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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 alters the abundance of cecal SCFAsThe relative concentration of butyrate (A) and propionate (B), but not acetate (C) was altered by VSG, and this did not differ depending on genotype. D) The acetate:butyrate ratio is increased following VSG. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. Also see Extended Data Table1. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
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Figure 11: VSG alters the abundance of cecal SCFAsThe relative concentration of butyrate (A) and propionate (B), but not acetate (C) was altered by VSG, and this did not differ depending on genotype. D) The acetate:butyrate ratio is increased following VSG. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. Also see Extended Data Table1. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.

Mentions: Changes in gut microbiota may influence host metabolism in part due to the ability of the microbiota to attain colonic dietary conversion, resulting mostly in the production of fatty acid end products. Pertinent to this, a wide range of data now links the production of SCFA to various metabolic outcomes36,37,39,40. To this end, we measured cecal short-chain fatty acids (SCFAs) and other organic acids produced by the gut microbiota. There were no differences in the total abundance of SCFA among the 4 groups (Extended Data Table1). The relative abundances of butyrate and propionate (Extended Data Fig6A-B), but not acetate (Extended Data Fig6C) were altered by VSG and this did not differ depending on genotype (2-way ANOVA with Tukey posthoc, p< 0.05). The resulting decrease in the acetate:butyrate ratio (Extended Data Fig6D, 2-way ANOVA with Tukey posthoc, p< 0.001) possibly indicates that acetate is more efficiently converted to butyrate following VSG. Consistent with the increase in Lactobacillus and Lactococcus, we also observed an increase in lactate following VSG (Extended Data Table1). Again, although such changes may indeed contribute to the benefits of VSG and other bariatric procedures, the present data suggest they are not sufficient to elicit metabolic improvements.


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 alters the abundance of cecal SCFAsThe relative concentration of butyrate (A) and propionate (B), but not acetate (C) was altered by VSG, and this did not differ depending on genotype. D) The acetate:butyrate ratio is increased following VSG. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. Also see Extended Data Table1. 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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Show All Figures
getmorefigures.php?uid=PMC4016120&req=5

Figure 11: VSG alters the abundance of cecal SCFAsThe relative concentration of butyrate (A) and propionate (B), but not acetate (C) was altered by VSG, and this did not differ depending on genotype. D) The acetate:butyrate ratio is increased following VSG. Data are presented as Tukey boxplots. * = p< 0.05, ** = p< 0.01, *** = p< 0.001. Also see Extended Data Table1. n= 12 WT-sham, 7 WT-VSG, 9 KO-sham, 8 KO-VSG.
Mentions: Changes in gut microbiota may influence host metabolism in part due to the ability of the microbiota to attain colonic dietary conversion, resulting mostly in the production of fatty acid end products. Pertinent to this, a wide range of data now links the production of SCFA to various metabolic outcomes36,37,39,40. To this end, we measured cecal short-chain fatty acids (SCFAs) and other organic acids produced by the gut microbiota. There were no differences in the total abundance of SCFA among the 4 groups (Extended Data Table1). The relative abundances of butyrate and propionate (Extended Data Fig6A-B), but not acetate (Extended Data Fig6C) were altered by VSG and this did not differ depending on genotype (2-way ANOVA with Tukey posthoc, p< 0.05). The resulting decrease in the acetate:butyrate ratio (Extended Data Fig6D, 2-way ANOVA with Tukey posthoc, p< 0.001) possibly indicates that acetate is more efficiently converted to butyrate following VSG. Consistent with the increase in Lactobacillus and Lactococcus, we also observed an increase in lactate following VSG (Extended Data Table1). Again, although such changes may indeed contribute to the benefits of VSG and other bariatric procedures, the present data suggest they are not sufficient to elicit metabolic improvements.

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