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Open Access

The gut-liver axis mechanism of increased susceptibility to non-alcoholic fatty disease in female offspring rats with prenatal caffeine exposure

Qian Wang^{^a^,¹}, Xiaoqian Lu^{^a^,¹}, Wen Hu^{^a^,^b}, Cong Zhang^{^a}, Kexin Liu^{^a^,^b}, Kai Tong^{^b}, Kaiqi Chen^{^a}, Hui Wang^{^a^,^b}()

a

Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China

b

Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China

Peer review under responsibility of Tsinghua University Press.

¹ These authors contributed equally to this work.

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Abstract

Caffeine intake during pregnancy is common, while its effect on gut microbiota composition of offspring and the relationship with susceptibility to adult diseases remains unclear. This study aimed to confirm the effects of prenatal caffeine exposure (PCE) on the gut microbiota composition and its metabolites in female offspring rats, and to further elucidate its underlying mechanism and intervention targets in adult non-alcoholic fatty disease (NAFLD). The results showed that the gut microbiota of PCE female offspring at multiple time points from infancy to adolescence were significantly changed with depletion of butyric acid-producing bacteria, leading to a decrease in butyric acid in adulthood. It was also found that PCE female offspring rats were sensitive to NAFLD induced by a postnatal high-fat diet (HFD), which is mainly related to the enhancement of hepatic triglyceride synthesis function. Through mechanism exploration, we found that HFD further reduced the fecal and serum butyric acid levels in the PCE female offspring, which was significantly negatively correlated with hepatic SREBP-1c/FASN mRNA expression and triglyceride level. In vivo and in vitro experiments confirmed that sodium butyrate (NaB) supplementation could reduce hepatic lipid accumulation through MCT1/GPR109A-AMPK, thereby effectively decreasing the susceptibility to NAFLD in the PCE female offspring rats.

Keywords

Pregnancy Caffeine Gut microbiota Butyric acid Non-alcoholic fatty liver disease

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Food Science and Human Wellness

Volume 13 Issue 6,
November 2024

Pages 3522-3535

DOI: 10.26599/FSHW.2023.9250035

Cite this article:

Wang Q, Lu X, Hu W, et al. The gut-liver axis mechanism of increased susceptibility to non-alcoholic fatty disease in female offspring rats with prenatal caffeine exposure. Food Science and Human Wellness, 2024, 13(6): 3522-3535. https://doi.org/10.26599/FSHW.2023.9250035

Fig. 1 Effects of PCE on gut microbiota composition in female offspring rats at PW3, PW6, PW8, and PW12. (A-C) Boxplot of the OTU number, Shannon index and Simpson index; (D-G) PCoA plot based on the Bray-Curtis distance of gut microbiota; (H-J) The relative abundance of F. prausnitzii, A. hadrus and B. longum in feces. ^*P < 0.05, ^**P < 0.01 vs. CON.
Fig. 2 Alterations in gut microbiota and fecal SCFAs of PCE female adult offspring rats. (A) The top 10 bacterial compositions at the phylum level; (B) LEfSe evolutionary branching diagram; (C) Histogram of LDA value distribution, differently enriched microbial groups with LDA > 2.0 were selected by LDA effect size analysis; (D) Changes of fecal SCFAs (acetic acid, propionic acid, butyric acid, isobutyric acid, pentanoic acid, isovaleric acid, caproic acid); (E) Correlation between the different metabolites and bacterial genera in a comparison described in Sangji diagram. Red is a positive correlation, and purple is a negative correlation; n=10 for 16S sequencing; n=6 for SCFA sequencing. ^*P < 0.05, ^**P < 0.01 vs. CON.
Fig. 3 Changes of liver histopathology, TG level, and related metabolic genes expression in PCE female adult offspring rats under the ND or HFD. (A, B) Liver H&E (400×) and ORO staining (400×); (C, D) Liver Kleiner score and TG content; (E-M) The mRNA expression of SREBP-1c, FASN, ACCα, ACLY, ATGL, CPT1α, PPARα, HSL, MTTP by RT-qPCR. Mean ± S.E.M., n=3 for H&E and ORO staining, n=10 for RT-qPCR. ^*P < 0.05, ^**P < 0.01 vs. CON+ND; ^#P < 0.05, ^##P < 0.01 vs. CON+HFD.
Fig. 4 Alterations in gut microbiota and fecal SCFAs of PCE female adult offspring rats under the HFD. (A) Boxplot of the OTU number of gut microbiota; (B-C) Boxplot of α-diversity (Shannon index and Simpson index); (D) β-Diversity (Bray-Curtis similarity index) analyses; (E) Histogram of LDA value distribution, differently enriched microbial groups with LDA > 2.0 were selected by LDA effect size (LEfSe) analysis. (F-G) The relative abundance of Anaerostipes and Lactobacillus under the ND and HFD; (H) Serum butyric acid level; (I) The correlation analysis between serum butyric acid and hepatic TG; (J-M) The correlation analysis between serum butyric acid and the mRNA expression of TG-related functional genes (FASN, SREBP-1c, ACLY and ACCα); (N, O) The mRNA expression of hepatic MCT1 and GPR109A; (P, Q) The protein expression of liver AMPK and p-AMPK by Western blot and relative expression analyzed by Image J. Mean ± S.E.M., n=6 for SCFA profiling, n=3 for Western blot, n=10 for RT-qPCR. ^*P < 0.05, ^**P < 0.01 vs. CON+ND; ^#P < 0.05, ^##P < 0.01 vs. CON+HFD.
Fig. 5 Effects of NaB on lipid metabolism of HepG2 treated by PA. (A) Effect of different concentrations of PA (0.01, 0.05, 0.1, 0.5, 1 mmol/L) with different exposure time (24, 48, 72 h) on the survival rate of HepG2 cells. (B) ORO staining on HepG2 cells after treatment with 0.1 mmol/L PA and 5 mmol/L NaB. (C) TG level of HepG2 cells. (D-M) Alterations in hepatocyte lipid synthesis genes (SREBP-1c, FASN, ACCα, ACLY, ATGL, CPT1α, PPARα, HSL, MCT1, GPR109A) of HepG2 cells after treatment with 0.1 mmol/L PA and 5 mmol/L NaB. Mean ± S.E.M., n=3 for ORO staining, n=10 for RT-qPCR.^*P < 0.05, ^**P < 0.01 vs. CON; ^#P < 0.05, ^##P < 0.01 vs. PA.
Fig. 6 Changes of liver histopathology, TG level, and lipid metabolism-related gene expression in PCE female adult offspring rats under HFD after supplementation with NaB. (A-B) Liver H&E and ORO staining; (C-D) Liver Kleiner score and TG content; (E-M) The mRNA expression of SREBP-1c, FASN, ACCα, ACLY, ATGL, CPT1α, PPARα, HSL, MTTP; (N-O) The mRNA expression of MCT1 and GPR109A; (P-Q) The protein expression of liver AMPK and p-AMPK and relative expression analyzed by Image J. Mean ± S.E.M., n=3 for H&E, ORO staining and Western blot, n=10 for RT-qPCR. ^*P < 0.05, ^**P < 0.01 vs. CON+HFD; ^#P < 0.05, ^##P < 0.01 vs. PCE+HFD.

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