Diet-induced changes in maternal gut microbiota and metabolomic profiles influence programming of offspring obesity risk in rats - PubMed (original) (raw)
Diet-induced changes in maternal gut microbiota and metabolomic profiles influence programming of offspring obesity risk in rats
Heather A Paul et al. Sci Rep. 2016.
Abstract
Maternal obesity and overnutrition during pregnancy and lactation can program an increased risk of obesity in offspring. In this context, improving maternal metabolism may help reduce the intergenerational transmission of obesity. Here we show that, in Sprague-Dawley rats, selectively altering obese maternal gut microbial composition with prebiotic treatment reduces maternal energy intake, decreases gestational weight gain, and prevents increased adiposity in dams and their offspring. Maternal serum metabolomics analysis, along with satiety hormone and gut microbiota analysis, identified maternal metabolic signatures that could be implicated in programming offspring obesity risk and highlighted the potential influence of maternal gut microbiota on maternal and offspring metabolism. In particular, the metabolomic signature of insulin resistance in obese rats normalized when dams consumed the prebiotic. In summary, prebiotic intake during pregnancy and lactation improves maternal metabolism in diet-induced obese rats in a manner that attenuates the detrimental nutritional programming of offspring associated with maternal obesity. Overall, these findings contribute to our understanding of the maternal mechanisms influencing the developmental programming of offspring obesity and provide compelling pre-clinical evidence for a potential strategy to improve maternal and offspring metabolic outcomes in human pregnancy.
Conflict of interest statement
HA Paul, MR Bomhof and HJ Vogel declare no conflicts of interest. RA Reimer previously held a research grant from Beneo-Orafti Inc., manufacturer of Raftilose P95 and Raftiline HP, for a project unrelated to the current work.
Figures
Figure 1. Effect of oligofructose supplementation on maternal body weight, energy intake, body composition, glycemia and insulinemia.
During gestation and lactation, diet-induced obese dams were fed either a high-fat/sucrose diet (HFS obese control group), the high-fat/sucrose diet supplemented with 10% wt/wt oligofructose (OFS group), or a restricted amount of the high-fat/sucrose diet in order to match body weight to the OFS dams (WM). A lean reference group was maintained on control AIN-93 G diet through pregnancy and lactation for body weight and body composition measurements but was not included in statistical analysis. Maternal glycemia and insulinemia was determined from blood collected during oral glucose tolerance tests (OGTTs) performed on gestation day 14 and lactation day 19. Dams were fasted overnight (12 h) and an OGTT was performed after gavage with glucose (2 g/kg body weight). Blood samples were collected at 0, 15, 30, 60, 90 and 120 minutes during the OGTT. (a) Maternal body weight during gestation and lactation (HFS, n = 11; OFS, n = 12; WM, n = 9). (b) Maternal energy intake during gestation and lactation (HFS, n = 7; OFS, n = 12; WM, n = 9; Independent-Samples Kruskall-Wallis Test with adjusted significance where *P < 0.05 compared to all other groups). (c) Maternal fat mass and percent body fat at weaning (HFS, n = 10; OFS, n = 9; WM, n = 8). (d,e) Maternal glycemia and insulinemia (HFS, n = 7; OFS, n = 12; WM, n = 9). (f) Area under the curve (AUC) for glucose and insulin concentrations during the OGTTs (HFS, n = 7; OFS, n = 12; WM, n = 9; Student’s t-test). Graphs represent mean +/− SEM. Mean values without a common letter are significantly different using one-way ANOVA (P < 0.05). For body weight, glycemia, and insulinemia measurements, the data were analyzed using repeated measures one-way ANOVA, where the between subjects factor was maternal diet and the within-subjects factor was time. If a statistically significant interaction was observed, a one-way ANOVA between groups was performed.
Figure 2. Effect of maternal oligofructose supplementation on offspring body weight and body composition.
Pregnant and lactating diet-induced obese dams were fed either a high-fat/sucrose diet (HFS obese control group), the high-fat/sucrose diet supplemented with 10% wt/wt oligofructose (OFS group), or a restricted amount of the high-fat/sucrose diet in order to match body weight to the OFS dams (WM). Offspring body weight was measured weekly and body composition analyzed at weaning using DXA scan. Offspring body weight was calculated using litter averages as individual values. (a) Offspring body weight throughout lactation (HFS, n = 12; OFS, n = 12; WM, n = 9). (b) Offspring fat mass and percent body fat (HFS offspring, n = 31, 15 males and 16 females; OFS offspring, n = 29, 13 males and 16 females; WM offspring, n = 30, 13 males and 16 females). Values are mean ± SEM. Mean values without a common letter are significantly different using one-Way ANOVA (P < 0.05).
Figure 3. Relative microbial abundance of fecal microbiota changes throughout pregnancy and lactation and is affected by diet.
Abundance of fecal microbiota from pregnant and lactating dams fed either a high-fat/sucrose diet (HFS obese control group), the high-fat/sucrose diet supplemented with 10% wt/wt oligofructose (OFS group), or a restricted amount of the high-fat/sucrose diet in order to match body weight to the OFS dams (WM) was determined using real-time qPCR. Microbial abundance was measured as 16 S rRNA gene copies per 20 ng DNA, and reported here as the relative abundance (%) of bacterial taxa per total bacteria. Longitudinal analysis of maternal fecal relative abundance on gestation days 1, 14, and 21 (G1, G14, G21), and lactation days 1 and 19 (L1, L19) was performed using repeated measures one-way ANOVA, where the between subjects factor was maternal diet and the within-subjects factor was timepoint (gestation days 1, 14 and 21 and lactation days 1 and 19). Values are mean ± SEM. Mean values without a common letter are significantly different using one-way ANOVA (P < 0.05) and indicate there was a significant interaction between time and maternal diet (P < 0.05). HFS, n = 11 except for A. muciniphila and C. coccoides where n = 10; OFS, n = 12; WM, n = 9.
Figure 4. Oligofructose feeding increases circulating levels of peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2).
Blood samples for PYY and GLP-1 area under the curve were collected during the glucose tolerance tests performed pre-pregnancy, on gestation day 14, and lactation day 19 from diet-induced obese dams fed either a high-fat/sucrose diet (HFS obese control group), the high-fat/sucrose diet supplemented with 10% wt/wt oligofructose (OFS group), or a restricted amount of the high-fat/sucrose diet in order to match body weight to the OFS dams (WM) during pregnancy and lactation. Portal blood samples for GLP-1 and GLP-2 measurement were collected at euthanasia of the dams. (a,b) Relative increase of PYY and GLP-1 area under the curve (AUC) on gestation day 14 and lactation day 19 compared to pre-pregnancy AUC (PYY: HFS, n = 11; OFS, n = 12; WM, n = 9; GLP-1: HFS, n = 11; OFS, n = 10; WM, n = 9). (c,d) Portal plasma GLP-1 and GLP-2 concentration (GLP-1: HFS, n = 10; OFS, n = 9; WM, n = 7, GLP-2: HFS, n = 10; OFS, n = 9; WM, n = 8). Means without a common letter are significantly different using one-way ANOVA (P < 0.05). For relative AUC measurements, the data were analyzed using repeated measures one-way ANOVA, where the between subjects factor was maternal diet and the within-subjects factor was timepoint (pre-pregnancy, gestation and lactation). If a statistically significant interaction was observed, one-way ANOVAs between groups was performed. *P < 0.05 Independent-Samples Kruskall-Wallis Test with adjusted significance.
Figure 5. Metabolomic analysis of maternal serum collected during pregnancy.
Comparison of maternal serum metabolites from dams fed a high-fat/sucrose diet (HFS obese control group), the high-fat/sucrose diet supplemented with 10% oligofructose (OFS group), or a restricted amount of the high-fat/sucrose diet to weight-match to the OFS group (WM) during gestation and lactation. (a–c) Pairwise OPLS-DA loadings plots comparing maternal serum metabolites from samples collected on gestation day 14. Metabolites included in the OPLS-DA modeling were selected following preliminary pairwise univariate analysis of the 57 metabolites identified and quantified by 1H NMR spectroscopy. Bold metabolites represent the variables that contributed most to the discrimination of dietary groups, which were identified using a combination of VIP > 1 and p(corr) > 0.4, with those contributing most to the separation located furthest from the center. The directions of the arrows indicate the maternal group corresponding to increased levels of those metabolites. HFS, n = 7; OFS, n = 12; WM n = 9.
Figure 6. Metabolomic analysis of maternal serum collected during lactation.
Comparison of maternal serum metabolites from dams fed a high-fat/sucrose diet (HFS obese control group), the high-fat/sucrose diet supplemented with 10% oligofructose (OFS group), or a restricted amount of the high-fat/sucrose diet to weight-match to the OFS group (WM) during gestation and lactation. (a–c) Pairwise OPLS-DA loadings plots comparing maternal serum metabolites from samples collected on lactation day 19. Metabolites included in the OPLS-DA modeling were selected following preliminary pairwise univariate analysis of the 57 metabolites identified and quantified by 1H NMR spectroscopy. Bold metabolites represent the variables that contributed most to the discrimination of dietary groups, which were identified using a combination of VIP > 1 and p(corr) > 0.4, with those contributing most to the separation located furthest from the center. The directions of the arrows indicate the maternal group corresponding to increased levels of those metabolites. HFS, n = 10; OFS, n = 9; WM, n = 8.
References
- Malik V. S., Willett W. C. & Hu F. B. Global obesity: trends, risk factors and policy implications. Nat. Rev. Endocrinol. 9, 13–27 (2013). -PubMed
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