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 β-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

Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.This is the publisher’s final pdf. The published article is copyrighted and published by the Nature Publishing Group. The published article can be found at: http://www.nature.com/ncomms/index.htm

Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-b-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders

Role of gut microbiota in the development of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic steatosis in the absence of other causes, such as chronic alcohol consumption, that cause secondary hepatic fat accumulation. NAFLD has become the most common liver disease worldwide over the past two decades, and the prevalence of NAFLD is 20–30% in Western countries. However, the mechanism of NAFLD remains unclear. The gut microbiota plays an important role in the metabolism of the host; in fact, it has been implicated in inflammatory diseases, metabolic syndrome and cardiovascular disease. Accumulating evidence has indicated that gut microbiota component changes are linked to human obesity, insulin resistance (IR), type 2 diabetes and NAFLD. Here, we provide insight into the role of gut microbiota, especially bile salt hydrolase (BSH) in modulating the bile acid pool and farnesoid X receptor (FXR), which promotes the synthesis of ceramide and contributes to the development of NAFLD. Keywords: Non-alcoholic fatty liver disease (NAFLD), Gut microbiota, Bile acid, Farnesoid X receptor (FXR), Ceramide, Bile salt hydrolase (BSH

Characterization of Functional Microorganisms in Representative Traditional Fermented Dongcai from Different Regions of China

Dongcai is loved for its delicious flavor and nutritional value. The microorganisms in Dongcai play a vital role in their flavor, quality, and safety, and the microbial communities of Dongcai vary greatly from region to region. However, it remains unknown what the predominant microorganisms are in different traditional Dongcai and how they affect its flavor. The objective of this study is to explore the microbial diversity of traditional fermented Dongcai in three representative Chinese regions (Tianjin, Sichuan, and Guangzhou) and further assess their microbial functions. The microbial diversity of fermented Dongcai in Guangdong has the lowest diversity compared to fermented Dongcai in Sichuan, which has the highest. The distribution of the main genera of fermented Dongcai varies from region to region, but Carnimonas, Staphylococcus, Pseudomonas, Sphingomonas, Burkholderia-Caballeronia-Paraburkholderia, and Rhodococcus are the dominant genera in common. In addition, halophilic bacteria (HAB, i.e., Halomonas Bacillus, Virgibacillus, etc.) and lactic acid bacteria (LAB, i.e., Weissella and Lactobacillus) are also highly abundant. Of these, Burkholderia-Caballeronia-Paraburkholderia, Rhodococcus, Sphingomonas, Ralstonia, and Chromohalobacter are dominant in the Sichuan samples. In the Tianjin samples, Lactobacillus, Weissella, Virgibacillus, Enterobacter, Klebsiella, and Pseudomonas are the most abundant. Predictions of microbial metabolic function reveal that carbohydrates, amino acids, polyketides, lipids, and other secondary metabolites are abundantly available for biosynthesis. In addition, the different flavors of the three types of Dongcai may be due to the fact that the abundance of HAB and LAB shows a significant positive correlation with the amounts of important metabolites (e.g., salt, acid, amino nitrogen, and sugar). These results contribute to our understanding of the link between the distinctive flavors of different types of Dongcai and the microorganisms they contain and will also provide a reference for the relationship between microbial communities and flavor substances in semi-fermented pickles

RESISTIN IS CRITICAL FOR HOMOCYSTEINE-INDUCED VASCULAR SMOOTH MUSCLE CELL MIGRATION: FURTHER EVIDENCE OF ADIPOKINE-VASCULAR INTERACTION

PhysiologySCI(E)0MEETING ABSTRACT322-3225

HIF1α-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages

Hypoxia-inducible factor (HIF) 1α is a metabolic regulator that plays an important role in immunologic responses. Previous studies have demonstrated that HIF1α participates in the M1 polarization of macrophages. To clarify the mechanism of HIF1α-induced polarization of M1 macrophage, myeloid-specific HIF1α overexpression (Lysm HIF1α lsl) mice were employed and the bone marrow-derived and peritoneal macrophages were isolated. RT-PCR results revealed that HIF1α overexpression macrophage had a hyperinflammatory state characterized by the upregulation of M1 markers. Cellular bioenergetics analysis showed lower cellular oxygen consumption rates in the Lysm HIF1α lsl mice. Metabolomics studies showed that HIF1α overexpression led to increased glycolysis and pentose phosphate pathway intermediates. Further results revealed that macrophage M1 polarization, induced by HIF1α overexpression, was via upregulating the mRNA expression of the genes related to the glycolysis metabolism. Our results indicate that HIF1α promoted macrophage glycolysis metabolism, which induced M1 polarization in mice

BissonWilliamEnvironMoleToxIntestineSelectiveFarnesoid.pdf

The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders