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. 2023 Oct 6;9(40):eadk1887.
doi: 10.1126/sciadv.adk1887. Epub 2023 Oct 6.

The maternal microbiome promotes placental development in mice

Geoffrey N Pronovost  1 , Kristie B Yu  1 , Elena J L Coley-O'Rourke  1 , Sahil S Telang  1 , Angela S Chen  1 , Helen E Vuong  1 , Drake W Williams  2 , Anisha Chandra  1 , Tomiko K Rendon  1 , Jorge Paramo  1 , Reuben H Kim  2 , Elaine Y Hsiao  1   3
Affiliations

The maternal microbiome promotes placental development in mice

Geoffrey N Pronovost et al. Sci Adv. .

Abstract

The maternal microbiome is an important regulator of gestational health, but how it affects the placenta as the interface between mother and fetus remains unexplored. Here, we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate cultured endothelial cell tube formation and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.

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Figures

Fig. 1.
Fig. 1.. The maternal microbiome promotes placental development.
(A) E14.5 placental weights by litter average [SPF (n = 10), GF (n = 10), ABX (n = 10), and GF CONV (n = 10)]. (B) E14.5 placental weights for each individual from litters shown in Fig. 1A [SPF (n = 80), GF (n = 81), ABX (n = 65), and GF CONV (n = 77)]. (C) Representative cross sections of E14.5 whole-placental μCT reconstructions from SPF, GF, ABX, and GF CONV litters. White hashed line distinguishes fetal placental labyrinth compartment; scale bar, 1 mm; Houndsfield scale ranges from −105 (light green) to 9728 (maroon). (D) Quantification of E14.5 whole-placental volumes from μCT reconstructions by litter average [SPF (n = 6), GF (n = 6), ABX (n = 6), and GF CONV (n = 5)]. (E) Quantification of fetal placental labyrinth volumes from μCT reconstructions shown in (D). Data represent mean ± SEM; statistics were performed with one-way ANOVA with Tukey post hoc test (litter averages) or with one-way nested with Sidak multiple comparisons correction (individual conceptuses). **P < 0.01, ***P < 0.001, and ****P < 0.0001.
Fig. 2.
Fig. 2.. The maternal microbiome promotes placental vascular development.
(A) Representative images of laminin-stained E14.5 placental labyrinth from SPF, GF, ABX, and GFCONV litters (scale bar, 100 μm). (B) Quantification of raw integrated density of laminin staining intensity, normalized to fetal labyrinth total area [SPF (n = 6), GF (n = 9), ABX (n = 10), and GF CONV (n = 5)]. (C) Quantification of E14.5 feto-placental arterial vascular volume [SPF (n = 9), GF (n = 11), ABX (n = 5), and GF CONV (n = 5)]. (D) Quantification of E14.5 feto-placental arterial vascular surface area [SPF (n = 9), GF (n = 11), ABX (n = 5), and GF CONV (n = 5)]. (E) Representative feto-placental arterial vascular reconstructions by μCT imaging of vascular casts from E14.5 SPF, GF, ABX, and GF CONV litters; scale bar, 1 mm. Data represent mean ± SEM; statistics were performed with one-way ANOVA with Tukey post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.
Fig. 3.
Fig. 3.. Maternal SCFA supplementation prevents impairments in placental growth and microvasculature induced by maternal microbiome depletion.
(A) E14.5 placental weights by litter average [ABX Na (n = 9) and ABX SCFA (n = 10); hashed line represents SPF average from Fig. 1A]. (B) Cross sections of E14.5 whole-placental μCT reconstructions from ABX Na and ABX SCFA litters. (C) E14.5 whole-placental volumes from μCT reconstructions by litter average [ABX Na (n = 6) and ABX SCFA (n = 5); hashed line represents SPF average from Fig. 1D]. (D) Fetal placental labyrinth volumes from μCT reconstructions shown in (D); hashed line represents SPF average value from Fig. 1E. (E) Laminin-stained E14.5 placental labyrinth from ABX Na and ABX SCFA litters; scale bar, 100 μm. (F) Raw integrated density of laminin staining, normalized to fetal labyrinth total area [ABX Na (n = 6) and ABX SCFA (n = 5); hashed line represents SPF average from Fig. 2C]. (G) Representative feto-placental arterial vascular reconstructions from E14.5 ABX Na and ABX SCFA litters; scale bar, 1 mm. (H) E14.5 feto-placental arterial vascular volume [ABX Na (n = 4) and ABX SCFA (n = 4); hashed line represents SPF average from Fig. 2D]. (I) E14.5 feto-placental arterial vascular surface area from litters shown in (H); hashed line represents SPF average shown in Fig. 2E. (J) HUVEC tube formation assays (scale bar, 250 μm), depicting negative control (no supplementation), positive control (2% FBS supplementation), acetate supplementation (Ace, 40 μm), butyrate supplementation (But, 5 μm), and propionate supplementation (Pro, 5 μm). (K) HUVEC tube formation assays (n = 6 independent experiments). Data represent mean ± SEM; statistics were performed with Student’s t test or one-way ANOVA with Tukey post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.
Fig. 4.
Fig. 4.. Maternal SCFA supplementation promotes placental growth and vascularization in protein-restricted dams.
(A) E14.5 placental weights by litter average [CD Na (n = 9), CD SCFA (n = 10), PR Na (n = 8), and PR SCFA (n = 10); hashed line represents SPF litter average value shown in Fig. 1A]. (B) Representative cross sections of E14.5 whole-placental μCT reconstructions from CD Na, CD SCFA, PR Na, and PR SCFA litters. (C) Quantification of E14.5 whole-placental volumes from μCT reconstructions by litter average [CD Na (n = 6), CD SCFA (n = 5), PR Na (n = 6), and PR SCFA (n = 5); hashed line represents SPF litter average value shown in Fig. 1D]. (D) Quantification of fetal placental labyrinth volumes from μCT reconstructions shown in (C); hashed line represents SPF litter average value shown in Fig. 1E. (E) Representative feto-placental arterial vascular reconstructions by μCT imaging of vascular casts from CD Na, CD SCFA, PR Na, and PR SCFA litters; scale bar, 1 mm. (F) Quantification of E14.5 feto-placental arterial vascular volume [CD Na (n = 5), CD SCFA (n = 5), PR Na (n = 5), and PR SCFA (n = 5); hashed line represents SPF litter average value shown in Fig. 2D]. (G) Quantification of E14.5 feto-placental arterial surface area from litters shown in (F); hashed line represents SPF litter average value shown in Fig. 2D. Data represent mean ± SEM; statistics were performed with two-way ANOVA with Tukey post hoc test. *P < 0.05, **P < 0.01, and ***P < 0.001.
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