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

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 and consequent activation of the intestinal farnesoid X receptor (FXR)-ceramide pathway, which ultimately results in the downregulation of white adipose tissue (WAT) thermogenic genes and 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. Elevated exposure to 4-hydroxyphenanthrene (4-OHPhe) is positively associated with obesity risk. Here, the authors show that exposure to 4-OHPhe downregulates expression of hydroxylamine reductase genes in Bacteroides uniformis, leading to altered gut microbiota-bile acid-FXR axis and suppression of adipose thermogenesis.