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The gut and genital tract microbiota of females represent very complex biological ecosystems that are in continuous communication with each other. The crosstalk between these two ecosystems impacts host physiological, immunological and metabolic homeostasis and vice versa. The vaginal microbiota evolved through a continuous translocation of species from the gut to the vagina or through a mother-to-child transfer during delivery. Though the organisms retain their physio-biochemical characteristics while in the vagina, the immune responses elicited by their metabolic by-products appear to be at variance with those in the gut. This has critical implications for the gynecological, reproductive as well as overall wellbeing of the host and by extension her offspring. The homeostatic and immunomodulatory effects of the bacterial fermentation products (short chain fatty acids, SCFAs) in the gut are better understood compared to the genital tract. While gut SCFAs prevent a leakage of bacteria and bacterial products from the gut in to circulation (leaky gut) and consequent systemic inflammation (anti-inflammatory/protective role); they have been shown to exhibit dysbiotic and proinflammatory effects in the genital tract that can lead to unfavorable gynecological and reproductive outcomes. Therefore, this review was conceived to critically examine the correlation between the female gut and genital tract microbiota. Secondly, we explored the metabolic patterns of the respective microbiota niches; and thirdly, we described the diverse effects of products of bacterial fermentation on immunological responses in the vaginal and rectal ecosystems.

The global obesity epidemic has necessitated the search for better intervention strategies including the exploitation of the health benefits of some gut microbiota and their metabolic products. Therefore, we examined the gut microbial composition and mechanisms of interaction with the host in relation to homoeostatic energy metabolism and pathophysiology of dysbiosis-induced metabolic inflammation and obesity. We also discussed the eubiotic, health-promoting effects of probiotics and prebiotics as well as epigenetic modifications associated with gut microbial dysbiosis and risk of obesity. High-fat/carbohydrate diet programmes the gut microbiota to one predominated by Firmicutes ( Clostridium ), Prevotella and Methanobrevibacter but deficient in beneficial genera/species such as Bacteroides , Bifidobacterium , Lactobacillus and Akkermansia . Altered gut microbiota is associated with decreased expression of SCFA that maintain intestinal epithelial barrier integrity, reduce bacterial translocation and inflammation and increase expression of hunger-suppressing hormones. Reduced amounts of beneficial micro-organisms also inhibit fasting-induced adipocyte factor expression leading to dyslipidaemia. A low-grade chronic inflammation (metabolic endotoxaemia) ensues which culminates in obesity and its co-morbidities. The synergy of high-fat diet and dysbiotic gut microbiota initiates a recipe that epigenetically programmes the host for increased adiposity and poor glycaemic control. Interestingly, these obesogenic mechanistic pathways that are transmittable from one generation to another can be modulated through the administration of probiotics, prebiotics and synbiotics. Though the influence of gut microbiota on the risk of obesity and several intervention strategies have been extensively demonstrated in animal models, application in humans still requires further robust investigation.

In addition to being a passage for sperm, menstruum, and the baby, the human vagina and its microbiota can influence conception, pregnancy, the mode and timing of delivery, and the risk of acquiring sexually transmitted infections. The physiological status of the vaginal milieu is important for the wellbeing of the host as well as for successful reproduction. High estrogen states, as seen during puberty and pregnancy, promote the preservation of a homeostatic (eubiotic) vaginal microenvironment by stimulating the maturation and proliferation of vaginal epithelial cells and the accumulation of glycogen. A glycogen-rich vaginal milieu is a haven for the proliferation of facilitated by the production of lactic acid and decreased pH. and their antimicrobial and anti-inflammatory products along with components of the epithelial mucosal barrier provide an effective first line defense against invading pathogens including bacterial vaginosis, aerobic vaginitis-associated bacteria, viruses, fungi and protozoa. An optimal host-microbial interaction is required for the maintenance of eubiosis and vaginal health. This review explores the composition, function and adaptive mechanisms of the vaginal microbiome in health and those disease states in which there is a breach in the host-microbial relationship. The potential impact of vaginal dysbiosis on reproduction is also outlined.

The immunological response to bacterial vaginosis (BV) remains poorly understood and recurrent BV is still a major public health burden especially in the pregnant population. This article reviews the potential mechanisms by which BV-associated bacteria suppress and circumvent the host and microbial defence responses, and propagate their survival/dominance without overt inflammation. We discuss the composition of cervicovaginal mucosal barrier and the mechanism by which BV circumvents host defence: the degradation of the mucosal barrier and immunoglobulin A (IgA); the BV-associated organism Gardnerella vaginalis haemolysin (vaginolysin); diminished IgA response against vaginolysin; mucosal sialic acid degradation, foraging and depletion; inhibition of IL-8-induced neutrophilic infiltration; and metabolite-induced incapacitation of neutrophil and monocyte chemotaxis. We also highlight the tolerance/resistance to both host and antimicrobial molecules mounted by BV-associated biofilms. A plausible role of sialic acid-binding immunoglobulin-like lectins (SIGLECS) was also suggested. Sialidase, which is often produced by G. vaginalis, is central to the immunosuppression, relapse and recurrence observed in BV, although it is supported by other hydrolytic enzymes, vaginolysin and immunomodulatory metabolites.

Multi-marker tests hold promise for identifying symptomatic women at risk of imminent preterm delivery (PTD, <37 week's gestation). This study sought to determine the relationship of inflammatory mediators and metabolites in cervicovaginal fluid (CVF) with spontaneous PTD (sPTD) and delivery within 14 days of presentation with symptoms of preterm labour (PTL). CVF samples from 94 (preterm = 19, term = 75) singleton women with symptoms of PTL studied between 19+0-36+6 weeks' gestation were analysed for cytokines/chemokines by multiplexed bead-based immunoassay, while metabolites were quantified by enzyme-based spectrophotometry in a subset of 61 women (preterm = 16, term = 45). Prevalence of targeted vaginal bacterial species was determined for 70 women (preterm = 14, term = 66) by PCR. Overall, 10 women delivered within 14 days of sampling. Predictive capacities of individual biomarkers and cytokine-metabolite combinations for sPTD and delivery within 14 days of sampling were analysed by logistic regression models and area under the receiver operating characteristic curve. Fusobacterium sp., Mubiluncus mulieris and Mycoplasma hominis were detected in more preterm-delivered than term women (P<0.0001), while, M. curtisii was found in more term-delivered than preterm women (P<0.0001). RANTES (0.91, 0.65-1.0), IL-6 (0.79, 0.67-0.88), and Acetate/Glutamate ratio (0.74, 0.61-0.85) were associated with delivery within 14 days of sampling (AUC, 95% CI). There were significant correlations between cytokines and metabolites, and several cytokine-metabolite combinations were associated with sPTD or delivery within 14 days of sampling (e.g. L/D-lactate ratio+Acetate/Glutamate ratio+IL-6: 0.84, 0.67-0.94). Symptomatic women destined to deliver preterm and within 14 days of sampling express significantly higher pro-inflammatory mediators at mid to late gestation. In this cohort, IL-6, Acetate/Glutamate ratio and RANTES were associated with delivery within 14 days of sampling, consistent with their roles in modulating infection-inflammation-associated preterm labour in women presenting with symptoms of preterm birth. Replication of these observations in larger cohorts of women could show potential clinical utility.

Inflammation-induced remodelling of gestational tissues that underpins spontaneous preterm birth (sPTB, delivery < 37 weeks' gestation) may vary by race and context. To explore relationships between markers of these pathological processes, we (a) characterised the cervicovaginal fluid (CVF) cytokine profiles of pregnant South African women at risk of PTB; (b) determined CVF matrix-metalloproteinase-9 (MMP-9) and its regulator tissue inhibitor of metalloproteinase-1 (TIMP-1); and (c) explored the predictive potential of these markers for sPTB. The concentrations of 10 inflammatory cytokines and MMP-9 and TIMP-1 were determined by ELISA in CVF samples from 47 non-labouring women at high risk of PTB. We studied CVF sampled at three gestational time points (GTPs): GTP1 (20-22 weeks, n = 37), GTP2 (26-28 weeks, n = 40), and GTP3 (34-36 weeks, n = 29) and analysed for changes in protein concentrations and predictive capacities (area under the ROC curve (AUC) and 95% confidence interval (CI)) for sPTB. There were 11 (GTP1), 13 (GTP2), and 6 (GTP3) women who delivered preterm within 85.3 ± 25.9, 51.3 ± 15.3, and 11.8 ± 7.5 (mean ± SD) days after assessment, respectively. At GTP1, IL-8 was higher (4-fold, p = 0.02), whereas GM-CSF was lower (~1.4-fold, p = 0.03) in the preterm compared with term women with an average AUC = 0.73. At GTP2, IL-1β (18-fold, p < 0.0001), IL-8 (4-fold, p = 0.03), MMP-9 (17-fold, p = 0.0007), MMP-9/TIMP-1 ratio (9-fold, p = 0.004), and MMP-9/GM-CSF ratio (87-fold, p = 0.005) were higher in preterm compared with term women with an average AUC = 0.80. By contrast, IL-10 was associated with term delivery with an AUC (95% CI) = 0.75 (0.55-0.90). At GTP3, IL-1β (58-fold, p = 0.0003), IL-8 (12-fold, p = 0.002), MMP-9 (296-fold, p = 0.03), and TIMP-1 (35-fold, p = 0.01) were higher in preterm compared with term women with an average AUC = 0.85. Elevated IL-1β was associated with delivery within 14 days of assessment with AUC = 0.85 (0.67-0.96). Overall, elevated MMP-9 at GTP3 had the highest (13.3) positive likelihood ratio for distinguishing women at risk of sPTB. Lastly, a positive correlation between MMP-9 and TIMP-1 at all GTPs ( ≥ 0.61, p < 0.01) for women delivering at term was only observed at GTP1 for those who delivered preterm ( = 0.70, p < 0.03). In this cohort, sPTB is associated with gestation-dependent increase in pro-inflammatory cytokines, decreased IL-10 and GM-CSF, and dysregulated MMP-9-TIMP-1 interaction. Levels of cytokine (especially IL-1β) and ECM remodelling proteins rise significantly in the final 2 weeks before the onset of labour when sPTB is imminent. The signalling mechanisms for these ECM remodelling observations remain to be elucidated.

Background: Maternal obesity is associated with several adverse reproductive outcomes. It is a growing public health burden in sub-Saharan Africa, a region with low resources and capacity to care for the large, affected population. Objectives: To assess the evidence of maternal obesity as a risk factor for caesarean delivery in women in sub-Saharan Africa. Methods: A systematic review of relevant original articles using PubMed, MEDLINE, and CINAHL was performed. Google Scholar and the reference lists of relevant systematic reviews and meta-analyses were also searched for other eligible studies. Observational studies assessing maternal body mass index (BMI) ≥ 30 kg/m2 before or during gestation and caesarean delivery as birth outcome were included. Results: All 17 studies were published between 2009 and 2021 and included 227,675 (236–153,102) participants. The prevalence of maternal obesity ranged from 3.9 to 44%. All except two studies (88%) indicated an association of obesity and risk of caesarean delivery in pregnant women in sub-Saharan Africa. Overweight/obese women had up to 4-fold increased risk of caesarean delivery compared to normal weight women. Three studies also reported a direct relationship between morbid obesity and prevalence of caesarean delivery in the sub-region. The risk of caesarean delivery appears to increase with increasing BMI e.g., >5 times in women with BMI ≥ 40 kg/m2 than in normal weight women. Conclusions: In sub-Saharan Africa, increased BMI in pregnancy is a risk factor for subsequent caesarean delivery. The risk of caesarean delivery appears to increase with increasing BMI. A robust meta-analysis and other patho-mechanistic studies can be conducted to confirm causal association. Culturally appropriate weight management and nutritional interventions should be implemented to reduce the incidence of obesity-induced caesarean delivery in sub-Saharan Africa.

BackgroundGlobally, 11% of babies are born preterm each year. Preterm birth (PTB) is a leading cause of neonatal death and under-five mortality and morbidity, with lifelong sequelae in those who survive. PTB disproportionately impacts low/middle-income countries (LMICs) where the burden is highest.ObjectivesThis scoping review sought to the evidence for interventions that reduce the risk of PTB, focusing on the evidence from LMICs and describing how context is considered in evidence synthesis.DesignWe conducted a scoping review, to describe this wide topic area. We searched five electronic databases (2009–2020) and contacted experts to identify relevant systematic reviews of interventions to reduce the risk of PTB. We included published systematic reviews that examined the effectiveness of interventions and their effect on reducing the risk of PTB. Data were extracted and is described narratively.Results139 published systematic reviews were included in the review. Interventions were categorised as primary or secondary. The interventions where the results showed a greater effect size and consistency across review findings included treatment of syphilis and vaginal candidiasis, vitamin D supplementation and cervical cerclage. Included in the 139 reviews were 1372 unique primary source studies. 28% primary studies were undertaken in LMIC contexts and only 4.5% undertaken in a low-income country (LIC) Only 10.8% of the reviews sought to explore the impact of context on findings, and 19.4% reviews did not report the settings or the primary studies.ConclusionThis scoping review highlights the lack of research evidence derived from contexts where the burden of PTB globally is greatest. The lack of rigour in addressing contextual applicability within systematic review methods is also highlighted. This presents a risk of inappropriate and unsafe recommendations for practice within these contexts. It also highlights a need for primary research, developing and testing interventions in LIC settings.

In order to improve spontaneous preterm birth (sPTB) risk stratification in a predominantly white cohort of non-labouring pregnant women, we analysed their vaginal microbiota, metabolite, cytokine and foetal fibronectin (FFN) concentrations at two gestational time points (GTPs): GTP1 (20 +0 –22 +6 weeks, preterm = 17; term = 32); and GTP2 (26 +0 –28 +6 weeks, preterm = 14; term = 31). At GTP1, the preterm-delivered women showed abundant G. vaginalis (AUC = 0.77) over L. crispatus and L. iners , and upregulation of 10 metabolites. At GTP2, the same women had more lactobacilli- and mixed anaerobes-dominated microbiota, upregulation of five metabolites, and decreased TNFR1, distinguishing them from their term counterparts (AUC = 0.88). From GTP1 to GTP2, sPTB was associated with increased microbiota α-diversity, and upregulation of pantothenate and urate. CXCL10 declined in the term-delivered women by ~3-fold, but increased in the preterm-delivered women (AUC = 0.68), enhanced by FFN (AUC = 0.74). Characterising the complex dynamic interactions between cervicovaginal microbial metabolites and host immune responses could enhance sPTB risk stratification.

Bacterial vaginosis (BV) is the most commonly diagnosed vaginal infection in women of reproductive age, with most patients unaware that they have BV due to its asymptomatic nature. BV is a dysbiotic condition defined by a deviation from the healthy Lactobacillus dominance to a polymicrobial anaerobic bacterial community that increases the risk of sexually transmitted infections and adverse reproductive outcomes, including spontaneous preterm birth. The increasing number of infectious agents in BV, biofilm persistence and antibiotic resistance in the vaginal canal hinder effective treatments with antibiotics leading to consistent recurrence of BV in many women (30–70%). Like in the gut, these vaginal drug-microbiome interactions termed pharmacomicrobiomics could alter drug disposition, mechanism of action, and toxicity that reduce the efficacy of antibiotics and increase the risk of persistent and recurrent BV and its sequelae. For instance, both vaginal epithelial and bacterial cells co-exist and possess enzymes that metabolize antibiotics, and transporter proteins that expel drugs and toxins, rendering them ineffective. Despite significant progress on pharmacomicrobiomics in the gut, little is known about this phenomenon in the vaginal microenvironment, which harbors a consequential microbiota and a major source of infection and antibiotic resistance. Therefore, to improve therapeutic outcomes and reduce the rate of persistent/recurrent BV and infection-associated preterm birth, we present an overview of the evidence pertaining to the effect of vaginal microbiome-drug interactions and efficacy of antibiotics against recurrent BV. We also highlight plausible mechanistic underpinnings of these interactions and implications for treatment modalities to combat infection-associated preterm birth.