Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.
Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXRint-/-) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXRint-/- mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.
Sun R
，Yang N
，Kong B
，Cao B
，Feng D
，Yu X
，Ge C
，Huang J
，Shen J
，Wang P
，Feng S
，Fei F
，Guo J
，He J
，Aa N
，Chen Q
，Pan Y
，Schumacher JD
，Yang CS
，Guo GL
，Aa J
，Wang G
... -
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The Hypoglycemic Effect of Berberine and Berberrubine Involves Modulation of Intestinal Farnesoid X Receptor Signaling Pathway and Inhibition of Hepatic Gluconeogenesis.
Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was determined. The results revealed that BBR (150 mg/kg) and M1 (50 mg/kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids, and purine. BBR showed a stronger modulatory effect on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.
Sun R
，Kong B
，Yang N
，Cao B
，Feng D
，Yu X
，Ge C
，Feng S
，Fei F
，Huang J
，Lu Z
，Xie Y
，Yang CS
，Guo GL
，Wang G
，Aa J
... -
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Berberine Directly Affects the Gut Microbiota to Promote Intestinal Farnesoid X Receptor Activation.
Intestinal bacteria play an important role in bile acid metabolism and in the regulation of multiple host metabolic pathways (e.g., lipid and glucose homeostasis) through modulation of intestinal farnesoid X receptor (FXR) activity. Here, we examined the effect of berberine (BBR), a natural plant alkaloid, on intestinal bacteria using in vitro and in vivo models. In vivo, the metabolomic response and changes in mouse intestinal bacterial communities treated with BBR (100 mg/kg) for 5 days were assessed using NMR- and mass spectrometry-based metabolomics coupled with multivariate data analysis. Short-term BBR exposure altered intestinal bacteria by reducing Clostridium cluster XIVa and IV and their bile salt hydrolase (BSH) activity, which resulted in the accumulation of taurocholic acid (TCA). The accumulation of TCA was associated with activation of intestinal FXR, which can mediate bile acid, lipid, and glucose metabolism. In vitro, isolated mouse cecal bacteria were incubated with three doses of BBR (0.1, 1, and 10 mg/ml) for 4 hours in an anaerobic chamber. NMR-based metabolomics combined with flow cytometry was used to evaluate the direct physiologic and metabolic effect of BBR on the bacteria. In vitro, BBR exposure not only altered bacterial physiology but also changed bacterial community composition and function, especially reducing BSH-expressing bacteria like Clostridium spp. These data suggest that BBR directly affects bacteria to alter bile acid metabolism and activate FXR signaling. These data provide new insights into the link between intestinal bacteria, nuclear receptor signaling, and xenobiotics.
Tian Y
，Cai J
，Gui W
，Nichols RG
，Koo I
，Zhang J
，Anitha M
，Patterson AD
... -
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Ramulus Mori (Sangzhi) alkaloids ameliorate high-fat diet induced obesity in rats by modulating gut microbiota and bile acid metabolism.
The objective of this study is to investigate the ability of Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) to ameliorate obesity and lipid metabolism disorders in rats subjected to a high-fat diet (HFD) through metagenomics, untargeted lipidomics, targeted metabolism of bile acid (BA), and BA pathways, providing a novel perspective on the management of metabolic disorders.
In this research, HFD-fed rats were concurrently administered SZ-A orally. We measured changes in body weight (BW), blood lipid profiles, and liver function to assess therapeutic effects. Liver lipid status was visualized through H&E and Oil Red O. Gut microbiota composition was elucidated using metagenomics. The LC-MS-targeted metabolomics approach was utilized to define the fecal BA profiles. Furthermore, the lipid metabolomics of adipose tissue samples was investigated using an LC-MS analysis platform. The expression levels of the BA receptor were determined by western blotting. Additionally, serum insulin (INS), glucagon-like peptide-1 (GLP-1), and inflammatory cytokines were quantified using an ELISA kit. The integrity of the colonic epithelial barrier was assessed using immunofluorescence.
SZ-A notably decreased BW and blood lipid levels in obese rats while also alleviating liver injury. Additionally, SZ-A reduced the serum levels of leptin (LEP), INS, and GLP-1, indicating its potential to modulate key metabolic hormones. Most notably, SZ-A substantially improved gut microbiota composition. Specifically, it reshaped the gut microbiota structure in HFD-fed rats by increasing the relative abundance of beneficial bacteria, such as Bacteroides, while decreasing the populations of potentially harmful bacteria, such as Dorea and Blautia. At the BA level, SZ-A decreased the levels of harmful BAs, including hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), 12-keto lithocholic acid (12-KLCA), lithocholic acid (LCA), and muricholic acid (MDCA). Between the model group and SZ-A, 258 differentially abundant metabolites were detected, with 72 upregulated and 186 downregulated. Furthermore, these BAs are implicated in the activation of the FXR-FGF15 and TGR5-GLP-1 pathways in the intestine. This activation helps to alleviate HFD-fed intestinal inflammation and restore intestinal barrier damage by modulating inflammatory cytokines and bolstering the intestinal barrier's capabilities.
Our findings indicate that SZ-A effectively modulates BW, serum lipid profiles, and liver function in HFD-fed rats. Moreover, SZ-A exerts a positive influence on inflammatory cytokines, thereby mitigating inflammation and promoting the restoration of the intestinal barrier. Significantly, our research indicates that adjusting the gut microbiome and BA levels could serve as an effective approach for both preventing and treating obesity and related metabolic dyslipidemia.
Shang X
，Fu Y
，Wang Y
，Yan S
... -
《Frontiers in Endocrinology》
ResearchGate
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钛学术
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