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

Abstract

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 BSHexpressing 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.

Berberine Influences Blood Glucose via Modulating the Gut Microbiome in Grass Carp

“…However, it has been proved that the main action site of BBR is the gut (Sun et al, 2016). BBR directly impacts the gut microbiota of mice and causes lipid-lowering effects via sequential events (Sun et al, 2016; Tian et al, 2018). It has been also proved that the glucose-lowering effect of BBR in rats is associated with the shift of the gut microbiota structure in BBR-treated rats (Zhang et al, 2012).…”

“…It has been proved that the action of BBR in rats is associated with the host metabolic phenotypes mediated by the structural modulation of gut microbiota (Zhang et al, 2012; Zhang et al, 2015b; Li et al, 2016; Wang Y. et al, 2017). Furthermore, BBR directly impacts the gut microbiota, thereby altering bile acid metabolism and activating intestinal farnesoid X receptor, which lead to lipid-lowering effects in mice (Sun et al, 2016; Tian et al, 2018). However, the association between the hypoglycemic/hypolipidemic actions of BBR and the gut microbiome in fish remains unknown.…”

Berberine and its structural analogs have differing effects on functional profiles of individual gut microbiomes

“…and Clostridium spp. ), 20 , 21 and Bacteoidetes-to-Firmicutes ratio and reduction of the gut microbiota diversity. 22 …”

“…and Clostridium spp. ), 20,21 and Bacteoidetes-to-Firmicutes ratio and reduction of the gut microbiota diversity. 22 Several studies have suggested that BBR's structural analogs could have similar or improved functions.…”

Discovery of 7,9-Disulfatetrahydroberberine as Novel Lipid-Lowering Agents

“… 9 Finally, BBR can decrease the expression of fatty acid translocase Cd36 intestinal cells through the farnesoid X receptor (FXR) signal pathway, promoting cholesterol efflux indirectly. 10 , 11 Despite the fact that a preliminary understanding of the molecular mechanism of BBR on lipid regulation is revealed, its specific macromolecule target has not been discovered yet. This greatly limits the structure modification of BBR for improving its hypolipidemic activity.…”