Characterization of Gastrointestinal Absorption of Salmon Milt‐Derived Oligodeoxyribonucleic Acids in Mice

Dietary nucleic acids exert physiological effects beyond serving as substrates for nucleic acid synthesis; however, their exact molecular forms that are absorbed in the small intestine remain unclear. In this study, we investigated the absorption forms of food‐derived DNA by comprehensively quantifying 31 nucleic acid monomers that permeated the intestinal membrane after oral administration, using LC–MS/MS. Hydrolyzed Oncorhynchus milt DNA (HD‐omDNA; mainly 1–4‐mer nucleotides), deoxyribonucleotides (dNTs), and deoxyribonucleosides (dNSs) were orally administered to mice, and blood samples were collected from the tail vein, aorta, and portal vein. Intestinal permeation was also assessed using the Ussing chamber method. Oral administration of HD‐omDNA, dNTs, or dNSs increased the plasma levels of pyrimidine dNSs—such as thymidine, deoxyuridine, and deoxycytidine—identifying them as the major forms of high‐molecular‐weight DNA absorbed into systemic circulation. Portal vein concentrations of these pyrimidine dNSs were elevated compared with vehicle controls, confirming their intestinal absorption. In contrast, purine nucleic acid monomers were metabolized to uric acid, as indicated by elevated portal vein concentrations of its precursors, hypoxanthine, and xanthine upon co‐administration with the xanthine oxidase inhibitor febuxostat. Notably, dinucleotides were also detected in portal vein plasma in vivo and on the basolateral side in Ussing chamber experiments, suggesting that dinucleotides are a previously unrecognized absorption form of HD‐omDNA. Collectively, these findings demonstrate that dietary DNA permeates the intestine mainly as pyrimidine dNSs, whereas dinucleotides are also an absorption form, revealing unique absorption characteristics of dietary deoxyribonucleotides and oligodeoxyribonucleotides.