Gut feelings about bacterial steroid-17,20-desmolase

Abstract

Advances in technology are only beginning to reveal the complex interactions between hosts and their resident microbiota that have co-evolved over centuries. In this review, we present compelling evidence that implicates the host-associated microbiome in the generation of 11β-hydroxyandrostenedione, leading to the formation of potent 11-oxy-androgens. Microbial steroid-17,20-desmolase cleaves the side-chain of glucocorticoids (GC), including cortisol (and its derivatives of cortisone, 5α-dihydrocortisol, and also (allo)- 3α, 5α-tetrahydrocortisol, but not 3α-5β-tetrahydrocortisol) and drugs (prednisone and dexamethasone). In addition to side-chain cleavage, we discuss the gut microbiome's robust potential to transform a myriad of steroids, mirroring much of the host's metabolism. We also explore the overlooked role of intestinal steroidogenesis and efflux pumps as a potential route for GC transport into the gut. Lastly, we propose several health implications from microbial steroid-17,20-desmolase function, including aberrant mineralocorticoid, GC, and androgen receptor signaling in colonocytes, immune cells, and prostate cells, which may exacerbate disease states.

Keywords: 11-Oxy-androgen; Cortisol; GALF; Glucocorticoid; Hydroxysteroid dehydrogenase; Microbiome; Steroid-17,20-desmolase; Sterolbiome.

Fig. 1.. Cortisol metabolism by the bacterial steroid desmolase pathway.

(A) Cortisol is side-chain cleaved by DesAB and/or reversibly reduced/oxidized by NAD(H)-dependent 20α- and 20β-hydroxysteroid dehydrogenases (HSDHs), encoded by desC and desE, respectively. (B) Genomic structure of steroid-17,20-desmolase operon in gut microbes, C. scindens ATCC 35704 and B. desmolans ATCC 43058. (C) Metabolism of glucocorticoids by DesAB parallels the biochemistry of sugar transketolation. (D) Released in bile, allo-tetrahydrocortisol, but not tetrahydrocortisol, is a substrate for DesAB, forming 11β-hydroxyandrosterone, which can be further metabolized by other gut microbes belonging to the genus Eggerthella and Bacteroides by 17β-HSDH activity.

Fig. 2.. Summary of similarities between host (left) and gut microbial (right) steroid metabolism.

3KS5αR, 3-ketosteroid-5α-reductase; 3KS5βR, 3-ketosteroid-5β-reductase; 3α-HSDH, 3α-hydroxysteroid dehydrogenase; 3β-HSDH, 3β-hydroxysteroid dehydrogenase; 17α-HSDH, 17α-hydroxysteroid dehydrogenase; 17β-HSDH, 17β-hydroxysteroid dehydrogenase; AKR1C1, aldo-keto reductase 1C1; AKR1C2, aldo-keto reductase 1C2; AKR1C3, aldo-keto reductase 1C3; AKR1C4, aldo-keto reductase 1C4; AKR1D1, aldo-keto reductase 1D1; AKR1C21, aldo-keto reductase 1C21; CBR1, carbonyl reductase 1; DesAB, steroid-17,20-desmolase; DesC, 20α-hydroxysteroid dehydrogenase; DesE, 20β-hydroxysteroid dehydrogenase; HSD17B2, 17β-hydroxysteroid dehydrogenase; SRD5A1,2, steroid-5α-reductase 1,2.

Fig. 3.. Structural Biology of DesC and DesE.

(A, top) DesC (PDB accession: 4OH1) monomer depicted with NADH and cortisol docking simulated by quantum mechanical molecular modeling. (Middle) DesC binding pocket showing predicted residues involved in a proton relay to replenish catalytic residue protonation. (Bottom) DesC homotetramer. (B, top) DesE (PDB accessions: 6M9U, 6OW4) monomer displaying a Rossmann fold with 7 central β-strands and surrounding α-helices. (Middle) DesE binding pocket showing NADH-binding residues Asp72, Asp101, Tyr200, Lys204, Ser235. (Bottom) DesE homotetramer.

Fig. 4.. Potential effect of glycyrrhetinic acid-like factors (GALFs) on 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1/2).

11β-HSD1/2 play a critical role in regulating the local concentration of active glucocorticoid, cortisol (C), by conversion to inactive glucocorticoid, cortisone (c). Presence of GALFs may inhibit 11β-HSD leading to aberrant glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) signaling as cortisol competes with aldosterone (A) for signaling through MR.