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<p>Elevated exposure to 4-hydroxyphenanthrene (4-OHPhe) is positively associated with obesity risk. However, the specific pathogenic mechanism remains unclear. Here, we use SHapley Additive exPlanations (SHAP) and logistic regression analysis to identify a strong association between 4-OHPhe and obesity. Mechanistically, exposure to 4-OHPhe significantly downregulates the expression of hydroxylamine reductase (<i>hcp</i>) genes in <i>Bacteroides uniformis</i> (<i>B. uniformis</i>), thereby inhibiting the removal of reactive oxygen species (ROS) and reducing the abundance of <i>B. uniformis.</i> The decline in <i>B. uniformis</i> abundance reduces hyodeoxycholic acid (HDCA) production, thereby activating the intestinal farnesoid X receptor (FXR)-ceramide pathway and ultimately downregulating white adipose tissue (WAT) thermogenic genes, leading to obesity in male mice. Both <i>B. uniformis</i> administration and HDCA treatment promote this thermogenic effect. These findings demonstrate that 4-OHPhe exacerbates obesity via impairment of gut microbiota composition, thereby establishing a mechanistic link between environmental toxins and host metabolism.</p>

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4-Hydroxyphenanthrene exacerbates obesity by altering gut microbiota and bile acid metabolism

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月13日

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  • Guoqiang Qin,
  • Zhen Xu,
  • Chao Yuan,
  • Yang Li,
  • Mengqian Zhang,
  • Zhixuan Zhou,
  • Jiahui Zhu,
  • Xiaosong Li,
  • Li Chen,
  • Chenyu Li,
  • Lehua Jiang,
  • Shan Huang,
  • Yarui Liu,
  • Hongzhi Sun,
  • Qing Wu,
  • Zhongze Fang

摘要

Elevated exposure to 4-hydroxyphenanthrene (4-OHPhe) is positively associated with obesity risk. However, the specific pathogenic mechanism remains unclear. Here, we use SHapley Additive exPlanations (SHAP) and logistic regression analysis to identify a strong association between 4-OHPhe and obesity. Mechanistically, exposure to 4-OHPhe significantly downregulates the expression of hydroxylamine reductase (hcp) genes in Bacteroides uniformis (B. uniformis), thereby inhibiting the removal of reactive oxygen species (ROS) and reducing the abundance of B. uniformis. The decline in B. uniformis abundance reduces hyodeoxycholic acid (HDCA) production, thereby activating the intestinal farnesoid X receptor (FXR)-ceramide pathway and ultimately downregulating white adipose tissue (WAT) thermogenic genes, leading to obesity in male mice. Both B. uniformis administration and HDCA treatment promote this thermogenic effect. These findings demonstrate that 4-OHPhe exacerbates obesity via impairment of gut microbiota composition, thereby establishing a mechanistic link between environmental toxins and host metabolism.