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FXR is a molecular target for the effects of vertical sleeve gastrectomy.

Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, Seeley RJ - Nature (2014)

Bottom Line: Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach.Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities.Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA.

ABSTRACT
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

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VSG and FXR alter the composition of cecal microbial communitiesA) Principal coordinates analysis (PCoA) plot of weighted UniFrac distances. Each dot represents a cecal community. The percentage of variation explained by each principal coordinate is shown in parentheses. B) Abundance gradient of Bacteroidetes and C) abundance gradient of Firmicutes. Gradients range from blue (indicating low relative abundance) to red (indicating high relative abundance). The same plots are shown for A–C). D) Relative abundance of Bacteroides was reduced in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice E) Relative abundance of one genus in the Porphyromonadaceae family was increased in WT-VSG compared to WT-sham operated mice, but was reduced in KO-VSG mice relative to KO-sham operated controls F) Relative abundance of Roseburia was increased in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice G) Among WT-VSG mice, the relative abundance of Roseburia was tightly correlated with fasting blood glucose. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
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Figure 5: VSG and FXR alter the composition of cecal microbial communitiesA) Principal coordinates analysis (PCoA) plot of weighted UniFrac distances. Each dot represents a cecal community. The percentage of variation explained by each principal coordinate is shown in parentheses. B) Abundance gradient of Bacteroidetes and C) abundance gradient of Firmicutes. Gradients range from blue (indicating low relative abundance) to red (indicating high relative abundance). The same plots are shown for A–C). D) Relative abundance of Bacteroides was reduced in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice E) Relative abundance of one genus in the Porphyromonadaceae family was increased in WT-VSG compared to WT-sham operated mice, but was reduced in KO-VSG mice relative to KO-sham operated controls F) Relative abundance of Roseburia was increased in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice G) Among WT-VSG mice, the relative abundance of Roseburia was tightly correlated with fasting blood glucose. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.

Mentions: Weighted UniFrac analysis (sensitive to abundances of taxa)33 showed separation of WT-VSG samples from WT-sham samples along the first component, indicating that VSG had a stronger effect on microbiota composition in WT mice than in KO mice (Fig 5A, Extended Data Fig3, Two-way ANOVA with Tukey posthoc). As shown in Fig 5B-C, the separation of samples in the PCoA plot reflects differences in the Bacteroidetes and Firmicutes levels. In light of these differences we further identified specific taxonomic changes that result from an interaction between genotype and surgery, as these may represent microbial groups that are critical to the potent effects of bariatric surgery—though future studies involving colonization of germ-free mice would be required for definitive evidence supporting a functional involvement.


FXR is a molecular target for the effects of vertical sleeve gastrectomy.

Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, Seeley RJ - Nature (2014)

VSG and FXR alter the composition of cecal microbial communitiesA) Principal coordinates analysis (PCoA) plot of weighted UniFrac distances. Each dot represents a cecal community. The percentage of variation explained by each principal coordinate is shown in parentheses. B) Abundance gradient of Bacteroidetes and C) abundance gradient of Firmicutes. Gradients range from blue (indicating low relative abundance) to red (indicating high relative abundance). The same plots are shown for A–C). D) Relative abundance of Bacteroides was reduced in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice E) Relative abundance of one genus in the Porphyromonadaceae family was increased in WT-VSG compared to WT-sham operated mice, but was reduced in KO-VSG mice relative to KO-sham operated controls F) Relative abundance of Roseburia was increased in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice G) Among WT-VSG mice, the relative abundance of Roseburia was tightly correlated with fasting blood glucose. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
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Related In: Results  -  Collection

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Figure 5: VSG and FXR alter the composition of cecal microbial communitiesA) Principal coordinates analysis (PCoA) plot of weighted UniFrac distances. Each dot represents a cecal community. The percentage of variation explained by each principal coordinate is shown in parentheses. B) Abundance gradient of Bacteroidetes and C) abundance gradient of Firmicutes. Gradients range from blue (indicating low relative abundance) to red (indicating high relative abundance). The same plots are shown for A–C). D) Relative abundance of Bacteroides was reduced in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice E) Relative abundance of one genus in the Porphyromonadaceae family was increased in WT-VSG compared to WT-sham operated mice, but was reduced in KO-VSG mice relative to KO-sham operated controls F) Relative abundance of Roseburia was increased in WT-VSG compared to WT-sham operated mice, but did not differ in KO mice G) Among WT-VSG mice, the relative abundance of Roseburia was tightly correlated with fasting blood glucose. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
Mentions: Weighted UniFrac analysis (sensitive to abundances of taxa)33 showed separation of WT-VSG samples from WT-sham samples along the first component, indicating that VSG had a stronger effect on microbiota composition in WT mice than in KO mice (Fig 5A, Extended Data Fig3, Two-way ANOVA with Tukey posthoc). As shown in Fig 5B-C, the separation of samples in the PCoA plot reflects differences in the Bacteroidetes and Firmicutes levels. In light of these differences we further identified specific taxonomic changes that result from an interaction between genotype and surgery, as these may represent microbial groups that are critical to the potent effects of bariatric surgery—though future studies involving colonization of germ-free mice would be required for definitive evidence supporting a functional involvement.

Bottom Line: Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach.Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities.Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA.

ABSTRACT
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Show MeSH
Related in: MedlinePlus