Uric acid builds up in the blood when the body cannot excrete it efficiently, leading to painful gout attacks, kidney stones, and other complications. Current treatments often rely on drugs that block uric acid production, but these can have side effects and do not work for everyone.
For many years, uric acid degradation is known as occurring mainly through an oxidative pathway, in which uricase enzymes use oxygen to break the purine ring and convert uric acid into allantoin. Humans and higher primates lack functional uricase, which is why they are particularly prone to uric acid accumulation and gout.
A new study published in Life Metabolism reports an alternative "reductive pathway" that functions without oxygen. In this route, uric acid is first reduced to a newly identified metabolite, "yanthine", and then further broken down by a sequence of reductive dearomatization and ring-cleaving reactions, ultimately yielding small molecules such as pyruvate and ammonia (Figure 1). This discovery revises the long-standing view of purine catabolism and highlights the metabolic versatility of gut bacteria in anaerobic environments.
Importantly, the study also detected "yanthine" circulating in human blood, with significantly higher levels in patients with gout compared with healthy individuals. This suggests that "yanthine" could serve as a biomarker for diagnosing or monitoring uric acid-related disorders. To explore therapeutic potential, the team engineered a probiotic strain of Escherichia coli to constitutively activate the reductive pathway. In a uricase-deficient mouse model of hyperuricemia, oral administration of this engineered strain significantly lowered blood uric acid levels, alleviated kidney injury, and remained stably colonized in the gut.
Together, these findings establish the reductive uric acid pathway as a major addition to the known repertoire of microbial metabolism. The work not only advances fundamental understanding of purine degradation but also points towards practical applications in biomarker discovery and the development of probiotic-based strategies to help control gout.
