Maternal Dietary Betaine Prevents High-Fat Diet-Induced Metabolic Disorders and Gut Microbiota Alterations in Mouse Dams and Offspring From Young to Adult

Jieying Liu, Lu Ding, Xiao Zhai, Dongmei Wang, Cheng Xiao, Xiangyi Hui, Tianshu Sun, Miao Yu, Qian Zhang, Ming Li, Xinhua Xiao, Jieying Liu, Lu Ding, Xiao Zhai, Dongmei Wang, Cheng Xiao, Xiangyi Hui, Tianshu Sun, Miao Yu, Qian Zhang, Ming Li, Xinhua Xiao

Abstract

Early life is a critical window for preventing the intergenerational transmission of metabolic diseases. Betaine has been proven to play a role in improving glucose and lipid metabolism disorders in animal models. However, whether maternal betaine supplementation plays a role in regulating gut microbiota in both dams and offspring remains unclear. In this study, C57BL/6 female mice were fed with control diet (Ctr), high-fat diet (HF), and high-fat with betaine supplementation (0.3% betaine in the diet, HFB) from 3 weeks prior to mating and lasted throughout pregnancy and lactation. After weaning, the offspring got free access to normal chow diet until 20 weeks of age. We found that maternal dietary betaine supplementation significantly improved glucose and insulin resistance, as well as reduced free fatty acid (FFA) concentration in dams and offspring from young to adult. When compared to the HF group, Intestinimonas and Acetatifactor were reduced by betaine supplementation in dams; Desulfovibrio was reduced in 4-week-old offspring of the HFB group; and Lachnoclostridium was enriched in 20-week-old offspring of the HFB group. Moreover, the persistent elevated genus Romboutsia in both dams and offspring in the HFB group was reported for the first time. Overall, maternal betaine could dramatically alleviate the detrimental effects of maternal overnutrition on metabolism in both dams and offspring. The persistent alterations in gut microbiota might play critical roles in uncovering the intergenerational metabolic benefits of maternal betaine, which highlights evidence for combating generational metabolic diseases.

Keywords: betaine; dams and offspring; glucose and lipid metabolism; gut microbiota; high-fat diet; intergeneration.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Liu, Ding, Zhai, Wang, Xiao, Hui, Sun, Yu, Zhang, Li and Xiao.

Figures

FIGURE 1
FIGURE 1
Betaine improves glucose and lipid metabolism in high-fat diet dams. Dams were analyzed after weaning. (A) General picture of body composition; (B) body weight (left) and body composition (right) changes during the betaine treatment; (C) oral glucose tolerance test (left) and the area under the curve (right); (D) fasting plasma glucose; (E) fasting insulin level; (F) HOMA-IR; (G) FFAs. Ctr, standard control diet; HF, high-fat diet; HFB, high-fat diet with betaine; HOMA-IR, homeostasis model assessment of insulin resistance; FFAs, free fatty acids. Data are expressed as means ± S.E.M. (n = 4–6/group). One-way and two-way ANOVA; *p < 0.05 and **p < 0.01 vs. Ctr, #p < 0.05 and ##p < 0.01 vs. HF.
FIGURE 2
FIGURE 2
Betaine alters the gut microbiota in high-fat diet dams. The cecal contents were collected from dams after weaning. (A) Shannon index (left) and Simpson index (right); (B) PCoA plots of gut microbiome; (C) relative abundance of the top 10 species at the genus level; (D) relative abundance of Intestinimonas; (E) relative abundance of Acetatifactor; (F) relative abundance of Romboutsia; (G) distinct taxa identified in the three groups using LEfSe analysis. The colors represent the group in which the indicated taxa is more abundant compared to the other group. Ctr, standard control diet; HF, high-fat diet; HFB, high-fat diet with betaine. Data are expressed as means ± S.E.M. (n = 4–6/group). One-way ANOVA; **p < 0.01 vs. Ctr, ##p < 0.01 vs. HF.
FIGURE 3
FIGURE 3
Maternal betaine ameliorates glucose and lipid metabolism induced by early-life high-fat diet in 4-week-old offspring. Offspring mice were analyzed at 4 weeks of age. (A) General picture of body composition; (B) body weight (left) and body composition (right) changes; (C) oral glucose tolerance test (left) and the area under the curve (right); (D) insulin tolerance test (left) and the area under the curve (right); (E) fasting plasma glucose; (F) fasting insulin level; (G) HOMA-IR; (H) FFAs. Ctr.4, 4-week-old offspring of dams fed with the standard control diet; HF.4, 4-week-old offspring of dams fed with the high-fat diet; HFB.4, 4-week-old offspring of dams fed with the high-fat diet with betaine. HOMA-IR, homeostasis model assessment of insulin resistance; FFAs, free fatty acids. Data are expressed as means ± S.E.M. (n = 4–6/group). One-way and two-way ANOVA; *p < 0.05 and **p < 0.01 vs. Ctr, #p < 0.05 and ##p < 0.01 vs. HF.
FIGURE 4
FIGURE 4
Maternal betaine alters the gut microbiota in early-life high-fat diet offspring at 4 weeks of age. The cecal contents were collected from offspring at 4 weeks of age. (A) Shannon index (left) and Simpson index (right); (B) PCoA plots of gut microbiome; (C) relative abundance of the top 10 species at the genus level; (D) relative abundance of Desulfovibrio; (E) relative abundance of Romboutsia; (F) distinct taxa identified in the three groups using LEfSe analysis. The colors represent the group in which the indicated taxa is more abundant compared to the other group. Ctr.4, 4-week-old offspring of dams fed with the standard control diet; HF.4, 4-week-old offspring of dams fed with the high-fat diet; HFB.4, 4-week-old offspring of dams fed with the high-fat diet with betaine. Data are expressed as means ± S.E.M. (n = 6–8/group). One-way ANOVA; *p < 0.05 vs. Ctr, #p < 0.05 vs. HF.
FIGURE 5
FIGURE 5
Maternal betaine protects 20-week-old offspring from glucose and lipid metabolic disorders induced by early-life high-fat diet. Offspring mice were analyzed at 20 weeks of age. (A) General picture of body composition; (B) body weight (left) and body composition (right) changes; (C) oral glucose tolerance test (left) and the area under the curve (right); (D) insulin tolerance test (left) and the area under the curve (right); (E) fasting plasma glucose; (F) fasting insulin level; (G) HOMA-IR; (H) FFAs. Ctr.20, 20-week-old offspring of dams fed with the standard control diet; HF.20, 20-week-old offspring of dams fed with the high-fat diet; HFB.20, 20-week-old offspring of dams fed with the high-fat diet with betaine. HOMA-IR, homeostasis model assessment of insulin resistance; FFAs, free fatty acids. Data are expressed as means ± S.E.M. (n = 5–8/group). One-way and two-way ANOVA; **p < 0.01 vs. Ctr, #p < 0.05 vs. HF.
FIGURE 6
FIGURE 6
Maternal betaine alters the gut microbiota in early-life high-fat diet offspring at 20 weeks of age. The cecal contents were collected from offspring at 20 weeks of age. (A) Shannon index (left) and Simpson index (right); (B) PCoA plots of gut microbiome; (C) relative abundance of the top 10 species at the genus level; (D) relative abundance of Desulfovibrio; (E) relative abundance of Romboutsia; (F) distinct taxa identified in the three groups using LEfSe analysis. The colors represent the group in which the indicated taxa is more abundant compared to the other group. Ctr.20, 20-week-old offspring of dams fed with the standard control diet; HF.20, 20-week-old offspring of dams fed with the high-fat diet; HFB.20, 20-week-old offspring of dams fed with the high-fat diet with betaine. Data are expressed as means ± S.E.M. (n = 5–6/group). One-way ANOVA; **p < 0.01 vs. Ctr, #p < 0.05 vs. HF.
FIGURE 7
FIGURE 7
Heatmap of the correlation analysis between the altered genera and glucose and lipid metabolic parameters in dams and offspring. Correlation results in dams after weaning and in offspring at 4 and 20 weeks of age are shown. HOMA-IR, the homeostasis model assessment of insulin resistance; GLU, glucose; AST, aspartate aminotransferase; ALT, alanine transaminase; FFA, free fatty acid; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride. Values show a significant correlation between the genera and metabolic parameters: *p < 0.05 and **p < 0.01.

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