Insights into the modulatory effects of host-gut microbial xanthine co-metabolism on high-fat diet-fed mice

Gut microbiota-mediated endobiotic and xenobiotic metabolism play crucial roles in disease progression, and drug therapy/toxicity. Our recent study suggested that gut microbiota-mediated xanthine metabolism is correlated with resistance to high-fat diet (HFD)-induced obesity. Here, we explored the role of host-gut microbial xanthine co-metabolism in the prevention and treatment of HFD-induced obesity by orally administration of Bifidobacterium longum, xanthine, and a xanthine oxidase inhibitor (topiroxostat). The findings indicate that xanthine exhibits a significantly protective effect against HFD-induced obesity. While B. longum, xanthine, and topiroxostat did not alleviate the dysbiosis of the weight and glucose metabolism of HFD-induced obesity (DIO) and obesity resistance (DIR) mice. 16S rRNA sequencing analyses revealed that treatments with B. longum significantly altered gut microbiota composition in HFD-fed and DIO mice. Microbial interaction network analysis revealed several Bacteroidetes species, such as Amulumruptor caecigallinarius and Muribaculum intestinale, as keystone taxa that were notably enriched by B. longum. Untargeted metabolomics analysis implied that xanthine might serve as a crucial molecule in regulating body weight, exerting a preventive effect on HFDinduced obesity. This study offers new perspectives on the influence of host-gut microbial xanthine cometabolism on HFD-fed mice and emphasizes the promising role of xanthine in promoting weight loss