The role of botanical triterpenoids and steroids in bile acid metabolism, transport, and signaling: Pharmacological and toxicological implications

Abstract

Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.

Keywords: Bile acid; Cholestasis; Gut microbes; Metabolic disorders; Phytosterol; Rheumatoid arthritis; Saponin; Triterpenoid.

Graphical abstract

Figure 1

(A) The structures of various botanical triterpenoid types; (B) The biosynthesis framework of triterpenoids and steroids; (C) The structures of common phytosterols and types of steroidal saponin aglycones.

Figure 2

(A) Structures of common unconjugated BAs and naming of BA variants; (B) Conjugation and hydroxyl modifications of BA backbone.

Figure 3

Gut flora-mediated BA metabolism in humans.

Figure 4

(A) FXR signaling mediated BA metabolism and transport in hepatocytes and enterocytes; (B) TGR5 signaling in representative cells.

Figure 5

Botanical triterpenoids and steroids that regulate gut microbes-based BA metabolism.

Figure 6

Botanical triterpenoids and steroids that act on BA transporters.

Figure 7

Botanical triterpenoids and steroids in regulation of TGR5 activities.

Figure 8

Botanical triterpenoids and steroids in regulation of FXR activities.

Figure 9

An overview of the roles of triterpenes and steroids from medicinal plants in IHC (A), metabolic diseases (B), and rheumatoid arthritis (C).

Figure 10

The research paradigm of botanical triterpenoids and steroids in BA signaling. (A) The regulatory effects on disease-related on microbial BAs; (B) The direct regulatory effects on BA receptors.