State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
EBioMedicine. 2015 Jul 10;2(8):968-84. doi: 10.1016/j.ebiom.2015.07.007. eCollection 2015 Aug.
Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation.
Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader-Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.
肠道微生物群已被认为是导致与饮食相关的肥胖的关键因素；然而，它在人类遗传性肥胖（如普拉德-威利综合征（PWS））相关疾病表型的发展中的作用仍然难以捉摸。在这项针对 PWS（n=17）和单纯性肥胖（n=21）儿童的住院干预试验中，富含不可消化碳水化合物的饮食可显著减轻体重，并伴有肠道微生物群结构的相应变化，同时降低血清抗原负荷和缓解炎症。对直接从宏基因组数据集中组装的 161 个流行细菌草案基因组的共丰度网络分析显示，碳水化合物发酵产生乙酸的功能基因组群相对增加。基于 NMR 的尿液代谢组学分析显示，饮食诱导了宿主代谢型的整体变化，并确定了显著降低的三甲胺 N-氧化物和吲哚硫酸，这两种宿主-细菌共代谢物已知可引起代谢恶化。与这些有害共代谢物的尿液水平相关的特定细菌基因组被发现编码通过肠道中胆碱或色氨酸发酵产生其前体的酶基因。当移植到无菌小鼠中时，与来自同一志愿者的干预后肠道微生物群相比，干预前的肠道微生物群诱导了更高的炎症和更大的脂肪细胞。我们的基于多组学的系统分析表明，肠道微生物群失调对儿童遗传性和单纯性肥胖都有重要的病因贡献，提示这可能是一种有效的缓解靶点。
管理不善的饮食和基因突变是肥胖相关疾病流行的两个主要驱动因素。对驱动因素与疾病终点之间因果关系的分子链缺乏了解，阻碍了疾病预防和治疗的进展。我们发现，具有普拉德-威利综合征遗传肥胖的儿童与具有饮食相关肥胖的儿童的肠道微生物群存在相似的失调。富含不可消化但可发酵碳水化合物的饮食可显著促进有益细菌群的生长，并减少毒素产生者，从而有助于缓解肥胖症的代谢恶化，而不论主要驱动因素如何。
