Vitamins as regulators of calcium-containing kidney stones - new perspectives on the role of the gut microbiome

Abstract

Calcium-based kidney stone disease is a highly prevalent and morbid condition, with an often complicated and multifactorial aetiology. An abundance of research on the role of specific vitamins (B6, C and D) in stone formation exists, but no consensus has been reached on how these vitamins influence stone disease. As a consequence of emerging research on the role of the gut microbiota in urolithiasis, previous notions on the contribution of these vitamins to urolithiasis are being reconsidered in the field, and investigation into previously overlooked vitamins (A, E and K) was expanded. Understanding how the microbiota influences host vitamin regulation could help to determine the role of vitamins in stone disease.

Conflict of interest statement

The authors declare no competing interests.

© 2023. Springer Nature Limited.

Figures

Fig. 1. Possible roles of the microbiota in host vitamin acquisition and homeostasis.

Members of the gut microbiota can a, produce vitamin A precursors and can convert β-carotene to retinoic acid and b, facilitate the interconversion among vitamin A vitamers,,. c, Gut microbiota is also well known to be able to produce sufficient amounts of vitamin B6 (refs. ,,,). d, Lipopolysaccharide from Gram-negative microorganisms reduces SVCT-1 expression and, in turn, SVCT-1-mediated uptake of vitamin C,. e, Vitamin C is also metabolized by gut bacteria such as E. coli, and Lactobacillus species to yield xylulose and short-chain fatty acids, respectively; host cells can further process xylulose to yield oxalate. f, Through local immune activation, the microbiota can increase the conversion of vitamin D into the active form 1,25(OH)2D by reducing the expression of FGF23, which normally inhibits CYP27B1-mediated conversion of vitamin D into active vitamin D,. g, Additionally, multiple members of the microbiota might have the ability to convert vitamin D analogues–. h, Humans also rely on gut bacteria for the production of vitamin K2 (refs. ,,,,,,). SVCT, sodium-dependent vitamin C transporter 1; D2/3, vitamin D2 and vitamin D3; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D.

Fig. 2. Structures of vitamins discussed in this Perspective.

Vitamin A (all-trans retinol) contains a β-ionone ring with an isoprenoid side chain and a hydroxyl functional group. Vitamin B6 is the generic name for six vitamers defined based on the R group and phosphorylation status. Vitamin C (ascorbic acid) weakly resembles a cyclic sugar molecule. Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) structures are defined as secosteroids. Vitamin E contains four tocopherols and four tocotrienols that are assigned the Greek letters α, β, γ and δ based on the functional group in R1 and R2. Vitamin K structures have a characteristic 2-methyl-1,4-naphthoquinone structure and a unique side chain. Vitamin K1 (phylloquinone) has a phytyl side chain and vitamin K2 (menaquinone) has a polyisoprenyl side chain.

Fig. 3. Vitamin D metabolic pathway.

Vitamin D2 and D3 — synthesized by the skin or acquired from ingestion — are circulated to the liver, where the hydroxylation of these vitamins by CYP27A1, CYP2R1 or CYP2J3 occurs. Vitamin D2 and D3 are converted into ergocalciferol (25-hydroxyergocalciferol) and calcifediol (25-hydroxycholecalciferol), respectively. Together, these products are referred to as 25-hydroxyvitamin D (shortened to 25(OH)D). In the proximal convoluted tubules of the kidneys and in some immune cells (not shown), 25(OH)D is converted into the active form calcitriol (also known as 1,25 dihydroxyvitamin D (1,25(OH)2D)), through hydroxylation by CYP27B1. Both 25(OH)D and 1,25(OH)2D can be degraded by CYP24A1 to maintain the necessary titres of vitamin D. CYP, cytochrome P450.