fermenting dietary fiber, and could also interact with the intestinal mucosa and thereby contribute to homeostasis. Consequently, the relationship between dietary fiber and Firmicutes is of interest, as well as the role of Firmicutes in host health. In this review, we summarize the current knowledge regarding the molecular mechanism of dietary fiber degradation by gut Firmicutes and explain the communication pathway of the dietary fiber-Firmicutes-host axis, and the beneficial effects of dietary fiber-induced Firmicutes and their metabolites on health. A better understanding of the dialogue sustained by the dietary fiber-Firmicutes axis and the host could provide new insights into probiotic therapy and novel dietary interventions aimed at increasing the abundance of Firmicutes (such as Faecalibacterium, Lactobacillus, and Roseburia) to promote health.

Dietary fiber-induced gut Firmicutes and their metabolites exhibit relevant health-promoting functions.Most of dietary fiber have a great effect on gut Firmicutes.Mechanisms of dietary fiber uptake by gut Firmicutes are outlined.Mechanisms of dietary fiber- gut Firmicutes-host interactions require more investigation for the development of dietary fiber in food production and host health.

Dietary compounds and traditional Chinese medicine ameliorate type 2 diabetes by modulating gut microbiota.

Diabetes mellitus (DM) and its complications are major public health concerns which strongly influence the quality of humans' life. Modification of gut microbiota has been widely used for the management of diabetes. In this review, the relationship between diabetes and gut microbiota, as well as the effects of different dietary components and traditional Chinese medicine (TCM) on gut microflora are summarized. Dietary compounds and TCM possessing bioactive components (fiber and phytochemicals) first change the composition of gut microbiota (inhibiting pathogens and promoting the beneficial bacteria growth) and then influence the production of their metabolites, which would further modify the intestinal environment through inhibiting the production of detrimental compounds (such as lipopolysaccharide, hydrogen sulfide, indol, etc.). Importantly, metabolites (short chain fatty acids and other bioactive components) fermented/degraded by gut microbiota can target multiple pathways in intestine, liver, pancreas, etc., resulting in the improvement of gut health, glycemic control, lipids profile, insulin resistance and inflammation. Furthermore, understanding the interaction between different dietary components and gut microbiota, as well as underlying mechanisms would help design different diet formula for the management of diabetes. Further researches could focus on the combination of different dietary components for preventing and treating diabetes, based on the principle of "multiple components against multiple targets" from the perspective of gut microbiota.

Metabolism and health effects of phyto-estrogens.

Phyto-estrogens are plant-derived compounds that can exert various estrogenic and anti-estrogenic effects, and are usually used as a natural alternative to estrogen replacement due to their health benefits, including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Phyto-estrogens are also considered as endocrine disruptors due to their structure similar to human female hormone 17-ß oestradiol. However, the issue of whether phyto-estrogens are beneficial or harmful to human health remains unknown, as this may depend on the dose, form, level and duration of administration of phyto-estrogens, and influence by genetics, metabolism, gut physiology, age, diet, and the health status of individuals. Clarification on this issue is necessary for the sake of their two-side effects on human health and rapidly increasing global consumption of phyto-estrogens. This review mainly includes the metabolism of phyto-estrogens and weighs the evidence for and against the purported health benefits and adverse effects of phyto-estrogens.

Effect of fermentation and sterilization on anthocyanins in blueberry.

BACKGROUND: Blueberry products have various health benefits due to their high content of dietary anthocyanins. The aim of this study was to investigate the impact of fermentation and sterilization on total anthocyanin content, composition and some quality attributes of blueberry puree. The blueberry puree used here was fermented for 40 h at 37 °C by Lactobacillus after sterilization. The method of ultra-performance liquid chromatography-mass spectrometry was optimized for the rapid analysis of anthocyanins. Quality attributes including pH, color, total soluble solids and viscosity were measured. RESULTS: A total of 21 anthocyanins and five anthocyanidins were quantified by ultra-performance liquid chromatography. Fermented blueberry had reduced total anthocyanin content (29%) and levels of individual anthocyanins compared with fresh blueberry. Total anthocyanin content was decreased 46% by sterilization, and different degradation behavior of individual anthocyanin was appeared between fermented and sterilized-fermented blueberry puree. Fermentation and sterilization decreased the total soluble solids and pH and changed color parameters, while minimally influencing viscosity. CONCLUSIONS: The loss of total anthocyanin content by fermentation was related to the unstable structure of blueberry anthocyanins. Anthocyanins are sensitive to temperature (>80 °C), and degradation of anthocyanins by sterilization in blueberry should be considered in the fermentation procedure. © 2016 Society of Chemical Industry.

Glucomannan promotes Bacteroides ovatus to improve intestinal barrier function and ameliorate insulin resistance.

Bioactive dietary fiber has been proven to confer numerous health benefits against metabolic diseases based on the modification of gut microbiota. The metabolic protective effects of glucomannan have been previously reported in animal experiments and clinical trials. However, critical microbial signaling metabolites and the host targets associated with the metabolic benefits of glucomannan remain elusive. The results of this study revealed that glucomannan supplementation alleviated high-fat diet (HFD)-induced insulin resistance in mice and that its beneficial effects were dependent on the gut microbiota. Administration of glucomannan to mice promoted the growth of Bacteroides ovatus. Moreover, colonization with B. ovatus in HFD-fed mice resulted in a decrease in insulin resistance, accompanied by improved intestinal barrier integrity and reduced systemic inflammation. Furthermore, B. ovatus-derived indoleacetic acid (IAA) was established as a key bioactive metabolite that fortifies intestinal barrier function via activation of intestinal aryl hydrocarbon receptor (AhR), leading to an amelioration in insulin resistance. Thus, we conclude that glucomannan acts through the B. ovatus-IAA-intestinal AhR axis to relieve insulin resistance.

The Hydrophilic Metabolite UMP Alleviates Obesity Traits through a HIF2α-ACER2-Ceramide Signaling Axis.

Metabolic abnormalities contribute to the pathogenesis of obesity and its complications. Yet, the understanding of the interactions between critical metabolic pathways that underlie obesity remains to be improved, in part owing to the lack of comprehensive metabolomics studies that reconcile data from both hydrophilic and lipophilic metabolome analyses that can lead to the identification and characterization of key signaling networks. Here, the study conducts a comprehensive metabolomics analysis, surveying lipids and hydrophilic metabolites of the plasma and omental adipose tissue of obese individuals and the plasma and epididymal adipose tissue of mice. Through these approaches, it is found that a significant accumulation of ceramide due to inhibited sphingolipid catabolism, while a significant reduction in the levels of uridine monophosphate (UMP), is critical to pyrimidine biosynthesis. Further, it is found that UMP administration restores sphingolipid homeostasis and can reduce obesity in mice by reversing obesity-induced inhibition of adipocyte hypoxia inducible factor 2a (Hif2α) and its target gene alkaline ceramidase 2 (Acer2), so as to promote ceramide catabolism and alleviate its accumulation within cells. Using adipose tissue Hif2α-specific knockout mice, the study further demonstrates that the presence of UMP can alleviate obesity through a HIF2α-ACER2-ceramide pathway, which can be a new signaling axis for obesity improvement.

The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice.

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.

Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling.

The gut microbiota is closely linked to atherosclerosis. However, the role of intestinal fungi, essential members of the complex microbial community, in atherosclerosis is poorly understood. Herein, we show that gut fungi dysbiosis is implicated in patients with dyslipidemia, characterized by higher levels of Candida albicans (C. albicans), which are positively correlated with plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Furthermore, C. albicans colonization aggravates atherosclerosis progression in a mouse model of the disease. Through gain- and loss-of-function studies, we show that an intestinal hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway mediates the effect of C. albicans. Mechanistically, formyl-methionine, a metabolite of C. albicans, activates intestinal HIF-2α signaling, which drives increased ceramide synthesis to accelerate atherosclerosis. Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment.

Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.

Targeted modification of gut microbiota and related metabolites via dietary fiber.

Intake of dietary fiber has been proven to have several beneficial effects in maintaining host homeostasis and health. Here, we investigated the effects of different fibers on gut microbiota and related metabolites in rats. Healthy rats were supplemented with guar gum, carrageenan, glucomannan, ß-glucan, arabinoxylan, apple pectin, xylan, arabinogalactan, and xanthan gum, and these dietary fibers exhibited commonality and specificity on gut microbiota and related metabolites. The abundance of Phascolarctobacterium, Prevotella, Treponema, Butyricimonas, Bacteroides, and Lactobacillus was selectively increased by different dietary fibers, whereas the abundance of Clostridium perfringens and Bacteroides fragilis were decreased by all of these fibers. Indole-3-lactic acid was significantly increased by ß-glucan treatment, indicating the relationship between indole-3-lactic acid and Lactobacillus. Furthermore, Some species from Bacteroides were validated to produce indole-3-lactic acid, indole-3-acetic acid, and kynurenine (such as B. fragilis, B. ovatus, B. thetaiotaomicron, and B. xylanisolvens). These results provide important information on dietary guidelines based on the modification of gut microecology.

Polysaccharides from red kidney bean alleviating hyperglycemia and hyperlipidemia in type 2 diabetic rats via gut microbiota and lipid metabolic modulation.

Crude polysaccharides extracted from red kidney bean (RK) display significant antidiabetic activity in type 2 diabetic mice, but the underlying mechanism and the core functional component has not been elucidated. In this study, the antidiabetic effect and mechanism of RK are investigated by serum metabolomics and high-throughput sequencing. In addition, the key component was identified by evaluating the improvement on glucose and lipid homeostasis in type 2 diabetic rats. Our data indicated that RK relieved the symptoms of hyperglycemia, hyperlipidemia in STZ-induced diabetic rats. RK not only improved the metabolic disturbance by regulating the biosynthesis of unsaturated fatty acids, but also modified gut microbiota composition by selectively enriching in key genera of Bacteroides, Phascolarctobacterium, Succinivibrio, Blautia. We further found the purified polysaccharides (RKP) were identified as the core biofunctional component in RK. Our present studies provide evidence that RKP are potential effective dietary supplement for type 2 diabetic individuals.

Comprehensive evaluation of the prebiotic properties of Dendrobium officinale polysaccharides, ß-glucan, and inulin during in vitro fermentation via multi-omics analysis.

Dietary fiber is crucial for human health mainly due to its impact on gut microbiota structure and metabolites. This study aimed to investigate the impact of Dendrobium officinale polysaccharides (DOP) and two common fibers (ß-glucan and inulin) on the gut microbiome structure and metabolic profile in vitro. Fecal samples were obtained from 30 healthy volunteers, which were then individually subjected to fermentation with each type of fiber. The results revealed that all fibers were efficiently degraded by gut microbiota, with DOP exhibiting a slower fermentation rate compared to ß-glucan and inulin. The fermentation of all fibers led to a significant increase in the production of short-chain fatty acids (SCFAs) and a reduction in branched-chain fatty acids (BCFAs), sulfides, phenols, and indole. Moreover, the abundance of unclassified Enterobacteriaceae, which was positively correlated with sulfide, phenols, and indole levels, was significantly reduced by all fibers. Additionally, DOP specifically promoted the growth of Parabacteroides, while ß-glucan and inulin promoted the growth of Bifidobacterium and Faecalibacterium. Taken together, these findings enhance our understanding of the role of DOP, ß-glucan, and inulin in modulating gut microbiota and metabolites, where the fermentation with fecal bacteria from different volunteers could provide valuable insights for personalized therapeutic approaches.

Parabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a.

Gut microbiota plays a key role in insulin resistance (IR). Here we perform a case-control study of Chinese adults (ChiCTR2200065715) and identify that Parabacteroides distasonis is inversely correlated with IR. Treatment with P. distasonis improves IR, strengthens intestinal integrity, and reduces systemic inflammation in mice. We further demonstrate that P. distasonis-derived nicotinic acid (NA) is a vital bioactive molecule that fortifies intestinal barrier function via activating intestinal G-protein-coupled receptor 109a (GPR109a), leading to ameliorating IR. We also conduct a bioactive dietary fiber screening to induce P. distasonis growth. Dendrobium officinale polysaccharide (DOP) shows favorable growth-promoting effects on P. distasonis and protects against IR in mice simultaneously. Finally, the reduced P. distasonis and NA levels were also validated in another human type 2 diabetes mellitus cohort. These findings reveal the unique mechanisms of P. distasonis on IR and provide viable strategies for the treatment and prevention of IR by bioactive dietary fiber.

Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.

Arabinoxylan ameliorates type 2 diabetes by regulating the gut microbiota and metabolites.

Type 2 diabetes (T2D) is a metabolic disease characterized by hyperglycemia. Intake of dietary fiber is inversely associated with risks of T2D. Here, metabolomics and 16S rRNA gene sequencing were employed to investigate the effects of arabinoxylan on gut microbiota and their metabolites in type 2 diabetic rats. T2D increased the abundance of opportunistic pathogens (such as Desulfovibrio and Klebsiella) and the levels of 12α-hydroxylated bile acids and acylcarnitines (C3) in diabetic rats, which eventually contribute to insulin resistance and hyperglycemia. Supplementation with arabinoxylan promoted the growth of fiber-degrading bacteria to increase short-chain fatty acids (SCFAs), as well as decreased the abundance of opportunistic pathogens. Arabinoxylan treatment also decreased the concentrations of 12α-hydroxylated bile acids, and increased the levels of equol, indolepropionate, and eicosadienoic acid. This study indicated that the beneficial effects of arabinoxylan on T2D may be partially attributed to the modification of gut microbiota and related metabolites.

Development and evaluation of a simultaneous strategy for pyrimidine metabolome quantification in multiple biological samples.

Pyrimidines are critical nutrients and key biomolecules in nucleic acid biosynthesis and carbohydrate and lipid metabolism. Here, we proposed the concept of the pyrimidine metabolome, which covers 14 analytes in pyrimidine de novo and salvage synthetic pathways, and established a novel analytical strategy with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to efficiently illustrate pyrimidine transient distribution and dynamic balance. The lower limits of quantification (LLOQs) of all analytes were less than 10 ng/mL. Acceptable inter- and intra-day relative deviation (<15%) was detected, and good stability was obtained under different storage conditions. Metabolomics analysis revealed pyrimidine metabolic diversity in the plasma and brain among species, and a visualization strategy exhibited that pyrimidine biosynthetic metabolism is quite active in brain. Distinct metabolic features were also observed in cells with pyrimidine metabolomic disorders during proliferation and apoptosis. Absolute concentrations of pyrimidine metabolites in different bio-samples offered reference data for future pyrimidine studies.

Interaction between polysaccharides and toll-like receptor 4: Primary structural role, immune balance perspective, and 3D interaction model hypothesis.

Various structural types of polysaccharides are recognized by toll-like receptor 4 (TLR4). However, the mechanism of interaction between the polysaccharides with different structures and TLR4 is unclarified. This review summarized the primary structure of polysaccharides related to TLR4, mainly including molecular weight, monosaccharide composition, glycosidic bonds, functional groups, and branched-chain structure. The optimal primary structure for interacting with TLR4 was obtained by the statistical analysis. Besides, the dual-directional regulation of TLR4 signaling cascade by polysaccharides was also elucidated from an immune balance perspective. Finally, the 3D interaction model of polysaccharides to TLR4-myeloid differentiation factor 2 (MD2) complex was hypothesized according to the LPS-TLR4-MD2 dimerization model and the polysaccharides solution conformation. The essence of polysaccharides binding to TLR4-MD2 complex is a multivalent non-covalent bond interaction. All the arguments summarized in this review are intended to provide some new insights into the interaction between polysaccharides and TLR4.

Efficient enrichment of total flavonoids from kale (Brassica oleracea L. var. acephala L.) extracts by NKA-9 resin and antioxidant activities of flavonoids extract in vitro.

This work established an effective method for kale flavonoids enrichment by resins. Resin screening, adsorption kinetics and isotherms, dynamic adsorption and desorption tests were conducted to optimize the appropriate resins and enrichment conditions. The results showed that NKA-9 was the optimum resin. The best adsorption conditions were 0.2 mg/mL flavonoids concentration, 12.5 bed volume (BV) sample volume and 2 BV/h adsorption rate. The desorption conditions were 3 BV of 80% ethanol at 2 BV/h elution rate. Under these conditions, the product purity was 31.16%. The purified flavonoids extract was mainly comprised of Kaempferol-3-O-sophoroside-7-O-diglucoside, Kaempferol-3,7,4'-O-d-triglucoside, Kaempferol-3-O-feruloyl-sophoroside-7-O-d-glucoside, and Kaempferol-3-O-sinapoyl-sophoroside. Moreover, it presented higher scavenging ability against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and hydroxyl (OH) radical than crude extract. In conclusion, kale flavonoids can be well concentrated by NKA-9 resin and the purified flavonoids extract has good antioxidant activity which can be potentially applied in food, cosmetic or pharmacy industries.