Gut Microbiota and Gestational Diabetes Mellitus: A Review of Host-Gut Microbiota Interactions and Their Therapeutic Potential - PubMed (original) (raw)

Review

Gut Microbiota and Gestational Diabetes Mellitus: A Review of Host-Gut Microbiota Interactions and Their Therapeutic Potential

Zubaidah Hasain et al. Front Cell Infect Microbiol. 2020.

Abstract

Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance recognized during pregnancy. GDM is associated with metabolic disorder phenotypes, such as obesity, low-grade inflammation, and insulin resistance. Following delivery, nearly half of the women with a history of GDM have persistent postpartum glucose intolerance and an increased risk of developing type 2 diabetes mellitus (T2DM), as much as 7-fold. The alarming upward trend may worsen the socioeconomic burden worldwide. Accumulating evidence strongly associates gut microbiota dysbiosis in women with GDM, similar to the T2DM profile. Several metagenomics studies have shown gut microbiota, such as Ruminococcaceae, Parabacteroides distasonis, and Prevotella, were enriched in women with GDM. These microbiota populations are associated with metabolic pathways for carbohydrate metabolism and insulin signaling, suggesting a potential "gut microbiota signature" in women with GDM. Furthermore, elevated expression of serum zonulin, a marker of gut epithelial permeability, during early pregnancy in women with GDM indicates a possible link between gut microbiota and GDM. Nevertheless, few studies have revealed discrepant results, and the interplay between gut microbiota dysbiosis and host metabolism in women with GDM is yet to be elucidated. Lifestyle modification and pharmacological treatment with metformin showed evidence of modulation of gut microbiota and proved to be beneficial to maintain glucose homeostasis in T2DM. Nonetheless, post-GDM women have poor compliance toward lifestyle modification after delivery, and metformin treatment remains controversial as a T2DM preventive strategy. We hypothesized modulation of the composition of gut microbiota with probiotics supplementation may reverse postpartum glucose intolerance in post-GDM women. In this review, we addressed gut microbiota dysbiosis and the possible mechanistic links between the host and gut microbiota in women with GDM. Furthermore, this review highlights the potential therapeutic use of probiotics in post-GDM women as a T2DM preventive strategy.

Keywords: gestational diabetes; gut microbiota; host microbial interactions; probiotics; short-chain fatty acids.

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Figures

Figure 1

Possible mechanisms of adherence of pathobionts and translocation across the epithelial layer of the gut in GDM. High-fat/low-fiber diet intake might have modulated the normal gut microbiota composition and increased the Gram-negative pathobionts. Elevation of Gram-negative pathobionts might have increased the LPS levels. There are several mechanisms as to how pathobionts and LPS are able to move across the epithelial layer of the gut. The first mechanism is by adherence to the mucosal layer. LPS and pathobionts might have crossed the epithelial layer of the gut through TLR 2/4 activation and is associated with the recruitment of MyD-88. LPS and pathobionts might have crossed the epithelial layer of the gut by binding to Nod1. DCs might have translocated pathobionts by phagocytosis and co-localization of the pathobionts from the intestinal lumen to the systemic circulation. Thin mucosal layer, depletion of tight junction proteins (ZO-1 and occludin), reduction of CB2, and elevation of CB1 may have increased the gut epithelial permeability (i.e., “leaky gut”). “Leaky gut” might have allowed translocation of LPS and pathobionts across the epithelial layer of the gut. LPS and pathobionts might have translocated from the intestinal lumen to the lamina propria and submucosa. LPS and pathobionts might have translocated from the submucosa to the systemic circulation and traveled to the peripheral tissues, including adipose, liver, and skeletal muscle. LPS, lipopolysaccharide; L, lipopolysaccharide; TLR2/4, toll-like receptor 2/4; Nod1, nod-like receptor 1; DC, dendritic cell; CB1/2, cannabinoid receptor 1/2; ZO-1, zona occludens 1; MyD-88, adapter proteins, myeloid differentiation factor.

Figure 2

Possible link between LPS and glucose intolerance in women with GDM. Translocation of LPS across the epithelial layer of the gut might have upregulated the pro-inflammatory CD8+ T cells and macrophages. Thus, elevation of LPS might have resulted in metabolic endotoxemia. LPS might have traveled to the peripheral tissues, including adipose, liver and skeletal muscle, and become bound to TLR. Activation of TLR might have recruited the adapter proteins MyD-88, IRAK, TAK1, and TRAF6 triggering macrophage infiltration and upregulation of inflammatory pathways (JNK/IKKβ/NF-κB). Upregulation of inflammatory pathways might have elevated pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. Upregulation of JNK/IKKβ/NF-κB might have elevated serine phosphorylation of the IRS-1Ser307, causing suppression of PI3-K, and downregulation of AktSer473. Reduction of AktSer473 phosphorylation might have impaired insulin signaling and reduced glucose uptake in peripheral tissues, leading to hyperglycemia in women with GDM. LPS, lipopolysaccharide; L, lipopolysaccharide; TLR2/4, toll-like receptor 2/4; adapter proteins MyD-88, myeloid differentiation factor; IRAK, interleukin-1 receptor-associated kinase; TAK1, transforming growth factor B-associated kinase 1; TRAF, TNF receptor-associated factor; JNK, C-Jun N-terminal kinase; IKKβ, inhibitory κB kinase-β; NF- κB, nuclear factor- κB; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; IR, insulin receptor; IRS-1, insulin receptor substrate-1; PI3-K, phosphatidylinositol 3-kinase; AKT, protein kinase B; G, glucose; I, insulin. Dashed lines indicate the possible effects of LPSs.

Figure 3

Possible link between SCFAs and glucose intolerance in women with GDM. High-fat/low-fiber diet intake might have altered the normal gut microbiota composition and dietary fermentation. Altered dietary fermentation might have caused excessive SCFAs production and excessive energy harvesting from the diet. SCFAs might have crossed the epithelial layer of the gut through the GPR 41/43 receptor and “leaky gut.” Elevation of SCFAs might have induced metabolic endotoxemia by activation of innate immune cells (CD8+ T cells upregulated higher than Treg cells) and macrophage infiltration. SCFAs traveled to the peripheral tissues, including adipose, liver, and skeletal muscle, and might have triggered elevation of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. In the adipose tissue, excessive SCFAs production might have stimulated adipogenesis beyond adipose tissue storage capacity and higher compared to the energy expenditure (low fatty acid oxidation). Elevation of lipolysis might have caused the overflow of FAs into the systemic circulation. In the liver and skeletal muscle, SCFAs might have increased FFAs uptake and increased lipogenesis, causing fat storage. Elevation of low-grade inflammation and adiposity might have impaired insulin signaling and reduced the glucose uptake, leading to hyperglycemia. Furthermore, excessive SCFAs, especially propionate, might have increased gluconeogenesis in the liver and elevated the plasma glucose levels. In conclusion, low-grade inflammation, insulin resistance, and elevated gluconeogenesis might have caused glucose intolerance in women with GDM. SCFA, short-chain fatty acid; GPR 41/43, G-protein-linked receptor 41/43; Treg cells, regulatory T cells; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; IR, insulin receptor; FA; fatty acid; FFA, free fatty acid; G, glucose. Dashed lines indicate the possible effects of SCFAs.

Figure 4

Possible roles of probiotics in post-GDM women. Probiotics may modulate gut microbiota composition by increasing the butyrate-producing gut microbiota and reducing the adherence of pathobionts to the gut epithelial mucosa. Elevation of butyrate-producing bacteria may improve dietary fermentation and promote SCFAs production. Probiotics may improve gut epithelial permeability by upregulating the expression of tight junction proteins (ZO-1 and occludin) and may downregulate CB1. Intact gut epithelial integrity with adequate mucosal layer and tight junctions may reduce pathobionts and LPS translocation and prevent metabolic endotoxemia. Probiotics may upregulate Treg cells and downregulate CD8+ T cells. Probiotics may also promote GLP-1 and PYY release. Moreover, probiotics may regulate lipid metabolism by maintaining adipogenesis, fatty acid oxidation, and suppression of lipolysis. Therefore, suppression of metabolic endotoxemia and adiposity, as well as elevation of GLP-1 and PYY, may increase insulin signaling and glucose uptake. Probiotics in an adequate amount may also regulate glucose metabolism by maintaining gluconeogenesis and promoting glycogen storage. In conclusion, probiotics may reduce systemic inflammation and improve lipid and glucose homeostasis in post-GDM women. SCFA, short-chain fatty acid; GPR 41/43, G-protein-linked receptor 41/43; CB1/2, cannabinoid receptor 1/2; ZO-1, zona occludens 1; Treg cells, regulatory T cells; GLP-1, glucagon like peptide-1; PYY, peptide YY; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; IR, insulin receptor; FFA, free fatty acid; G, glucose. Dashed lines indicate the possible effects of probiotics.

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Gut Microbiota and Gestational Diabetes Mellitus: A Review of Host-Gut Microbiota Interactions and Their Therapeutic Potential - PubMed (original) (raw)