Distinct Immune Responses Elicited From Cervicovaginal Epithelial Cells by Lactic Acid and Short Chain Fatty Acids Associated With Optimal and Non-optimal Vaginal Microbiota
Distinct Immune Responses Elicited From Cervicovaginal Epithelial Cells by Lactic Acid and Short Chain Fatty Acids Associated With Optimal and Non-optimal Vaginal Microbiota
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DOI：
10.3389/fcimb.2019.00446
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发表时间：
2020-01-10
影响因子：
5.7
通讯作者：
Tachedjian, Gilda
中科院分区：
文献类型：
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作者：
Delgado-Diaz, David J.;Tyssen, David;Tachedjian, Gilda
在细菌性阴道病(BV)中观察到的非最佳阴道微生物区系的典型特征是有益乳杆菌的枯竭和大量的厌氧菌。这些非最佳状态与亚临床宫颈阴道炎和艾滋病毒感染风险增加有关，与以乳杆菌为主的最佳阴道微生物群定居的妇女相比。乳酸(LA)是由阴道乳杆菌产生的一种主要有机酸代谢物，可引起宫颈阴道上皮细胞的抗炎作用，在BV过程中被大量消耗。然而，目前尚不清楚LA是否在阴道微生物区系存在的情况下保持其抗炎活性，这些代谢物包括短链脂肪酸(SCFAs)和琥珀酸，这两种物质也是由最佳阴道微生物区系产生的。此外，在BV期间存在较高浓度的SCFAs和琥珀酸对宫颈阴道上皮细胞的免疫调节作用尚不清楚。在这里，我们报告了在pH 3.9的生理相关浓度的SCFAs和琥珀酸存在下(如在乳杆菌占主导地位的微生物区系的女性中发现的)，LA诱导宫颈阴道上皮细胞处于抗炎状态，并抑制由Toll样受体(TLR)激动剂Polyinosinic：Polycytidyic和Pam3CSK4引发的炎症。当宫颈阴道上皮细胞用代表BV的阴道微生物代谢产物混合物处理时，在pH值为7时，含有较低浓度的LA但较高浓度的SCFA/琥珀酸，没有观察到抗炎作用。相反，代表BV的阴道微生物代谢产物混合物在长期和持续的治疗过程中对宫颈阴道上皮细胞的免疫反应起着失调作用。基础和TLR诱导的促炎细胞因子包括肿瘤坏死因子-α的产生增加，但包括RANTES和IP-10在内的趋化因子的基础产生减少，证明了这一点。对BV阴道微生物组分的进一步鉴定表明，醋酸是一种重要的阴道微生物组代谢物，能够对一系列宫颈阴道上皮细胞靶点产生不同的免疫调节作用。这些发现表明，SCFAs水平的升高是BV患者宫颈阴道炎的一个潜在来源，并支持LA对宫颈阴道上皮细胞的独特抗炎特性，以及LA或LA产生的乳酸菌在逆转与艾滋病毒风险增加相关的生殖器炎症方面的作用。
Non-optimal vaginal microbiota, as observed in bacterial vaginosis (BV), is typically characterized by a depletion of beneficial lactobacilli and an abundance of numerous anaerobes. These non-optimal conditions are associated with subclinical cervicovaginal inflammation and an increased risk of HIV infection compared to women colonized with optimal vaginal microbiota dominated by lactobacilli. Lactic acid (LA) is a major organic acid metabolite produced by vaginal lactobacilli that elicits anti-inflammatory effects from cervicovaginal epithelial cells and is dramatically depleted during BV. However, it is unclear if LA retains its anti-inflammatory activity in the presence of vaginal microbiota metabolites comprising short chain fatty acids (SCFAs) and succinic acid, which are also produced by an optimal vaginal microbiota. Furthermore, the immunomodulatory effect of SCFAs and succinic acid on cervicovaginal epithelial cells at higher concentrations present during BV is unknown. Here we report that in the presence of physiologically relevant concentrations of SCFAs and succinic acid at pH 3.9 (as found in women with lactobacillus-dominated microbiota) LA induced an anti-inflammatory state in cervicovaginal epithelial cells and inhibited inflammation elicited by the toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid and Pam3CSK4. When cervicovaginal epithelial cells were treated with a vaginal microbiota metabolite mixture representative of BV, containing a lower concentration of LA but higher concentrations of SCFA/succinic acid at pH 7, no anti-inflammatory was observed. Rather, the vaginal microbiota metabolite mixture representative of BV dysregulated the immune response of cervicovaginal epithelial cells during prolonged and sustained treatments. This was evidenced by increased basal and TLR-induced production of pro-inflammatory cytokines including tumor necrosis factor-alpha, but decreased basal production of chemokines including RANTES and IP-10. Further characterization of individual components of the BV vaginal microbiota mixture suggested that acetic acid is an important vaginal microbiota metabolite capable of eliciting diverse immunomodulatory effects on a range of cervicovaginal epithelial cell targets. These findings indicate that elevated levels of SCFAs are a potential source of cervicovaginal inflammation in women experiencing BV, and support the unique anti-inflammatory properties of LA on cervicovaginal epithelial cells as well as a role for LA or LA-producing lactobacilli to reverse genital inflammation associated with increased HIV risk.