Composition of Maternal Circulating Short-Chain Fatty Acids in Gestational Diabetes Mellitus and Their Associations with Placental Metabolism

Abstract

Short-chain fatty acids (SCFAs), which are produced by gut microbiota from dietary fiber, have become candidates for gestational diabetes mellitus (GDM) treatment. However, the associations of circulating SCFAs with maternal-neonatal clinical parameters in GDM and further influences on placental immune-metabolic responses are unclear. Acetate, propionate, and butyrate were decreased in GDM during the second and third trimesters, especially in those with abnormal glucose tolerance at three "oral glucose tolerance test" time points. Butyrate was closely associated with acetate and propionate in correlation and dynamic trajectory analysis. Moreover, butyrate was negatively correlated with white blood cell counts, neutrophil counts, prepregnancy BMI, gestational weight gain per week before GDM diagnosis, and ponderal index but positively correlated with total cholesterol and low-density lipoprotein levels in all pregnancies. On the premise of reduced SCFA contents in GDM, the placental G-protein-coupled receptors 41 and 43 (GPR41/43) were decreased, and histone deacetylases (HDACs) were increased, accompanied by enhanced inflammatory responses. The metabolic status was disturbed, as evidenced by activated glycolysis in GDM. Maternal circulating acetate, propionate, and butyrate levels were associated with demographic factors in normal and GDM women. They influenced placental function and fetal development at birth through GPRs or HDACs, providing more evidence of their therapeutic capacity for GDM pregnancies.

Keywords: gestational diabetes mellitus (GDM); immune; metabolism; placental metabolome; short-chain fatty acid (SCFAs).

Figure 1

The levels of three dominant SCFAs and total SCFA were decreased among GDM pregnancies. (A–D) Circulating levels of acetic, propionic, butyric, and total acids in T2. (E–H) Circulating levels of acetic, propionic, butyric, and total acids in T3. (I–K) Circulating levels of acetic, propionic, and butyric acid among the control and GDM subtypes in T3. Data are presented as the mean ± SD. * p < 0.05, significant difference vs. control group.

Figure 2

Relationships between SCFAs. (A,B) Correlation analysis between SCFAs in all pregnancies in T2 and T3. (C–E) Dynamic trajectory analysis between butyric acid and acetic or propionic acid in all pregnancies.

Figure 3

Correlation analysis between acetic, propionic, and butyric acid contents and clinical indicators in T2. (A–D) Associations between acetic acid and WBC, NEU counts, TCHO, or HDL levels in either group. (E,F) Associations between propionic acid and insulin levels. (G) Comparisons of GDM diagnostic models including acetic, propionic, butyric acid, and other parameters. WBC, white blood cell; NEU, neutrophil; TCHO, total cholesterol; HDL, high-density lipoprotein.

Figure 4

Correlation analysis between acetic, propionic, and butyric acid contents and clinical indicators in T3. (A–C) Associations between acetic acid and WBC, NEU counts or LDL level in either group. (D,E) Associations between propionic acid and insulin level or p-BMI in either group. (F) Associations between butyric acid and GWG ratio in either group.

Figure 5

Butyric acid was a closely related clinical indicator in T3 among all pregnancies. (A–G) Associations between butyric acid and WBC counts, NEU counts, p-BMI, GWG ratio, PI, TCHO, and LDL levels. WBC, white blood cell; NEU, neutrophil; p-BMI, pre-pregnancy BMI; GWG, gestational weight gain; PI, Ponderal Index; TCHO, total cholesterol; LDL, low-density lipoprotein.

Figure 6

GPR41 and GPR43 were decreased, accompanied by enhanced proinflammatory responses in GDM pregnancies. (A,B) mRNA levels of GPR41/43 measured by real-time PCR. (C–N) mRNA levels of cytokines measured by real-time PCR. Data are presented as the mean ± SD. * p < 0.05, ** p < 0.01, significant difference vs. control group. GPR41, G-protein-coupled receptors 41; GPR43, G-protein-coupled receptors 43.

Figure 7

Placental glycolysis and the TCA cycle were compromised under hyperglycemic conditions. (A,B): Heatmaps of the detected intermediates in glycolysis and the TCA cycle, respectively. ATP, adenosine triphosphate; ADP, adenosine diphosphate; GTP, guanosine triphosphate; GDP, guanosine diphosphate; NAD, nicotinamide adenine dinucleotide. * p < 0.05.