Alterations in the Gut Microbiota in Pregnant Women with Pregestational Type 2 Diabetes Mellitus

Abstract

Human gut dysbiosis is associated with type 2 diabetes mellitus (T2DM); however, the gut microbiome in pregnant women with pregestational type 2 diabetes mellitus (PGDM) remains unexplored. We investigated the alterations in the gut microbiota composition in pregnant women with or without PGDM. The gut microbiota was examined using 16S rRNA sequencing data of 234 maternal fecal samples that were collected during the first (T1), second (T2), and third (T3) trimesters. The PGDM group presented a reduction in the number of gut bacteria taxonomies as the pregnancies progressed. Linear discriminant analyses revealed that Megamonas, Bacteroides, and Roseburia intestinalis were enriched in the PGDM group, whereas Bacteroides vulgatus, Faecalibacterium prausnitzii, Eubacterium rectale, Bacteroides uniformis, Eubacterium eligens, Subdoligranulum, Bacteroides fragilis, Dialister, Lachnospiraceae, Christensenellaceae R-7, Roseburia inulinivorans, Streptococcus oralis, Prevotella melaninogenica, Neisseria perflava, Bacteroides ovatus, Bacteroides caccae, Veillonella dispar, and Haemophilus parainfluenzae were overrepresented in the control group. Correlation analyses showed that the PGDM-enriched taxa were correlated with higher blood glucose levels during pregnancy, whereas the taxonomic biomarkers of normoglycemic pregnancies exhibited negative correlations with glycemic traits. The microbial networks in the PGDM group comprised weaker microbial interactions than those in the control group. Our study reveals the distinct characteristics of the gut microbiota composition based on gestational ages between normoglycemic and PGDM pregnancies. Further longitudinal research involving women with T2DM at preconception stages and investigations using shotgun metagenomic sequencing should be performed to elucidate the relationships between specific bacterial functions and PGDM metabolic statuses during pregnancy and to identify potential therapeutic targets. IMPORTANCE The incidence of pregestational type 2 diabetes mellitus (PGDM) is increasing, with high rates of serious adverse maternal and neonatal outcomes that are strongly correlated with hyperglycemia. Recent studies have shown that type 2 diabetes mellitus is associated with gut microbial dysbiosis; however, the gut microbiome composition and its associations with the metabolic features of patients with PGDM remain largely unknown. In this study, we investigated the changes in the gut microbiota composition in pregnant women with and without PGDM. We identified differential taxa that may be correlated with maternal metabolic statuses during pregnancy. Additionally, we observed that the number of taxonomic and microbial networks of gut bacteria were distinctly reduced in women with hyperglycemia as their pregnancies progressed. These results extend our understanding of the associations between the gut microbial composition, PGDM-related metabolic changes, and pregnancy outcomes.

Keywords: bacterial metabolic pathway; gut microbiota; pregestational diabetes mellitus; pregnancy; taxonomic biomarker.

FIG 1

Participants and sample statistics. PGDM, pregestational diabetes mellitus; 75-g OGTT, 75-g oral glucose tolerance test; ACOG, American College of Obstetricians and Gynecologists.

FIG 2

Gut microbiota composition in pregnant women with or without PGDM. (A) Comparison of alpha diversity indices (Chao1, Shannon, and Simpson) within and between the PGDM (red) and control (blue) groups from T1 to T3. (B) Bacterial community dissimilarities within and between the PGDM (red) and control (blue) groups from T1 to T3. (C) PCoA of the Bray-Curtis dissimilarities of the two groups from T1 to T3; ellipses represent 95% confidence intervals (CIs). (D) Heat map of the top 10 OTUs in both groups in different trimesters. (E) Comparison of the relative abundances of the top 10 OTUs within and between the PGDM (red) and control (blue) groups from T1 to T3. (F) Linear discriminant analysis score of the taxonomic biomarkers for the women with PGDM and healthy controls. The colors of the bars indicate the log₂ fold changes in the relative abundances for the taxonomic biomarkers between the women with and without PGDM. The color of the y axis label indicates the phylum of each OTU. (G) Comparison of the relative abundances of the taxonomic biomarkers within and between the PGDM (red) and control (blue) groups from T1 to T3. The dotted line of the graph with each box plot represents the average. F, Friedman test. Significances based on P and Q values are separated by a slash. ns, not significant (P or Q > 0.1); *, P or Q < 0.05; **, P or Q < 0.01; ***, P or Q < 0.001.

FIG 3

Spearman’s rank correlation heat map of specific OTUs and clinical indices regardless of PGDM status in the first (A), second (B), and third (C) trimesters. Features that have at least one significant sign are shown. The colors of the cells represent the r value of the correlation coefficient. *, P < 0.05.

FIG 4

Gut microbial networks in pregnant women with or without PGDM in different trimesters. (A to C) Control group from T1 to T3. (D to E) PGDM group from T1 to T3. Nodes represent OTUs; the sizes indicate the eigenvector centrality, and the colors indicate the phylum of each OTU. Edges represent microbial correlations; gray and blue indicate positive and negative correlations, respectively. Edge thickness indicates correlation strength, and only the high-confidence interactions (Q < 0.05) with high absolute correlation coefficients (>0.3) are presented.