Gut microbiota-mediated xanthine metabolism is associated with resistance to high-fat diet-induced obesity
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Bin Wei1, Sijia Wang1, Yakun Wang1
1College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
Abstract:
Resistance to high-fat diet-induced obesity (DIR) has been observed in mice fed a high-fat diet and may provide a potential approach for anti-obesity drug discovery. However, the metabolic status, gut microbiota composition, and its associations with DIR are still unclear. Here, ultraperformance liquid chromatography-tandem mass spectrometry-based urinary metabolomic and 16S rRNA gene sequencing-based fecal microbiome analyses were conducted to investigate the relationship between metabolic profile, gut microbiota composition, and body weight of C57BL/6J mice on chow or a high-fat diet for 8 weeks. PICRUSt analysis of 16S rRNA gene sequences predicted the functional metagenomes of gut bacteria. The results demonstrated that feeding a high-fat diet increased body weight and fasting blood glucose of high-fat diet-induced obesity (DIO) mice and altered the host-microbial co-metabolism and gut microbiota composition. In DIR mice, high-fat diet did not increase body weight while fasting blood glucose was increased significantly compared to chow fed mice. In DIR mice, the urinary metabolic pattern was shifted to a distinct direction compared to DIO mice, which was mainly contributed by xanthine. Moreover, high-fat diet caused gut microbiota dysbiosis in both DIO and DIR mice, but in DIR mice, the abundance of Bifidobacteriaceae, Roseburia, and Escherichia was not affected compared to mice fed a chow diet, which played an important role in the pathway coverage of FormylTHF biosynthesis I. Meanwhile, xanthine and pathway coverage of FormylTHF biosynthesis I showed significant positive correlations with mouse body weight. These findings suggest that gut microbiota-mediated xanthine metabolism correlates with resistance to high-fat DIO.
Insights
Mice resistant to high-fat diet-induced obesity (DIR) exhibit distinct metabolic profiles and gut microbiota compared to obese mice (DIO). Xanthine metabolism, influenced by gut bacteria, correlates with this resistance, offering potential anti-obesity strategies.
Area of Science:
- Metabolomics and Microbiomics
- Obesity Research
- Gut Microbiota and Host Metabolism
Background:
- High-fat diet-induced obesity (DIO) is a growing concern, yet mechanisms of resistance (DIR) remain unclear.
- Understanding the interplay between diet, metabolism, and gut microbiota in DIR is crucial for anti-obesity drug discovery.
- Previous studies have not fully elucidated the metabolic status and gut microbial composition in DIR mice.
Purpose of the Study:
- To investigate the relationship between metabolic profile, gut microbiota composition, and body weight in mice resistant to high-fat diet-induced obesity (DIR).
- To compare the metabolic and microbial characteristics of DIR mice with diet-induced obesity (DIO) and control mice.
- To identify potential biomarkers and pathways associated with resistance to diet-induced obesity.
Main Methods:
- C57BL/6J mice were fed either a chow or high-fat diet for 8 weeks.
- Urinary metabolomic analysis using ultraperformance liquid chromatography-tandem mass spectrometry.
- Fecal microbiome analysis using 16S rRNA gene sequencing and PICRUSt for functional metagenome prediction.
Main Results:
- High-fat diet increased body weight and fasting blood glucose in DIO mice, but not body weight in DIR mice.
- DIR mice exhibited a distinct urinary metabolic pattern compared to DIO mice, primarily driven by xanthine.
- Gut microbiota dysbiosis occurred in both DIO and DIR mice, but specific beneficial bacteria (Bifidobacteriaceae, Roseburia, Escherichia) were maintained in DIR mice, impacting FormylTHF biosynthesis I.
Conclusions:
- Gut microbiota composition and function are significantly altered in mice resistant to high-fat diet-induced obesity.
- Xanthine metabolism, influenced by gut microbiota, is a key factor associated with resistance to diet-induced obesity.
- Targeting gut microbiota-mediated xanthine metabolism may offer a novel therapeutic strategy for combating obesity.
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