Gut Microbiota and Critical Metabolites: Potential Target in Preventing Gestational Diabetes Mellitus?

Abstract

Gestational diabetes mellitus (GDM) is an intractable issue that negatively impacts the quality of pregnancy. The incidence of GDM is on the rise, becoming a major health burden for both mothers and children. However, the specific etiology and pathophysiology of GDM remain unknown. Recently, the importance of gut microbiota and related metabolic molecules has gained prominence. Studies have indicated that women with GDM have significantly distinct gut microbiota and gut metabolites than healthy pregnant women. Given that the metabolic pathways of gut flora and related metabolites have a substantial impact on inflammation, insulin signaling, glucose, and lipid metabolism, and so on, gut microbiota or its metabolites, such as short-chain fatty acids, may play a significant role in both pathogenesis and progression of GDM. Whereas the role of intestinal flora during pregnancy is still in its infancy, this review aims to summarize the effects and mechanisms of gut microbiota and related metabolic molecules involved in GDM, thus providing potential intervention targets.

Keywords: gestational diabetes mellitus; gut microbiota; gut microecology; interaction; short-chain fatty acids.

Figure 1

Roles of gut microbiota dysbiosis in GDM. Figure legend: Akt^Ser473: Protein kinase B^Serine473; IKK: Inhibitory B kinase; IRS1: Insulin receptor substrate-1; JNK: C-Jun N-terminal kinase; LPS: Lipopolysaccharide; NF-κB: Nuclear factor kappa-B; PI3-K: Phosphatidylinositol 3-kinase; TLR: Toll-like receptor. The gut barrier consists of mucus, intercellular tight junctions, immunoglobulins, antimicrobial peptides secreted by Paneth cells, microbes, and other components. Raises in Gram-negative pathobionts are linked to LPS biosynthesis. Elevated LPS and pathobionts can adhere to the mucosal layer, cross the epithelial layer of the gut via TLR2/4 activation, and translocate via phagocytosis and DC co-localization, ultimately entering systemic circulation and causing metabolic endotoxemia. Further, gut microbiota dysbiosis may result in thinning of the mucosal layer and disruption of the intercellular tight junctions in GDM patients. The compromised intestinal barrier can facilitate the migration of LPS and pathobionts. LPS and pathobionts bind to and activate TLR. TLR activation triggers macrophage infiltration and inflammation pathways, such as JNK, IKK, and NF-κB, which might evoke serine phosphorylation of IRS-1+Ser307, resulting in suppression of PI3-K and AktSer473. This procedure will impair insulin signaling and reduce glucose uptake in peripheral tissues, resulting in hyperglycemia in GDM women. The figure was created with BioRender.com. URL: https://biorender.com (accessed on 24 June 2023).

Figure 2

Roles of SCFAs in GDM. Figure legend: Inadequate SCFAs may be associated with increased permeability of gut epithelium. Inadequate SCFAs also reduce adipose tissue lipid storage capacity, inhibit fatty acid oxidation, and increase lipolysis, which then raises serum FFA levels and increases lipid storage in the liver and muscle. Simultaneously, insufficient SCFAs may be unable to maintain the balance of anti-inflammatory and proinflammatory cells, leading to low-grade inflammation. Elevated serum FFA levels, increased lipid storage in the liver and muscle, and low-grade inflammation may all contribute to insulin resistance and hyperglycemia in women with GDM. On the other hand, excessive SCFA production may lead to extra energy harvesting capacity and FFA overflow, increasing lipid storage in the liver and skeletal muscle and leading to obesity. Excessive SCFAs may upregulate gluconeogenesis pathways and suppress glycolysis pathways and insulin signaling in peripheral tissues, resulting in hyperglycemia and insulin resistance. The figure was created with BioRender.com. URL: https://biorender.com (accessed on 24 June 2023).

Figure 3

Treatment for GDM. Figure legend: CHO: Carbohydrates. Dietary restrictions, exercise, probiotics (prebiotics), and insulin may help alleviate symptoms of GDM. The figure was created with BioRender.com. URL: https://biorender.com (accessed on 24 June 2023).