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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

Improved bioclinical parameters and inflammatory conditions after the intervention. (a) Anthropometric markers. (b) Hepatic function markers. (c) Plasma glucose homeostasis. (d) Plasma lipid homeostasis. (e) Inflammation related markers. Data are shown as mean ± s.e.m. Wilcoxon matched-pairs signed rank test (two-tailed) was used to analyze variation between each two-time points in PWS or SO children. *P < 0.05, **P < 0.01. For most of the bioclinical variables, PWS n = 17 and SO n = 21; For OGTT Glycaemia AUC and OGTT Insulinemia AUC, PWS n = 16 and SO n = 20; For CRP, W.B.C., SAA, AGP, Adiponectin and IL-6, PWS n = 16 and SO n = 19. BMI: body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; OGTT: Oral glucose tolerance test; LDL: low-density lipoprotein; CRP: C reactive protein; W.B.C.: White blood cell count; SAA: serum amyloid A protein; AGP: α-acid glycoprotein; LBP: Lipopolysaccharide binding protein.
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f0010: Improved bioclinical parameters and inflammatory conditions after the intervention. (a) Anthropometric markers. (b) Hepatic function markers. (c) Plasma glucose homeostasis. (d) Plasma lipid homeostasis. (e) Inflammation related markers. Data are shown as mean ± s.e.m. Wilcoxon matched-pairs signed rank test (two-tailed) was used to analyze variation between each two-time points in PWS or SO children. *P < 0.05, **P < 0.01. For most of the bioclinical variables, PWS n = 17 and SO n = 21; For OGTT Glycaemia AUC and OGTT Insulinemia AUC, PWS n = 16 and SO n = 20; For CRP, W.B.C., SAA, AGP, Adiponectin and IL-6, PWS n = 16 and SO n = 19. BMI: body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; OGTT: Oral glucose tolerance test; LDL: low-density lipoprotein; CRP: C reactive protein; W.B.C.: White blood cell count; SAA: serum amyloid A protein; AGP: α-acid glycoprotein; LBP: Lipopolysaccharide binding protein.

Mentions: Almost all relevant bioclinical parameters indicate a significant alleviation of the metabolic deteriorations in children with both genetic and simple obesity after 30 days of the dietary intervention (Fig. 2). With one-month intervention, the SO cohort lost 9.5 ± 0.4% (mean ± s.e.m.) of their initial bodyweight, and the PWS cohort 7.6 ± 0.6% (Fig. 2a). Both PWS and SO children showed significant improvement in markers of metabolic health (Tables S4 and S5). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood were reduced, indicating improved liver condition (Fig. 2b). Glucose homeostasis was significantly improved (Fig. 2c). Blood levels of total cholesterol, triglycerides, and low-density lipoprotein (LDL) were decreased (Fig. 2d). The PWS cohort was followed for two more months on the WTP diet. They lost a total of 18.3 ± 1.0% of their initial bodyweight and showed continued improvement in several metabolic parameters (Fig. 2a–d). In addition, the PWS cohort showed a modest improvement in their overall hyperphagia behavior (Table S6). GD02 reduced his bodyweight from 140.1 kg to 83.6 kg after 285 days in the hospital. He then continued this intervention at home and reduced to 73.2 kg after 430 days on this diet. All his metabolic parameters came to normal range (Table S7). This extended dietary intervention can thus significantly alleviate the metabolic deteriorations in human genetic obesity, in which the diet-induced weight loss can be comparable to that achievable by gastric bypass surgery (Papavramidis et al., 2006).


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)

Improved bioclinical parameters and inflammatory conditions after the intervention. (a) Anthropometric markers. (b) Hepatic function markers. (c) Plasma glucose homeostasis. (d) Plasma lipid homeostasis. (e) Inflammation related markers. Data are shown as mean ± s.e.m. Wilcoxon matched-pairs signed rank test (two-tailed) was used to analyze variation between each two-time points in PWS or SO children. *P < 0.05, **P < 0.01. For most of the bioclinical variables, PWS n = 17 and SO n = 21; For OGTT Glycaemia AUC and OGTT Insulinemia AUC, PWS n = 16 and SO n = 20; For CRP, W.B.C., SAA, AGP, Adiponectin and IL-6, PWS n = 16 and SO n = 19. BMI: body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; OGTT: Oral glucose tolerance test; LDL: low-density lipoprotein; CRP: C reactive protein; W.B.C.: White blood cell count; SAA: serum amyloid A protein; AGP: α-acid glycoprotein; LBP: Lipopolysaccharide binding protein.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4563136&req=5

f0010: Improved bioclinical parameters and inflammatory conditions after the intervention. (a) Anthropometric markers. (b) Hepatic function markers. (c) Plasma glucose homeostasis. (d) Plasma lipid homeostasis. (e) Inflammation related markers. Data are shown as mean ± s.e.m. Wilcoxon matched-pairs signed rank test (two-tailed) was used to analyze variation between each two-time points in PWS or SO children. *P < 0.05, **P < 0.01. For most of the bioclinical variables, PWS n = 17 and SO n = 21; For OGTT Glycaemia AUC and OGTT Insulinemia AUC, PWS n = 16 and SO n = 20; For CRP, W.B.C., SAA, AGP, Adiponectin and IL-6, PWS n = 16 and SO n = 19. BMI: body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; OGTT: Oral glucose tolerance test; LDL: low-density lipoprotein; CRP: C reactive protein; W.B.C.: White blood cell count; SAA: serum amyloid A protein; AGP: α-acid glycoprotein; LBP: Lipopolysaccharide binding protein.
Mentions: Almost all relevant bioclinical parameters indicate a significant alleviation of the metabolic deteriorations in children with both genetic and simple obesity after 30 days of the dietary intervention (Fig. 2). With one-month intervention, the SO cohort lost 9.5 ± 0.4% (mean ± s.e.m.) of their initial bodyweight, and the PWS cohort 7.6 ± 0.6% (Fig. 2a). Both PWS and SO children showed significant improvement in markers of metabolic health (Tables S4 and S5). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood were reduced, indicating improved liver condition (Fig. 2b). Glucose homeostasis was significantly improved (Fig. 2c). Blood levels of total cholesterol, triglycerides, and low-density lipoprotein (LDL) were decreased (Fig. 2d). The PWS cohort was followed for two more months on the WTP diet. They lost a total of 18.3 ± 1.0% of their initial bodyweight and showed continued improvement in several metabolic parameters (Fig. 2a–d). In addition, the PWS cohort showed a modest improvement in their overall hyperphagia behavior (Table S6). GD02 reduced his bodyweight from 140.1 kg to 83.6 kg after 285 days in the hospital. He then continued this intervention at home and reduced to 73.2 kg after 430 days on this diet. All his metabolic parameters came to normal range (Table S7). This extended dietary intervention can thus significantly alleviate the metabolic deteriorations in human genetic obesity, in which the diet-induced weight loss can be comparable to that achievable by gastric bypass surgery (Papavramidis et al., 2006).

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