Uric acid promotes dietary lipid absorption through microbiome and metabolomic remodeling via a liver-gut endocrine axis

  • Cell Host Microbe. 2026 Jun 3:S1931-3128(26)00181-2. doi: 10.1016/j.chom.2026.05.005.
Cheng Tian  1 ,  Xiaozhen Guo  2 ,  Dongmei Wang  3 ,  Qiubing Chen  4 ,  Haokun Shen  5 ,  Xin Li  6 ,  Chenyu Liu  5 ,  Yunfei Qi  5 ,  Yanhao Chen  5 ,  Linwei Wang  7 ,  Yangyang Wang  2 ,  Yutang Cao  8 ,  Yan Liu  5 ,  Hao Yin  4 ,  Yan Chen  5 ,  Xiaosong Gu  9 ,  Chunping Jiang  10 ,  Liming Tang  11 ,  Cen Xie  12 ,  Qiurong Ding  13
Affiliations
  • 1. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 3. Department of Gastrointestinal Surgery, Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
  • 4. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
  • 5. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 6. Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
  • 7. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
  • 8. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 9. Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
  • 10. Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China; Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China; Renhuai People's Hospital, Renhuai, Guizhou Province, China. Electronic address: [email protected].
  • 11. Department of Gastrointestinal Surgery, Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, China. Electronic address: [email protected].
  • 12. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: [email protected].
  • 13. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; Shanghai Key Laboratory of Reproductive Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 42235504 DOI: 10.1016/j.chom.2026.05.005
Abstract

Hyperuricemia closely correlates with obesity, yet high uric acid (UA) is largely viewed as a consequence or biomarker of obesity rather than a causal driver. Integrating human clinical analyses with animal studies, we redefine UA as a liver-derived endocrine regulator that drives obesity by modulating gut ecology. UA remodels the gut microbiota, selectively depleting Lactobacillus johnsonii by disrupting peptidoglycan synthesis. This depletion reduces microbial phenyllactic acid (PLA)-a metabolite produced by L. johnsonii Lactate Dehydrogenase that we identify as an endogenous suppressor of intestinal Peroxisome Proliferator-activated Receptor alpha (PPARα) signaling. Consequently, PPARα disinhibition upregulates fatty acid transporters, accelerating lipid absorption and promoting obesity. Leveraging human genetic data, we pinpoint lysine acetyltransferase 5 (TIP60) as a master regulator of hepatic UA production. Hepatic TIP60 ablation lowers UA, restoring the L. johnsonii-PLA axis and conferring obesity resistance. These findings establish a UA-driven liver-gut axis and nominate TIP60 inhibition as a dual-target therapy for obesity and hyperuricemia.

Keywords
Lactobacillus johnsonii; gut microbiota; intestinal lipid absorption; obesity; phenyllactic acid; purine metabolism; uric acid.
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