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Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice.

Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Muccioli GM, Neyrinck AM, Possemiers S, Van Holle A, François P, de Vos WM, Delzenne NM, Schrenzel J, Cani PD - Diabetes (2011)

Bottom Line: Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation.We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.

ABSTRACT

Objective: To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.

Research design and methods: Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.

Results: In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.

Conclusions: We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

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Changes in the gut microbiota improve glucose tolerance and reduce plasma triglyceride content, tissue weight, oxidative stress, and muscle lipid accumulation. A: Plasma glucose profile following 1 g/kg glucose oral challenge in freely moving mice. Inset shows the mean area under the curve (AUC) measured between 0 and 120 min after glucose load in the Ob-CT (■) and the Ob-Pre (○) mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test. B: White adipose tissue weight expressed as the percentage of total body weight of the Ob-CT and Ob-Pre mice. Mean ± SEM. n = 8 mice/group. *P < 0.05, determined by a two-tailed Student t test. C: Muscle weight (Vastus lateralis) expressed as the percentage of total body weight. D: Plasma triglyceride content. E: Muscle lipid content. F: Muscle triglycerides. G: Muscle lipoprotein lipase (LPL) mRNA expression. H: Adipose tissue lipid peroxidation markers (TBARS). I: Plasma LPS levels in the same set of mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test.
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Figure 3: Changes in the gut microbiota improve glucose tolerance and reduce plasma triglyceride content, tissue weight, oxidative stress, and muscle lipid accumulation. A: Plasma glucose profile following 1 g/kg glucose oral challenge in freely moving mice. Inset shows the mean area under the curve (AUC) measured between 0 and 120 min after glucose load in the Ob-CT (■) and the Ob-Pre (○) mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test. B: White adipose tissue weight expressed as the percentage of total body weight of the Ob-CT and Ob-Pre mice. Mean ± SEM. n = 8 mice/group. *P < 0.05, determined by a two-tailed Student t test. C: Muscle weight (Vastus lateralis) expressed as the percentage of total body weight. D: Plasma triglyceride content. E: Muscle lipid content. F: Muscle triglycerides. G: Muscle lipoprotein lipase (LPL) mRNA expression. H: Adipose tissue lipid peroxidation markers (TBARS). I: Plasma LPS levels in the same set of mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test.

Mentions: The changes in the gut microbiota composition were associated with significantly lower fasting glycemia and markedly improved glucose tolerance (Fig. 3A). However, it should be noted that body weight was not significantly affected by the treatment (body weight [g]: Ob-CT 46.79 ± 1.28, Ob-Pre 43.06 ± 1.58; P = 0.1), whereas fat mass (Fig. 3B) and cumulative food intake (g) (Ob-CT 466.8 ± 13.8, Ob-Pre 319.6 ± 20.6; P = 0.00034) were significantly lower than Ob-CT. In contrast, muscle mass significantly increased (Fig. 3C). Overall, these data indicate a decreased fat to muscle mass ratio in the Ob-Pre group. Interestingly, plasma triglycerides (Fig. 3D) and muscle lipid (total, triglycerides, and phospholipids) content were dramatically reduced in the prebiotic-treated mice (Fig. 3E and F) (nanogram of phospholipids per microgram of tissue: Ob-CT 29.05 ± 2.55, Ob-Pre 20.05 ± 2.49; P = 0.02). In addition, we found that prebiotic treatment significantly increased muscle lipoprotein lipase mRNA expression (about 70%) (Fig. 3G). This increase may be one of the mechanisms leading to the reduced plasma and muscle lipid content observed in Ob-Pre mice. Further supporting the link between oxidative stress and metabolic disturbances, we found that the prebiotic treatment reduced the adipose tissue lipid peroxide content by ∼50% (Fig. 3H). Moreover, multivariate analyses suggested that metabolic footprints (e.g., the content of plasma triglycerides and fat deposit lipid peroxides) can be used as potential biomarkers of glucose tolerance (Supplementary Fig. 3).


Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice.

Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Muccioli GM, Neyrinck AM, Possemiers S, Van Holle A, François P, de Vos WM, Delzenne NM, Schrenzel J, Cani PD - Diabetes (2011)

Changes in the gut microbiota improve glucose tolerance and reduce plasma triglyceride content, tissue weight, oxidative stress, and muscle lipid accumulation. A: Plasma glucose profile following 1 g/kg glucose oral challenge in freely moving mice. Inset shows the mean area under the curve (AUC) measured between 0 and 120 min after glucose load in the Ob-CT (■) and the Ob-Pre (○) mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test. B: White adipose tissue weight expressed as the percentage of total body weight of the Ob-CT and Ob-Pre mice. Mean ± SEM. n = 8 mice/group. *P < 0.05, determined by a two-tailed Student t test. C: Muscle weight (Vastus lateralis) expressed as the percentage of total body weight. D: Plasma triglyceride content. E: Muscle lipid content. F: Muscle triglycerides. G: Muscle lipoprotein lipase (LPL) mRNA expression. H: Adipose tissue lipid peroxidation markers (TBARS). I: Plasma LPS levels in the same set of mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 3: Changes in the gut microbiota improve glucose tolerance and reduce plasma triglyceride content, tissue weight, oxidative stress, and muscle lipid accumulation. A: Plasma glucose profile following 1 g/kg glucose oral challenge in freely moving mice. Inset shows the mean area under the curve (AUC) measured between 0 and 120 min after glucose load in the Ob-CT (■) and the Ob-Pre (○) mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test. B: White adipose tissue weight expressed as the percentage of total body weight of the Ob-CT and Ob-Pre mice. Mean ± SEM. n = 8 mice/group. *P < 0.05, determined by a two-tailed Student t test. C: Muscle weight (Vastus lateralis) expressed as the percentage of total body weight. D: Plasma triglyceride content. E: Muscle lipid content. F: Muscle triglycerides. G: Muscle lipoprotein lipase (LPL) mRNA expression. H: Adipose tissue lipid peroxidation markers (TBARS). I: Plasma LPS levels in the same set of mice. Mean ± SEM. n = 10 mice/group. *P < 0.05, determined by a two-tailed Student t test.
Mentions: The changes in the gut microbiota composition were associated with significantly lower fasting glycemia and markedly improved glucose tolerance (Fig. 3A). However, it should be noted that body weight was not significantly affected by the treatment (body weight [g]: Ob-CT 46.79 ± 1.28, Ob-Pre 43.06 ± 1.58; P = 0.1), whereas fat mass (Fig. 3B) and cumulative food intake (g) (Ob-CT 466.8 ± 13.8, Ob-Pre 319.6 ± 20.6; P = 0.00034) were significantly lower than Ob-CT. In contrast, muscle mass significantly increased (Fig. 3C). Overall, these data indicate a decreased fat to muscle mass ratio in the Ob-Pre group. Interestingly, plasma triglycerides (Fig. 3D) and muscle lipid (total, triglycerides, and phospholipids) content were dramatically reduced in the prebiotic-treated mice (Fig. 3E and F) (nanogram of phospholipids per microgram of tissue: Ob-CT 29.05 ± 2.55, Ob-Pre 20.05 ± 2.49; P = 0.02). In addition, we found that prebiotic treatment significantly increased muscle lipoprotein lipase mRNA expression (about 70%) (Fig. 3G). This increase may be one of the mechanisms leading to the reduced plasma and muscle lipid content observed in Ob-Pre mice. Further supporting the link between oxidative stress and metabolic disturbances, we found that the prebiotic treatment reduced the adipose tissue lipid peroxide content by ∼50% (Fig. 3H). Moreover, multivariate analyses suggested that metabolic footprints (e.g., the content of plasma triglycerides and fat deposit lipid peroxides) can be used as potential biomarkers of glucose tolerance (Supplementary Fig. 3).

Bottom Line: Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation.We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.

ABSTRACT

Objective: To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.

Research design and methods: Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.

Results: In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.

Conclusions: We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

Show MeSH
Related in: MedlinePlus