A multi national research team has recently reported that children with a form of genetic obesity, known as Prader-Willi Syndrome (PWS), shared a similar imbalance in their gut microbiota as children with simple obesity.
In a hospitalized intervention trial, children with PWS or simple obesity participated in an intense 12 or 4 weeks dietary intervention program. Besides providing balanced macro- and micro-nutrients for human needs, the interventional diet based on whole-grains, traditional Chinese medicinal foods and prebiotics, was also rich in non-digestible but fermentable carbohydrates and phytochemicals aiming at changing the gut microbiota. At the end of the intervention, children with PWS and simple obesity both showed better behavioral control of food cravings, significant reduction in bodyweight, improvement in multiple metabolic biomarkers, alleviation of systemic inflammation, and concomitant reduction in serum levels of pro-inflammatory toxins produced by gut bacteria. The best responder of the PWS volunteers continued the intervention diet at home and experienced significant weight loss from 140 kg to 73 kg after nearly 18 months of adherence to the diet, without the need for rigorous exercises.
High throughput next generation sequencing showed that the interventional diet induced significant structural changes in the gut microbiota - it promoted the growth of beneficial bacteria such as bifidobacteria and reduced detrimental bacteria such as proinflammatory toxin producers and those that are capable of converting dietary fats and proteins into toxic metabolites that increase risk of cardiovascular events. Researchers also transplanted human gut microbiota into germ-free mice and found that the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer, strengthening the notion that the diet-induced changes of the gut microbiota have contributed to health improvement of the human hosts.
In previous studies on gut microbiota and health, many analyses have been conducted at genus or higher taxonomic levels. However, different strains within the same bacterial species have been found to contain up to 30% genomic differences and can function very differently in relation to human health, making strain/genome-level analysis necessary. Aided by a new canopy-based algorithm, this study assembled more than 100 high quality draft genomes of prevalent gut bacteria directly from metagenomic datasets, enabling researchers to examine the strain-level response of gut bacteria to the dietary intervention.
Researchers also monitored changes in urine metabolites over the course of the dietary intervention using a NMR-based metabolomic approach. They found significant reduction of toxic metabolites that are known to increase risk of cardio-vascular events. By correlating bacterial changes with variations in urine metabolites, researchers identified specific bacterial genomes that encode the genes for producing obesity-related toxic metabolites by fermenting dietary fats or proteins. These toxin-producers may become potential targets for obesity control.
This study has brought to light the hypothesis that gut microbiota ecosystems function very much like rain forest ecosystems, in which different species form functional groups called "guilds" that adapt interactively to environmental perturbations. Using co-abundance network analysis, the researchers clustered the prevalent bacterial genomes in the gut microbiota into what they call Genome Interaction Groups (GIGs), members of which thrive or decline together, just as guilds in a rain forest. Furthermore, in a rain forest ecosystem, the tall trees serve as "foundation species" to maintain the environmental conditions necessary for all other members of the ecosystem to thrive beneath. In this study researchers found that one GIG containing Bifidobacterium species became predominant after the dietary intervention and was negatively correlated with several other GIGs containing toxin-producing bacteria. This Bifidobacterium-containing GIG may function like a foundation species to maintain a healthier gut microbiota after the intervention. These analyses provide a new conceptual framework for further dissection of the structural and functional relationships of the complex gut microbiota that are relevant to human health.
This study demonstrates a common etiological contribution of dysbiotic gut microbiota in both genetically predisposed and simple obesity. It also highlights the importance of understanding functional interactions within the gut microbiota at the individual strain/genome level and identifying the foundational species that act as backbone of a healthy gut microbiota ecosystem. These results suggest great potential for gut microbiota targeted drug development and nutritional treatment for both genetic and simple obesity, to improve the health status and quality of life of children with these conditions.
This study was led by Prof. Liping Zhao from Shanghai Jiao Tong University, Prof. Aihua Yin from Guangdong Women and Children's Hospital, and Prof. Huiru Tang from Wuhan Institute of Mathematics and Physics, Chinese Academy of Sciences Scientists. The paper was published on-line in EBioMedicine.