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Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.

Zhang C, Yin A, Li H, Wang R, Wu G, Shen J, Zhang M, Wang L, Hou Y, Ouyang H, Zhang Y, Zheng Y, Wang J, Lv X, Wang Y, Zhang F, Zeng B, Li W, Yan F, Zhao Y, Pang X, Zhang X, Fu H, Chen F, Zhao N, Hamaker BR, Bridgewater LC, Weinkove D, Clement K, Dore J, Holmes E, Xiao H, Zhao G, Yang S, Bork P, Nicholson JK, Wei H, Tang H, Zhang X, Zhao L - EBioMedicine (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Unlabelled: 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.

Research in context: 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.

No MeSH data available.


Related in: MedlinePlus

Impaired metabolism of gnotobiotic mice transplanted with pre-intervention gut microbiota from a PWS patient. (a) Body weight curves of gnotobiotic mice receiving the fecal microbiota from GD58 before (Day 0, red) and after (Day 90, green) the intervention. For mice receiving pre-intervention microbiota, 1 to 14 days after transplantation, n = 10, and 15 to 28 days, n = 5; For mice receiving post-intervention microbiota, 1 to 14 days after transplantation, n = 9, and 15 to 28 days, n = 4. (b) Adiposity index (%Fat mass/body weight) of gnotobiotic mice at 2 and 4 weeks after fecal transplantation. (c) Hematoxylin- and eosin-stained sections of epididymal fat pads (100 × magnification). Cell area of adipocyte in epididymal fat pad is shown as mean ± s.e.m. (d) RT-qPCR analysis of expression of Tnfα, Tlr4 and Il6 in the liver, ileum and colon. All mRNA quantification data were normalized to the housekeeping gene Glyceraldehyde-3-phosphate dehydrogenase (Gapdh). Gene expression levels are normalized to that of mice 2 weeks after inoculation with pre-intervention microbiota. The median of the data in each group is shown. Student t-test (two-tailed, in (a), (b) and (c)) or Mann–Whitney U test (two-tailed, in (d),) was used to analyze variation between gnotobiotic mice receiving pre- and post-intervention microbiota. *P < 0.05, **P < 0.01. In (b) to (d), for mice receiving pre-intervention microbiota, n = 5; for mice receiving post-intervention microbiota, n = 4.
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f0035: Impaired metabolism of gnotobiotic mice transplanted with pre-intervention gut microbiota from a PWS patient. (a) Body weight curves of gnotobiotic mice receiving the fecal microbiota from GD58 before (Day 0, red) and after (Day 90, green) the intervention. For mice receiving pre-intervention microbiota, 1 to 14 days after transplantation, n = 10, and 15 to 28 days, n = 5; For mice receiving post-intervention microbiota, 1 to 14 days after transplantation, n = 9, and 15 to 28 days, n = 4. (b) Adiposity index (%Fat mass/body weight) of gnotobiotic mice at 2 and 4 weeks after fecal transplantation. (c) Hematoxylin- and eosin-stained sections of epididymal fat pads (100 × magnification). Cell area of adipocyte in epididymal fat pad is shown as mean ± s.e.m. (d) RT-qPCR analysis of expression of Tnfα, Tlr4 and Il6 in the liver, ileum and colon. All mRNA quantification data were normalized to the housekeeping gene Glyceraldehyde-3-phosphate dehydrogenase (Gapdh). Gene expression levels are normalized to that of mice 2 weeks after inoculation with pre-intervention microbiota. The median of the data in each group is shown. Student t-test (two-tailed, in (a), (b) and (c)) or Mann–Whitney U test (two-tailed, in (d),) was used to analyze variation between gnotobiotic mice receiving pre- and post-intervention microbiota. *P < 0.05, **P < 0.01. In (b) to (d), for mice receiving pre-intervention microbiota, n = 5; for mice receiving post-intervention microbiota, n = 4.

Mentions: To compare the capacity of gut microbiota to induce metabolic deteriorations before and after the intervention, we transplanted the gut microbiota from the same PWS volunteer (GD58) before and after the intervention, into germ-free wild-type C57BL/6J mice. Mice that received the pre-intervention human fecal microbiota 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 (Fig. 7a). By the end of the trial, pre-intervention microbiota recipients showed significantly greater fat mass as a percentage of body weight (Fig. 7b). Histological examination of epididymal fat pads revealed that the size of adipocytes in pre-intervention microbiota recipients was smaller than in post-intervention recipients at 2 weeks after the transplantation, consistent with toxicity of the microbiota, but then significantly bigger at 4 weeks. Adipocytes from the post-intervention microbiota recipients did not change over time (Fig. 7c). The initial weight loss was associated with appreciably higher inflammatory responses in pre-intervention transplant recipients, as measured by RT-qPCR of TNFα, IL6 and TLR4 gene expression in liver, ileum and colon at 2 weeks after transplantation (Fig. 7d), suggesting that when transplanted into germfree mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention gut microbiota from the same volunteer.


Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.

Zhang C, Yin A, Li H, Wang R, Wu G, Shen J, Zhang M, Wang L, Hou Y, Ouyang H, Zhang Y, Zheng Y, Wang J, Lv X, Wang Y, Zhang F, Zeng B, Li W, Yan F, Zhao Y, Pang X, Zhang X, Fu H, Chen F, Zhao N, Hamaker BR, Bridgewater LC, Weinkove D, Clement K, Dore J, Holmes E, Xiao H, Zhao G, Yang S, Bork P, Nicholson JK, Wei H, Tang H, Zhang X, Zhao L - EBioMedicine (2015)

Impaired metabolism of gnotobiotic mice transplanted with pre-intervention gut microbiota from a PWS patient. (a) Body weight curves of gnotobiotic mice receiving the fecal microbiota from GD58 before (Day 0, red) and after (Day 90, green) the intervention. For mice receiving pre-intervention microbiota, 1 to 14 days after transplantation, n = 10, and 15 to 28 days, n = 5; For mice receiving post-intervention microbiota, 1 to 14 days after transplantation, n = 9, and 15 to 28 days, n = 4. (b) Adiposity index (%Fat mass/body weight) of gnotobiotic mice at 2 and 4 weeks after fecal transplantation. (c) Hematoxylin- and eosin-stained sections of epididymal fat pads (100 × magnification). Cell area of adipocyte in epididymal fat pad is shown as mean ± s.e.m. (d) RT-qPCR analysis of expression of Tnfα, Tlr4 and Il6 in the liver, ileum and colon. All mRNA quantification data were normalized to the housekeeping gene Glyceraldehyde-3-phosphate dehydrogenase (Gapdh). Gene expression levels are normalized to that of mice 2 weeks after inoculation with pre-intervention microbiota. The median of the data in each group is shown. Student t-test (two-tailed, in (a), (b) and (c)) or Mann–Whitney U test (two-tailed, in (d),) was used to analyze variation between gnotobiotic mice receiving pre- and post-intervention microbiota. *P < 0.05, **P < 0.01. In (b) to (d), for mice receiving pre-intervention microbiota, n = 5; for mice receiving post-intervention microbiota, n = 4.
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f0035: Impaired metabolism of gnotobiotic mice transplanted with pre-intervention gut microbiota from a PWS patient. (a) Body weight curves of gnotobiotic mice receiving the fecal microbiota from GD58 before (Day 0, red) and after (Day 90, green) the intervention. For mice receiving pre-intervention microbiota, 1 to 14 days after transplantation, n = 10, and 15 to 28 days, n = 5; For mice receiving post-intervention microbiota, 1 to 14 days after transplantation, n = 9, and 15 to 28 days, n = 4. (b) Adiposity index (%Fat mass/body weight) of gnotobiotic mice at 2 and 4 weeks after fecal transplantation. (c) Hematoxylin- and eosin-stained sections of epididymal fat pads (100 × magnification). Cell area of adipocyte in epididymal fat pad is shown as mean ± s.e.m. (d) RT-qPCR analysis of expression of Tnfα, Tlr4 and Il6 in the liver, ileum and colon. All mRNA quantification data were normalized to the housekeeping gene Glyceraldehyde-3-phosphate dehydrogenase (Gapdh). Gene expression levels are normalized to that of mice 2 weeks after inoculation with pre-intervention microbiota. The median of the data in each group is shown. Student t-test (two-tailed, in (a), (b) and (c)) or Mann–Whitney U test (two-tailed, in (d),) was used to analyze variation between gnotobiotic mice receiving pre- and post-intervention microbiota. *P < 0.05, **P < 0.01. In (b) to (d), for mice receiving pre-intervention microbiota, n = 5; for mice receiving post-intervention microbiota, n = 4.
Mentions: To compare the capacity of gut microbiota to induce metabolic deteriorations before and after the intervention, we transplanted the gut microbiota from the same PWS volunteer (GD58) before and after the intervention, into germ-free wild-type C57BL/6J mice. Mice that received the pre-intervention human fecal microbiota 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 (Fig. 7a). By the end of the trial, pre-intervention microbiota recipients showed significantly greater fat mass as a percentage of body weight (Fig. 7b). Histological examination of epididymal fat pads revealed that the size of adipocytes in pre-intervention microbiota recipients was smaller than in post-intervention recipients at 2 weeks after the transplantation, consistent with toxicity of the microbiota, but then significantly bigger at 4 weeks. Adipocytes from the post-intervention microbiota recipients did not change over time (Fig. 7c). The initial weight loss was associated with appreciably higher inflammatory responses in pre-intervention transplant recipients, as measured by RT-qPCR of TNFα, IL6 and TLR4 gene expression in liver, ileum and colon at 2 weeks after transplantation (Fig. 7d), suggesting that when transplanted into germfree mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention gut microbiota from the same volunteer.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Unlabelled: 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.

Research in context: 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.

No MeSH data available.


Related in: MedlinePlus