The Study Of Gut Microbiota-targeted Dietary Intervention Of Pediatric Genetic Obsesity And Related Metabolic Disorders

Metabolic diseases such as obesity,nonalcoholic fatty liver disease?NAFLD?and diabetes have become a worldwide devastating epidemic in recent decades.The drastic changes of diet habit and the genetic predisposition are thought to be two major factors contributing to the rising incidence of metabolic diseases in modern humans.Recent studies have found that gut microbiota act as an important driving factor in the development of dietary induced obesity and related metabolic diseases.But whether gut microbiota is also involved in the development of human obesity caused by genetic deficiency?Whether the gut microbiota-targeted dietary intervention could improve genetic obesity?What is the mechanism by which the gut microbiota-targeted dietary intervention contributes to metabolic deteriorates?These are still problems that plague scientists.Prader-Willi syndrome?PWS?is one of the most common human genetic diseases leading to obesity.In this study,through the clinical trials of PWS and simple obese?SO?children by gut microbiota-targeted dietary intervention and gut microbiota transplantation experiments using germ-free mice,we study the relationships among diet,gut microbiota and genetic obesity,and explore the underlying molecular mechanisms.In our hospitalized intervention trial with PWS?n=17?and SO?n=21?children,we found that a diet rich in non-digestible carbohydrates could induce significant weight loss and improvement of obesity-related phenotypes such as liver function,glucose metabolism,lipid metabolism,metabolic endoxemia and systemic inflammatory response in PWS children,as well as in SO children.The dietary intervention also significantly alleviate the hyperphagia in PWS children.Bar-coded pyrosequencing of 16S rRNA gene V1-V3 region showed that there is no significant difference between the gut microbiota of PWS and SO children before dietary intervention,while the dietary intervention could significantly altered the gut microbiota of all the obese children and there is still no difference between PWS and SO children after dietary intervention.Procrustes analysis Procrustes analysis showed that metabolic phenotypes and microbiota structure of all the obese children showed a significant correlation between improvement of physiological pattern and the shift of gut microbiota during the dietary intervention.Some bacterial metabolites such as acetate which has beneficial effect to the host were significantly increased,while the fermented product of protein such as isobutyric acid and isovaleric acid were significantly dereased after dietary intervention.Then,gut microbiota from a PWS human donor before and after a dietary weight loss program was transplanted into germ-free C57BL/6J male mice,named PreM and PostM groups respectively,and fed on normal chow diet for 4 weeks.PreM group showed significantly decreased bodyweight during the first two weeks after transplantation,and then regained the lost weight in the following two weeks.Mice that received the post-intervention human fecal microbiota lost no bodyweight.Rather,they maintained weight for 4 days after transplantation and then returned to normal growth.Meanwhile,PreM group showed higher level of endotoxin load and systematic and peripheric inflammation on the 2^nd week.However,although still no difference on the 2^nd week,there are significantly increased body and hepatic fat accumulation in the PreM group on the 4^thh week.The gut microbiota in PreM and PostM groups were significantly different from each other and was more resembling with their respective donor.Among the 45 discriminating operational taxonomic units?OTUs?,6 OTUs,including those from Bifidobacterium and Lactobacillus,were consistently lower,while 32 OTUs,such as those from Bacteroides,Parabacteroides,Ruminococcus and Bilophila,were consistently higher in PreH and PreM groups compared with those in PostH and PostM groups.RNA-sequencing revealed that,in comparison with PostM group,PreM group showed a foregoing pro-steatotic transcriptional response in liver featuring by the repression of lipid beta-oxidation and the activation of lipid absorption and cholesterol uptake before the pathology of liver steatosis.Moreover,peroxisome proliferator-activated receptor alpha?PPAR??,which was repressed in PreM group,may act as crucial regulator of the hepatic transcriptional profile of lipid metabolism between two groups.In conclusion,our study not only underscored that the gut microbiota-targeted dietary intervention could significantly improve the obesity-related phenotypes in genetically obese children with PWS,but also revealed the potential mechanism in the development of the obesity and NAFLD mediated by gut microbiota.These reults suggested that gut microbiota plays a crucial casual role in the development of obesity induced by genetic deficiencies,which adds new understanding of the relationship between gut microbiota and obesity related diseases.Therefore,the modulation of gut microbiota through dietary intervention could be a valuable and promising method to manage metabolic diseases such as obesity and NAFLD.