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Altered gut bacterial and metabolic signatures and their interaction in gestational diabetes mellitus.

ABSTRACT: Emerging evidence indicates that the gut microbiome can modulate metabolic homeostasis, and thus may influence the development of gestational diabetes mellitus (GDM). However, whether and how the gut microbiome and its correlated metabolites change in GDM is uncertain. Herein we compare the gut microbial compositions, and fecal and urine metabolomes, of 59 patients with GDM versus 48 pregnant healthy controls (HCs). We showed that the microbial and metabolic signatures of GDM patients were significantly different from those of HCs. Compared to HCs, the GDM subjects were characterized by enriched bacterial operational taxonomic units (OTUs) of the family Lachnospiraceae, and depleted OTUs of the families Enterobacteriaceae and Ruminococcaceae. Some altered gut microbes were significantly correlated with glucose values and fetal ultrasonography indexes. Moreover, we identified four fecal and 15 urine metabolites that discriminate GDM from HC. These differential metabolites are mainly involved in carbohydrate and amino acid metabolism. Significantly, co-occurrence network analysis revealed that Lachnospiraceae and Enterobacteriaceae bacterial OTUs formed strong co-occurring relationships with metabolites involved in carbohydrate and amino acid metabolism, suggesting that disturbed gut microbiome may mediate GDM. Furthermore, we identified a novel combinatorial marker panel that could distinguish GDM from HC subjects with high accuracy. Together our findings demonstrate that altered microbial composition and metabolic function may be relevant to the pathogenesis and pathophysiology of GDM.

SUBMITTER: Wang X

PROVIDER: S-EPMC7714515 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The roles of gut microbiota and metabolomics in women with gestational diabetes mellitus (GDM) are not well understood. This study investigated the gut metabolomic profiling of GDM rats and GDM rats treated with probiotic supplements. Associations between gut metabolites and microbiota were also studied in GDM rats. Liquid chromatography-mass spectrometry was used to detect gut metabolites in GDM rats and GDM rats treated with probiotic supplements of 0.5 g (low-dose group) or 1 g (high-dose group) for 15 days. Each gram of probiotic supplement contained 5 × 107 colony-forming units (CFU) of Lactobacillus rhamnosus LGG and 1 × 108 CFU of Bifidobacterium animalis subspecies lactis Bb12. The association between gut metabolites and microbiota in GDM rats was investigated using Spearman's correlation. Finally, 10 rats in the normal pregnant group, eight rats in the GDM model group, eight GDM rats in the low-dose probiotics group, and nine GDM rats in the high-dose probiotics group were further studied. Serum parameters and pancreatic and colon histology were significantly changed in GDM rats, and these were restored using probiotic supplements. In total, 999 gut metabolites were detected in the feces, and GDM rats were distinguished from normal rats. The levels of 44 metabolites were increased in GDM rats, and they were alleviated using probiotic supplements. Changes in metabolites in GDM rats were associated with amino acids and bile acids metabolism signaling pathways. Furthermore, changes in metabolites after probiotic supplementation were associated with porphyrin and chlorophyll metabolism pathways. We found that the Allobaculum genus displayed strong positive correlations, whereas the Bryobacter and Gemmatimonas genera displayed strong negative correlations with metabolisms of amino acids and bile acids in GDM rats. The Lactobacillus and Bifidobacterium genera were positively correlated with gut metabolites. Overall, our results showed that metabolism signaling pathways of amino acids and bile acids are associated with the development of GDM. Probiotic supplements alleviate the pathology of GDM through the metabolism pathways of amino acids, bile acids, porphyrin, and chlorophyll.

Project description:Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-α levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-α antagonist, we observed that the pro-NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia.

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Altered gut bacterial and metabolic signatures and their interaction in gestational diabetes mellitus.

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