UV and MS Identification of Urolithins and Nasutins, the Bioavailable Metabolites of Ellagitannins and Ellagic Acid in Different Mammals

Abstract

Urolithins are microbial metabolites produced from ellagic acid after the intake of dietary ellagitannins by different animals. Urolithin metabolites have distinct UV spectra that enable their detection and differentiation by HPLC coupled with UV photodiode array detectors. Correlations between structural characteristics, including conjugation, with the UV spectra and retention times are established. The production of urolithin derivatives in different animals feeding on ellagitannins, including rodents (rats and mice), humans, pigs, squirrels, beavers, sheep, bull calves, birds, and insects, was investigated. All mammals produced urolithins, and their glucuronyl and sulfate conjugates were the main metabolites detected in plasma and urine. Unconjugated urolithins were detected in feces, ruminal content, and beaver castoreum. Different urolithin hydroxylation patterns were observed for different animal species, suggesting that the microbiota responsible for the metabolism of ellagitannins in each animal species produces dehydroxylases for the removal of specific hydroxyls from the ellagic acid residue. Metabolites were characterized using HR HPLC-TOF-MS and ion trap MS/MS. Insects and birds feeding on ellagitannin-containing foods did not produce urolithins, although they released ellagic acid. Beavers and pigs were able to produce dehydroxyellagic acid derivatives (nasutin A), showing that in some cases the removal of hydroxyl groups from the ellagic acid nucleus can be carried out before the lactone ring is opened to produce urolithins.

Urolithin B, a newly identified regulator of skeletal muscle mass

“…The first product of ellagic acid catabolism is urolithin D, and successive loss of hydroxy groups result in the formation of urolithins C, A, and B 3. All mammals seem able to produce urolithins from ellagitannins found in food 4, 5. In healthy humans, urolithins A and B are most abundant 5, 6.…”

Natural Dibenzo-α-Pyrones and Their Bioactivities

“…In plants, gallic acid (54), which is biosynthesized via the shikimate pathway [67], was considered as the precursor of ellagitannins [68]. The ellagitannins would be transformed into ellagic acid (55), and then into a series of urolithins (Scheme 1) [6,7,63]. However, in microorganisms, dibenzo-α-pyrones are biosynthesized via the polyketide pathway [3,25].…”

“…Four urolithins, namely urolithin A (40), isourolithin A (41), urolithin B (42) and urolithin C (43) were isolated from Trapa natans (Trapaceae) [4] and Caesalpinia sappan (Caesalpiniaceae) [53]. These urolithins ( Figure 3) were also isolated from animal feces [6,7]. Other dibenzo-α-pyrones isolated from plants included sabilactone (38) from Sabina vulgaris [54] and sarolactone (39) from Hypericum japonicum [55].…”

“…After administration of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]acetate and [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]acetate to cultured lichen mycobionts of Graphis spp., acetate units were incorporated into the 6H-dibenzo[b,d]pyran-6-one derivatives including alternariol (10), AME (11) and graphislactones A-F (18-23) [3]. Alternariol (10) could suffer oxidative demethylation at C-1, hydroxylation at C-4, and O-methylation at C-9 to lead formation of graphislactones E (22) and F (23).…”

“…They are usually isolated from fungi [1], mycobionts [2,3], plants [4,5], and animal feces containing the transformed products of plant-derived ellagitannins and ellagic acid by intestinal bacteria [6,7]. Many of them possess a wide spectrum of biological activities, spanning from toxicity on human and animals [8], cytotoxic activity [9], phytoxicity [10], antioxidant [6],…”