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<p>Obesity and its associated metabolic complications represent a global health crisis, yet effective microbiota-targeted pharmacotherapies remain limited. Here, we report that GV-971 (sodium oligomannate), a marine-derived oligosaccharide originally developed for Alzheimer’s disease, exerts potent anti-obesity and metabolic benefits by reprogramming gut microbial and host signaling networks. In high-fat diet-induced obese mice, GV-971 reduced adiposity, improved glucose homeostasis, and alleviated hepatic steatosis without affecting food intake. Multi-omics and causal intervention experiments revealed that GV-971 selectively decreased the abundance of <i>Clostridium scindens</i>, a keystone bacterium responsible for secondary bile acid synthesis. This decrease downregulated the expression of the <i>baiF</i> gene encoding 7α-hydroxysteroid dehydrogenase, leading to reduced intestinal deoxycholic acid (DCA) levels and inhibition of intestinal farnesoid X receptor (FXR) signaling. Restoration of <i>C. scindens</i> abundance, <i>baiF</i> expression, or DCA supplementation abrogated the metabolic benefits of GV-971, confirming the causal role of the <i>C. scindens</i>-DCA-FXR axis. Mechanistically, inhibition of intestinal FXR promoted thermogenic gene expression and white adipose tissue browning, thus enhancing systemic energy expenditure. These findings uncover a bacterium-metabolite-host signaling pathway underlying the effects of GV-971 and establish microbiota-directed FXR modulation as a promising therapeutic approach for obesity and metabolic disease.</p>

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GV-971 remodels the gut microbiota-bile acid-FXR axis to ameliorate obesity and metabolic dysfunction

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月21日

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  • Na Zhang,
  • Xinyu Ye,
  • Kai Wang,
  • Yameng Hu,
  • Zixi Wang,
  • Lichun Huang,
  • Xi Chen,
  • Ding Yan,
  • Wen Fu,
  • Qian Xue,
  • Shihao Sun,
  • Yihan Xu,
  • Daolin Tang,
  • Xin Chen,
  • Li Zhou,
  • Jinbao Liu

摘要

Obesity and its associated metabolic complications represent a global health crisis, yet effective microbiota-targeted pharmacotherapies remain limited. Here, we report that GV-971 (sodium oligomannate), a marine-derived oligosaccharide originally developed for Alzheimer’s disease, exerts potent anti-obesity and metabolic benefits by reprogramming gut microbial and host signaling networks. In high-fat diet-induced obese mice, GV-971 reduced adiposity, improved glucose homeostasis, and alleviated hepatic steatosis without affecting food intake. Multi-omics and causal intervention experiments revealed that GV-971 selectively decreased the abundance of Clostridium scindens, a keystone bacterium responsible for secondary bile acid synthesis. This decrease downregulated the expression of the baiF gene encoding 7α-hydroxysteroid dehydrogenase, leading to reduced intestinal deoxycholic acid (DCA) levels and inhibition of intestinal farnesoid X receptor (FXR) signaling. Restoration of C. scindens abundance, baiF expression, or DCA supplementation abrogated the metabolic benefits of GV-971, confirming the causal role of the C. scindens-DCA-FXR axis. Mechanistically, inhibition of intestinal FXR promoted thermogenic gene expression and white adipose tissue browning, thus enhancing systemic energy expenditure. These findings uncover a bacterium-metabolite-host signaling pathway underlying the effects of GV-971 and establish microbiota-directed FXR modulation as a promising therapeutic approach for obesity and metabolic disease.