The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics

Abstract

The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans, accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an "endocrine organ" with potential to alter host physiology, perhaps to their own favor. We propose the term "sterolbiome" to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed.

Keywords: APC, adenomatous polyposis coli; BA, bile acids; BSH, bile salt hydrolases; Bile acids; CA, cholic acid; CDCA, chenodeoxycholic acid; COX-2, cyclooxygenase-2; CRC, colorectal cancer; CYP27A1, sterol-27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; DCA, deoxycholic acid; EGFR, epidermal growth factor receptor; FAP, familial adenomatous polyposis; FGF15/19, fibroblast growth factor 15/19; FXR, farnesoid X receptor; GABA, γ-aminobutyric acid; GPCR, G-protein coupled receptors; Gut microbiome; HMP, Human Microbiome Project; HSDH, hydroxysteroid dehydrogenase; LCA, lithocholic acid; LOX, lipooxygenase; MetaHIT, Metagenomics of the Human Intestinal Tract; Metabolite; NSAIDs, non-steroidal anti-inflammatory drugs; PKC, protein kinase C; PSC, primary sclerosing cholangitis; PXR, pregnane X receptor; Sterolbiome; Therapeutic agent; UDCA, ursodeoxycholic acid; VDR, vitamin D receptor.

Graphical abstract

Figure 1

Pathway from cholesterol to lithocholic acid in the human ecosystem. CDCA is synthesized in the liver via the neutral pathway through a series of oxidative steps. LCA is produced by members of the gut microbiome through a multi-step biochemical pathway, the first half of which is oxidative followed by a net 2 electron reduction.

Figure 2

Metabolism of CDCA by the gut microbiome. As bile salts enter the gut and are rapidly deconjugated by BSH enzymes expressed by a diverse group of gut bacteria and archaea. Hydroxy groups at C3 (A ring) and C7 (B ring) can be epimerized through the concerted action of both α- and β-hydroxysteroid dehydrogenase enzymes. Epimerization at the C7 position results in the 7β-hydroxy bile acid UDCA, a therapeutic molecule used in treatment of GI disorders. Both CDCA and UDCA result in formation of a common 3-dehydro-4-LCA structure during the oxidative arm of the bile acid 7α-dehydroxylating and 7β-dehydroxylating pathways, each of which overlaps in many enzymatic steps. This 3-dehydro-4-LCA structure can be reduced at the C4 position yielding either LCA (5β-hydrogen) or allo-LCA (5α-hydrogen).

Figure 3

Targeted inhibition of bile acid 7β-dehydroxylating pathway hypothesized to improve therapeutic potential of UDCA in prevention of colon cancer development.