Periodontitis and Gestational Diabetes Mellitus: A Potential Inflammatory Vicious Cycle

Abstract

Periodontitis is a chronic inflammatory immune disease associated with a dysbiotic state, influenced by keystone bacterial species responsible for disrupting the periodontal tissue homeostasis. Furthermore, the severity of periodontitis is determined by the interaction between the immune cell response in front of periodontitis-associated species, which leads to the destruction of supporting periodontal tissues and tooth loss in a susceptible host. The persistent bacterial challenge induces modifications in the permeability and ulceration of the sulcular epithelium, which facilitates the systemic translocation of periodontitis-associated bacteria into distant tissues and organs. This stimulates the secretion of pro-inflammatory molecules and a chronic activation of immune cells, contributing to a systemic pro-inflammatory status that has been linked with a higher risk of several systemic diseases, such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). Although periodontitis and GDM share the common feature of systemic inflammation, the molecular mechanistic link of this association has not been completely clarified. This review aims to examine the potential biological mechanisms involved in the association between periodontitis and GDM, highlighting the contribution of both diseases to systemic inflammation and the role of new molecular participants, such as extracellular vesicles and non-coding RNAs, which could act as novel molecular intercellular linkers between periodontal and placental tissues.

Keywords: extracellular vesicles; gestational diabetes mellitus; periodontitis; systemic inflammation.

Figure 1

Direct and indirect mechanisms involved in the link between Gestational Diabetes Mellitus (GDM) and Periodontitis. A pro-inflammatory state contributes to GDM development and higher periodontitis severity. Among the direct mechanisms, periodontal bacteria or their byproducts are released into systemic circulation and can translocate into placental tissues, increasing the possibility of placental inflammation. Indirect mechanisms refer to the increase in pro-inflammatory mediators from periodontal pockets into circulation, reaching the liver and placenta, and vice-versa. Regarding extracellular vesicles (EVs), they may act via direct or indirect mechanisms, contributing to the cross-talk of both diseases. Perio-sEVs: periodontal-derived small extracellular vesicles; PAMPs: pathogen-associated molecular patterns; IL-1β: interleukin 1 beta; TNF-α: tumor necrosis factor alpha; CRP: C-reactive protein; IL-6: interleukin 6; DAMPs: damage-associated molecular patterns; TLR-2: toll-like receptor 2; TLR-4: toll-like receptor 4; NLRP-3: NOD-, LRR-, and pyrin domain-containing protein 3; MMPs: metalloproteinases; PdEVs: placental derived extracellular vesicles; hPL: human lactogen placental; PlGF: placental growth factor; Perio-EVs: periodontal-derived extracellular vesicles.

Figure 2

Role of periodontal-derived extracellular vesicles (Perio-sEVs) and placenta-derived extracellular vesicles (PdEVs) in Gestational Diabetes Mellitus (GDM) development. PdEVs are increased in plasma from GDM pregnant women along with C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). PdEVs act as signal carriers between different cell types, and their cargo and bioactivity are also modified in GDM conditions. Overexpression or underexpression of certain microRNAs (miRNAs) can generate epigenetic modifications in recipient cells. A pro-inflammatory state can also be maintained by the release of PdEVs into the circulation and gingival crevicular fluid (GCF), which may aggravate periodontitis severity and contribute to the onset of GDM.

Figure 3

Proposed model of the association between Periodontitis and Gestational Diabetes Mellitus (GDM). In GDM conditions, hyperglycemia, oxidative stress, and placental-derived extracellular vesicles (PdEVs) contribute to a systemic and periodontal pro-inflammatory state and may directly affect periodontitis progression. Periodontitis, through bacterial translocation, pro-inflammatory mediators, and periodontal-derived sEVs (Perio-sEVs) released into systemic circulation, may contribute to GDM development over systemic inflammation and generate direct effects in the placenta. The low-grade systemic inflammation activation is mediated by the acute phase response in the liver and pro-inflammatory cytokines, which can be triggered by both diseases and alter their development. Thus, GDM and periodontitis are biologically connected in a “vicious cycle” that generates a cross-link via systemic inflammation activation. PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; Perio-sEVs: periodontal-derived small extracellular vesicles; miRNA: microRNA; CRP: C-reactive protein; IL-6: interleukin 6; TNF-α: tumor necrosis factor alpha; TLR-2: toll-like receptor 2; TLR-4: toll-like receptor 4; NF-kB: nuclear factor kappa B; NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; IL-1β: interleukin 1 beta; MMPs: metalloproteinases; PdEVs: placental-derived extracellular vesicles; hPL: human lactogen placental; PlGF: placental growth factor; Perio-EVs: periodontal-derived extracellular vesicles.