Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway

Abstract

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 (FXR) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXR 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.

Berberine Directly Affects the Gut Microbiota to Promote Intestinal Farnesoid X Receptor Activation

“…1C). Previous studies indicated that 2 or 8 weeks of BBR treatment affected bile acid biosynthesis (Guo et al, 2016;Sun et al, 2017). Analysis of bile acid composition showed that 5 days of BBR treatment significantly increased taurine-conjugated bile acid levels in the feces, liver, and ileum (Fig.…”

“…Since BBR has low bioavailability, modulation of gut bacteria might be one possible mechanism for its antidiabetic and antiobesity effects (Han et al, 2011;Xie et al, 2011). Recent evidence suggested that the lipidlowering effect of BBR involves modulation of bile acid composition and activation of intestinal FXR signaling (Guo et al, 2016;Sun et al, 2017). However, the underlying mechanisms by which BBR modulates the intestinal bacteria community leading to microbially induced signals have not been explored.…”

The gut microbiota modulator berberine ameliorates collagen‐induced arthritis in rats by facilitating the generation of butyrate and adjusting the intestinal hypoxia and nitrate supply

“…It is well known that oral berberine is poorly absorbed and exhibits an extremely low plasma exposure and a high gut accumulation (24)(25)(26)(27)(28)(29). To determine whether berberine exerted a local action in the gut under arthritis status, we compared the pharmacokinetics and tissue distribution of berberine in normal and CIA rats after 14 d of oral administration at a dose of 200 mg/kg.…”

“…The evidence indicated that orally administered berberine showed an extremely low bioavailability (<1%) and a dominant gut accumulation (24) and that the positive charge on the nitrogen atom in the berberine molecule promotes its binding to bacteria where it exerts an antibacterial effect. Recent studies indicated that berberine lowered hyperlipidemia and modulated bile acid metabolism by altering the gut microbiota and the SCFA production (25–29). Moreover, our recently published data showed that berberine exerted an antiarthritic effect in a gut‐dependent manner (30).…”

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

“…TMC is a potent FXR antagonist and its accumulation decreases FXR signaling in the intestine (55)(56)(57). Intestinal FXR knockout animals have been shown to be resistant to diet-induced obesity, insulin resistance, and NAFLD (58)(59)(60). It has also been shown that loss of intestinal FXR activity leads to induced GLP-1 (glucagon-like peptide 1) production, which leads to improved glucose metabolism (61).…”