Recently, Associate Professor Liu Yanteam from the School of Public Health at Sun Yat-sen University has, for the first time, unveiled the mechanism by which gut symbiotic bacteria A. indistinctus activates the intestinal urate transporter receptor ATP binding cassette subfamily G member 2 (ABCG2), promoting the excretion of intestinal urate salts and reducing the risk of hyperuricemia. The relevant findings have been published in Cell-Host & Microbe.
The mechanism by which symbiotic fungus A. indistinctus improves hyperuricemia. Image provided by the interviewee.
In recent years, the prevalence of hyperuricemia in China has continued to rise, with the overall prevalence exceeding 14%, affecting nearly 200 million people and becoming the "fourth high" following the "three highs." Hyperuricemia is not only the most direct cause of gouty arthritis but is also closely associated with major chronic diseases and increased risk of death, including metabolic syndrome, cardiovascular and cerebrovascular diseases, and chronic kidney disease.
However, existing uric acid-lowering drugs mostly come with significant side effects, and long-term use can lead to severe liver and kidney damage, as well as cardiovascular disease risk. Changes in the composition and function of the intestinal microbiota are closely related to the occurrence and development of various metabolic diseases, including hyperuricemia. A comprehensive analysis of the role of intestinal microbiota metabolism in the regulation of uric acid metabolism will provide new ideas and approaches for the development of interventions for the prevention and treatment of hyperuricemia.
This study used cross-cohort metagenomic analysis to discover that the relative abundance and centrality of symbiotic fungus A. indistinctus were significantly reduced in patients with hyperuricemia. The likelihood of developing hyperuricemia increased by 26% in populations with low abundance of A. indistinctus. Further computer simulation analysis, multi-omics integration analysis, and molecular biology experiments confirmed that uric acid was the key effector molecule for A. indistinctus to lower uric acid.
Once A. indistinctus successfully colonizes the intestine, it can upregulate the expression of ABCG2 by promoting the binding of peroxisome proliferator-activated receptor gamma (PPARγ) to the promoter region of the intestinal uric acid transporter ABCG2 and promote the formation of a dimer between PDZ domain-containing protein 1 (PDZK1) and ABCG2, transporting ABCG2 from the cytoplasm to the brush border membrane of intestinal epithelial cells, thereby enhancing intestinal uric acid excretion capacity.
This study, for the first time, elucidates a new mechanism for the regulation of uric acid metabolism stability from the perspective of microbiota-host co-metabolism, providing new ideas for the establishment of early prevention and treatment measures for hyperuricemia. One related research result has been granted a national invention patent.
Related paper information: https://doi.org/10.1016/j.chom.2024.02.001
