Vaginal host immune-microbiome interactions in a cohort of primarily African-American women who ultimately underwent spontaneous preterm birth or delivered at term

Florova, Violetta; Romero, Roberto; Tarca, Adi L.; Galaz, José; Motomura, Kenichiro; Ahmad, Madison M.; Hsu, Chaur‐Dong; Hsu, Richard; Tong, Anna; Ravel, Jacques; Theis, Kevin R.; Gomez‐Lopez, Nardhy

doi:10.1016/j.cyto.2020.155316

Cited by 20 publications

(23 citation statements)

References 114 publications

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“…We did not find any association between cytokine levels and conditions of abnormal vaginal microbiota (i.e., BV or intermediate flora). These results are in contrast with previous works showing that BV by Nugent score is associated with a significant increase in several proinflammatory cytokines/chemokines, such as IL-1α, IL-1β, IL-6, and IL-8 (Balkus et al, 2010;Kyongo et al, 2015;Florova et al, 2021).…”

Section: Discussioncontrasting

confidence: 99%

New Insights into Vaginal Environment During Pregnancy

Marangoni

Laghi

Zagonari

et al. 2021

Front. Mol. Biosci.

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During pregnancy, the vaginal ecosystem undergoes marked changes, including a significant enrichment with Lactobacillus spp. and profound alterations in metabolic profiles. A deep comprehension of the vaginal environment may shed light on the physiology of pregnancy and may provide novel biomarkers to identify subjects at risk of complications (e.g., miscarriage, preterm birth). In this study, we characterized the vaginal ecosystem in Caucasian women with a normal pregnancy (n = 64) at three different gestational ages (i.e., first, second and third trimester) and in subjects (n = 10) suffering a spontaneous first trimester miscarriage. We assessed the vaginal bacterial composition (Nugent score), the vaginal metabolic profiles (1H-NMR spectroscopy) and the vaginal levels of two cytokines (IL-6 and IL-8). Throughout pregnancy, the vaginal microbiota became less diverse, being mainly dominated by lactobacilli. This shift was clearly associated with marked changes in the vaginal metabolome: over the weeks, a progressive reduction in the levels of dysbiosis-associated metabolites (e.g., biogenic amines, alcohols, propionate, acetate) was observed. At the same time, several metabolites, typically found in healthy vaginal conditions, reached the highest concentrations at the end of pregnancy (e.g., lactate, glycine, phenylalanine, leucine, isoleucine). Lower levels of glucose were an additional fingerprint of a normal vaginal environment. The vaginal levels of IL-6 and IL-8 were significantly associated with the number of vaginal leukocytes, as well as with the presence of vaginal symptoms, but not with a condition of dysbiosis. Moreover, IL-8 concentration seemed to be a good predictor of the presence of vaginal Candida spp. Cytokine concentrations were negatively correlated to lactate, serine, and glycine concentrations, whereas the levels of 4-hydroxyphenyllactate, glucose, O-acetylcholine, and choline were positively correlated with Candida vaginal loads. Finally, we found that most cases of spontaneous abortion were associated with an abnormal vaginal microbiome, with higher levels of selected metabolites in the vaginal environment (e.g., inosine, fumarate, xanthine, benzoate, ascorbate). No association with higher pro-inflammatory cytokines was found. In conclusion, our analysis provides new insights into the pathophysiology of pregnancy and highlights potential biomarkers to enable the diagnosis of early pregnancy loss.

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Section: Discussioncontrasting

confidence: 99%

New Insights into Vaginal Environment During Pregnancy

Marangoni

Laghi

Zagonari

et al. 2021

Front. Mol. Biosci.

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“…Despite a large body of evidence supporting the role of vaginal microbiota in sPTB, the mechanism for this remains poorly understood. A cluster of studies have reported associations between Lactobacillus deplete or dysbiotic vaginal microbiota and local inflammation at the cervicovaginal interface in the context of PTB, however, immunophenotyping has been limited to analysing cervicovaginal cytokines, chemokines and β defensin 12 , 18 , 19 .…”

Section: Introductionmentioning

confidence: 99%

Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response

et al. 2022

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There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1β and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB.

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“…A nonoptimal CST IV cervicovaginal microbiome is common in Black women and has been associated with negative maternal-child health outcomes, including obstetric complications, spontaneous preterm birth, and neonatal morbidity and mortality (Brown et al, 2018(Brown et al, , 2018Callahan et al, 2017;DiGiulio et al, 2015;Elovitz et al, 2019;Fettweis et al, 2019;Florova et al, 2021;Gerson et al, 2020a;Hočevar et al, 2019;Ravel et al, 2011;Romero et al, 2014;Tabatabaei et al, 2019Tabatabaei et al, , 2019Zhou et al, 2007). This underlying biological risk is further amplified by a variety of environmental factors that contribute to a high risk in utero environment, including, but not limited to, obesity, diabetes and consumption of a diet that deficient in dietary fibers (Brookheart et al, 2019;Danese and Lewis, 2017;Gerson et al, 2020b;Shivakoti et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Generally, CST I, II, III and V are dominated by the presence of Lactobacillus species while the nonoptimal cervicovaginal microbiome, CST IV, is defined by an absence of Lactobacillus and the presence of a wide array of anaerobic bacteria, including Gardnerella vaginalis and Atopobium vaginae (Fredricks et al, 2005; Gajer et al, 2012; Greenbaum et al, 2019; redondo-Lopez et al, 1990; Ravel et al, 2011; Romero et al, 2014). During pregnancy, Black women are more likely to harbor CST IV microbiota that have been associated with increased incidence of obstetric complications, inflammation in the intrauterine environment, spontaneous preterm birth, and neonatal morbidity (Brown et al, 2018, 2018; Callahan et al, 2017; DiGiulio et al, 2015; Elovitz et al, 2019; Fettweis et al, 2019; Florova et al, 2021; Gerson et al, 2020a; Hočevar et al, 2019; Ravel et al, 2011; Romero et al, 2014; Tabatabaei et al, 2019, 2019; Zhou et al, 2007). The risk associated with CST IV may be further amplified by a variety of environmental factors that promote chronic and systemic inflammation, including maternal stress and trauma, infection, and consumption of a high-fat, low-fiber diet (Brookheart et al, 2019; Danese and Lewis, 2017; Gerson et al, 2020b; Shivakoti et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Collectively, these patterns highlight a critical need for elucidation into the biological mechanisms underlying these increased risks. Among these well-documented social and environmental determinants of racial health disparities, the cervicovaginal microbiota has emerged as an important biological contributor to maternal and offspring health outcomes (Aagaard et al, 2012;Brown et al, 2019;Elovitz et al, 2019;Fettweis et al, 2019;Florova et al, 2021;Gajer et al, 2012;Lorch and Enlow, 2016;Owens and Fett, 2019;Ravel et al, 2011;Romero et al, 2014;Serrano et al, 2019;Williams and Sternthal, 2010). In contrast to the gut microbiota, an optimal cervicovaginal microbiome consists of minimally diverse microbial communities that recent cultivation-independent approaches have classified into five primary community state types (CST) (France et al, 2020;Ravel et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Colonization at birth with human CST IV cervicovaginal microbiota alters development and increases neonatal mortality in mice

Jašarević

Hill

et al. 2021

Preprint

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Profound racial health disparities contribute to maternal-infant morbidity and mortality. An emergent risk factor is the maternal microbiota, whereby compositional alterations impact maternal health and offspring development during pregnancy and beyond. The presence of a nonoptimal CST IV cervicovaginal microbiota, more common in Black and Hispanic women, is associated with increased risk of preterm birth and adverse birth outcomes. Through examination of the biological mechanisms by which vertical transmission of microbiota from mother to offspring influences postnatal development, we found that exposing cesarean delivered mice with CST IV cervicovaginal microbiota from pregnant women produced lasting effects on offspring metabolic, immune, and neural outcomes. We then examined how compounding effects of a typical high-risk, proinflammatory in utero environment, characterized by a maternal obesogenic state and the presence of G. vaginalis, would affect the offspring response to CST IV microbial gut colonization. The resultant developmental immaturity, coupled with an exaggerated immune response induced by exposure to risk-associated maternal microbiota, resulted in a profound increase in neonatal mortality, supporting the critical importance of elucidating the multifactorial biological mechanisms involved in high-risk pregnancies.

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Vaginal host immune-microbiome interactions in a cohort of primarily African-American women who ultimately underwent spontaneous preterm birth or delivered at term

Cited by 20 publications

References 114 publications

New Insights into Vaginal Environment During Pregnancy

New Insights into Vaginal Environment During Pregnancy

Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response

Colonization at birth with human CST IV cervicovaginal microbiota alters development and increases neonatal mortality in mice

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