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  • br Role of the Funding Sources Research grants

    2018-10-25


    Role of the Funding Sources Research grants were received from the Smoking Research Foundation, the Tsuchiya Foundation, the Japan Science and Technology Agency (AS242Z02592P), the Japan Heart Foundation, the Scientific Support Programs for Cancer Research Grant-in-Aid for Scientific Research on Innovative Areas (221S0001) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and JSPS KAKENHI Grants-in-Aid for Scientific Research (B) (Generative Research Fields, Grant number 26310106). These grants supported part of the laboratory work and writing of this report.
    Conflicts of Interest/Disclosures
    Author Contributions
    Acknowledgments
    Introduction Prader–Willi syndrome (PWS) is the most common form of human genetic obesity caused by mutations in the paternal genes on chromosome 15q11.2–q13 (Butler, 2011). Bodyweight management of children with PWS has proven to be extraordinarily difficult as they have a low muscle tone that tends to result in less physical activity than normal, a chronic and uncontrollable feeling of hunger, and a deficit of satiety that drives their constant food-craving behavior. The molecular chain of causation between these drivers and obesity development in PWS children remains largely uncharacterized (Lacroix et al., 2014). Accumulating evidence suggests that a dysbiotic gut microbiota may work as a contributing factor in diet-related obesity (Backhed et al., 2004; Zhao, 2013). Germfree mice were shown to be resistant to high-sugar, high-fat, “Western” diet-induced obesity (Backhed et al., 2007). Transplantation of gut microbiota from obese mice or humans increased fat deposits in germfree mouse recipients (Turnbaugh et al., 2008; Ridaura et al., 2013). Development of adiposity and insulin resistance in mice could be significantly reduced by diminishing the gut microbiota with broad-spectrum sphingosine kinase inhibitor (Cani et al., 2008). Transplantation of gut microbiota from healthy donors improved insulin resistance in the first six weeks in obese human volunteers (Vrieze et al., 2012). A diet based on whole-grains, traditional Chinese medicinal foods and prebiotics (WTP diet), has been shown to reduce endotoxin producers and enrich beneficial bifidobacteria in the gut of obese adult human volunteers, leading to decreased endotoxin in the bloodstream and significant alleviation of inflammation, adiposity and insulin resistance (Xiao et al., 2014; Fei and Zhao, 2013). Thus, compelling evidence suggests that the gut microbiota serves as a pivotal contributing factor in the development of diet-related obesity in both mice and humans. Intriguingly, gut microbiota may even be involved in genetically predisposed obesity in mice. Removal of most of the gut microbiota with broad-spectrum antibiotics effectively reduced the development of adiposity and insulin resistance in genetically obese mice including leptin-deficient ob/ob mice and toll-like receptor 5 knockout mice (Cani et al., 2008; Vijay-Kumar et al., 2010). Transplantation of gut microbiota from these two strains of genetically obese animals into germ free wild type mice also conferred parts of the obesity phenotype on the recipients (Vijay-Kumar et al., 2010; Turnbaugh et al., 2006). However, the role of gut microbiota in genetically predisposed obesity in humans has not been characterized so far. Whether modulation of the gut microbiota can contribute to alleviation of metabolic deteriorations in human genetic obesity becomes an interesting question. To tackle this question, we recruited children morbidly obese with PWS or diet-related simple obesity (SO) for a hospitalized intervention with the WTP diet (Xiao et al., 2014). By using a top-down systems strategy to combine metagenomic characterization of the gut microbiota, metabolomic profiling of co-metabolites between host and gut bacteria, and transplantation of human gut microbiota to germfree mice, we showed a potentially significant contribution of dysbiotic gut microbiota to the metabolic deteriorations associated with genetically predisposed obesity, as with simple obesity. These results imply a gut microbiota-mediated path towards obesity-related metabolic diseases, common to diet-related and genetically predisposed obesity.