Imperial College London

Dr David MacIntyre

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Reader in Reproductive Systems Medicine
 
 
 
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Contact

 

+44 (0)20 7594 2195d.macintyre Website

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

211 results found

Whelan E, Kalliala I, Semertzidou A, Raglan O, Bowden S, Kechagias K, Markozannes G, Cividini S, McNeish I, Marchesi J, MacIntyre D, Bennett P, Tsilidis K, Kyrgiou Met al., 2022, Risk Factors for Ovarian Cancer: An Umbrella Review of the Literature, Cancers, Vol: 14, Pages: 2708-2708

<jats:p>Several non-genetic factors have been associated with ovarian cancer incidence or mortality. To evaluate the strength and validity of the evidence we conducted an umbrella review of the literature that included systematic reviews/meta-analyses that evaluated the link between non-genetic risk factors and ovarian cancer incidence and mortality. We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews and performed a manual screening of references. Evidence was graded into strong, highly suggestive, suggestive or weak based on statistical significance of the random effects summary estimate and the largest study in a meta-analysis, the number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, and presence of excess significance bias. We identified 212 meta-analyses, investigating 55 non-genetic risk factors for ovarian cancer. Risk factors were grouped in eight broad categories: anthropometric indices, dietary intake, physical activity, pre-existing medical conditions, past drug history, biochemical markers, past gynaecological history and smoking. Of the 174 meta-analyses of cohort studies assessing 44 factors, six associations were graded with strong evidence. Greater height (RR per 10 cm 1.16, 95% confidence interval (CI) 1.11–1.20), body mass index (BMI) (RR ≥ 30 kg/m2 versus normal 1.27, 95% CI 1.17–1.38) and three exposures of varying preparations and usage related to hormone replacement therapy (HRT) use increased the risk of developing ovarian cancer. Use of oral contraceptive pill reduced the risk (RR 0.74, 95% CI 0.69–0.80). Refining the significance of genuine risk factors for the development of ovarian cancer may potentially increase awareness in women at risk, aid prevention and early detection.</jats:p>

Journal article

Ng S, Chen M, Kundu S, Wang X, Zhou Z, Zheng Z, Qing W, Sheng H, Wang Y, He Y, Bennett P, MacIntyre D, Zhou Het al., 2022, Large-scale characterisation of the pregnancy vaginal microbiome and sialidase activity in a low-risk Chinese population, Publisher: Nature Research

Vaginal microbiota-host interactions are linked to preterm birth (PTB), which continues to be the primary cause of global childhood mortality. Despite the majority of PTB occuring in Asia, studies of the pregnancy vaginal microbiota are largely limited to Northern American and European populations. Here, we characterised the vaginal microbiome of 2689 pregnant Chinese women using metataxonomics and in a subset (n=823), the relationship between vaginal microbiota composition, sialidase activity and leukocyte presence and pregnancy outcomes. Vaginal microbiota were most frequently dominated by Lactobacillus crispatus or L. iners , with the latter associated with vaginal leukocyte presence. Women with high sialidase activity were enriched for bacterial vaginosis-associated genera including Gardnerella, Atopobium and Prevotella . Vaginal microbiota composition, high sialidase activity and/or leukocyte presence was not associated with PTB risk suggesting underlying differences in the vaginal microbiota and/or host immune responses of Chinese women, possibly accounting for low PTB rates in this population. <h4>Importance</h4> Specific vaginal microorganisms or ‘vaginal microbiota’, are associated with preterm birth, which is the primary cause of death in children under 5yrs of age worldwide. Despite most preterm births occuring in Asia, almost all studies of the pregnancy vaginal microbiota have been limited to Northern American and European women. Here, we studied the vaginal microbiota in a large cohort of 2689 pregnant Chinese women and showed that it was most frequently dominated by Lactobacillus crispatus or L. iners . The latter was associated with leukocyte infiltration of vaginal secretions. Women with high activity of the enzyme sialidase, were frequently colonised by species associated with the common condition bacterial vaginosis, including Gardnerella, Atopobium and Prevotella species. Vaginal microbiota, high sialidase activity and/or

Working paper

Arianoglou M, Kim SH, Bennett PR, MacIntyre DA, Terzidou Vet al., 2022, Investigation of the Biological Role of a Novel microRNA (miRNA) Biomarker in the Aetiology of Preterm Birth (PTB), Publisher: SPRINGER HEIDELBERG, Pages: 198-198, ISSN: 1933-7191

Conference paper

MacIntyre DA, Pruski P, Correia G, Lewis H, Capuccini K, Inglese P, Chan D, Brown R, Kindinger L, Lee YS, Smith A, Marchesi J, McDonald J, Cameron S, Alexander-Hardiman K, David A, Stock S, Norman J, Terzidou V, Teoh TG, Sykes L, Bennett PR, Takats Zet al., 2022, Rapid Assessment of Vaginal Microbiota Host Interactions During Pregnancy and Preterm Birth by Direct On-Swab Desorption Electrospray Ionization Mass Spectrometry, Publisher: SPRINGER HEIDELBERG, Pages: 53-53, ISSN: 1933-7191

Conference paper

Kundu S, Lee Y, Sykes L, Chan D, Lewis H, Brown R, Kindinger L, Dell A, Feizi T, Haslam S, Liu Y, Marchesi J, MacIntyre D, Bennett Pet al., 2022, The Effect of Secretor Status and the Vaginal Microbiome on Birth Outcome, Publisher: SPRINGER HEIDELBERG, Pages: 197-197, ISSN: 1933-7191

Conference paper

Chan D, Bennett P, Lee YS, Kundu S, Teoh TG, Adan M, Ahmed S, Brown RG, David A, Lewis H, Gimeno- Molina B, Norman J, Stock S, Terzidou V, Kropf P, Botto M, MacIntyre D, Sykes Let al., 2022, Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response, Nature Communications, Vol: 13, ISSN: 2041-1723

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.

Journal article

Grewal K, Lee Y, Smith A, Brosens J, Bourne T, Al-Memar M, Kundu S, MacIntyre D, Bennett Pet al., 2022, Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation, BMC Medicine, Vol: 20, ISSN: 1741-7015

BackgroundEmerging evidence supports an association between vaginal microbiota composition and risk of miscarriage, however the underlying mechanisms are poorly understood. We aim to investigate the vaginal microbial composition and the local immune response in chromosomally normal and abnormal miscarriages and compare this to uncomplicated pregnancies delivering at term.Methods We used 16S rRNA gene based metataxonomics to interrogate the vaginal microbiota in a cohort of 167 women, 93 miscarriages (54 euploid and 39 aneuploid using molecular cytogenetics) and 74 women who delivered at term and correlate this with the aneuploidy status of the miscarriages. We also measured the concentrations of IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, IL-1β, IL-18 and IL-10 in cervical vaginal fluid.Results We show that euploid miscarriage is associated with a significantly higher prevalence of Lactobacillus spp. deplete vaginal microbial communities compared to aneuploid miscarriage (P=0.01). Integration of matched cervicovaginal fluid immune-profiles showed that Lactobacillus spp. depleted vaginal microbiota associated with pro-inflammatory cytokine levels most strongly in euploid miscarriage compared to viable term pregnancy (IL-1β; P<0.001, IL-8; P=0.01, IL-6; P<0.001). ConclusionOur data suggest the vaginal microbiota plays an important aetiological role in euploid miscarriage and may represent a target to modify risk of pregnancy loss.

Journal article

Kim SH, MacIntyre D, Sykes L, Arianoglou M, Bennett P, Terzidou Vet al., 2022, Whole blood holding time prior to plasma processing alters microRNA expression profile, Frontiers in Genetics, Vol: 12, ISSN: 1664-8021

MicroRNAs (miRNAs) can exhibit aberrant expression under different physiological and pathological conditions. Therefore, differentially expressed circulating miRNAs have been a focus of biomarker discovery research. However, the use of circulating miRNAs comes with challenges which may hinder the reliability for their clinical application. These include varied sample collection protocols, storage times/conditions, sample processing and analysis methods. This study focused on examining the effect of whole blood holding time on the stability of plasma miRNA expression profiles. Whole blood samples were collected from healthy pregnant women and were held at 4°C for 30 min, 2 h, 6 h or 24 h prior to processing for plasma isolation. Plasma RNA was extracted and the expression of 179 miRNAs were analyzed. Unsupervised principal component analysis demonstrated that whole blood holding time was a major source of variation in miRNA expression profiles with 53 of 179 miRNAs showing significant changes in expression. Levels of specific miRNAs previously reported to be associated with pregnancy-associated complications such as hsa-miR-150-5p, hsa-miR-191-5p, and hsa-miR-29a-3p, as well as commonly used endogenous miRNA controls, hsa-miR-16-5p, hsa-miR-25-3p, and hsa-miR-223-3p were significantly altered with increase in blood holding time. Current protocols for plasma-based miRNA profiling for diagnostics describe major differences in whole blood holding periods ranging from immediately after collection to 26 h after. Our results demonstrate holding time can have dramatic effects on analytical reliability and reproducibility. This highlights the importance of standardization of blood holding time prior to processing for plasma in order to minimize introduction of non-biological variance in miRNA profiles.

Journal article

Ng S, Chen M, Kundu S, Wang X, Zhou Z, Zheng Z, Qing W, Sheng H, Wang Y, He Y, Bennett PR, MacIntyre DA, Zhou Het al., 2021, Large-scale characterisation of the pregnancy vaginal microbiome and sialidase activity in a low-risk Chinese population, npj Biofilms and Microbiomes, Vol: 7, Pages: 1-11, ISSN: 2055-5008

Vaginal microbiota-host interactions are linked to preterm birth (PTB), which continues to be the primary cause of global childhood mortality. Due to population size, the majority of PTB occurs in Asia, yet there have been few studies of the pregnancy vaginal microbiota in Asian populations. Here, we characterized the vaginal microbiome of 2689 pregnant Chinese women using metataxonomics and in a subset (n = 819), the relationship between vaginal microbiota composition, sialidase activity and leukocyte presence and pregnancy outcomes. Vaginal microbiota were most frequently dominated by Lactobacillus crispatus or L. iners, with the latter associated with vaginal leukocyte presence. Women with high sialidase activity were enriched for bacterial vaginosis-associated genera including Gardnerella, Atopobium and Prevotella. Vaginal microbiota composition, high sialidase activity and/or leukocyte presence was not associated with PTB risk suggesting underlying differences in the vaginal microbiota and/or host immune responses of Chinese women, possibly accounting for low PTB rates in this population.

Journal article

Short C-E, Quinlan R, Preda V, Wang X, Smith A, Marchesi J, Lee Y, MacIntyre D, Bennett P, Taylor Get al., 2021, Vaginal microbiota, genital inflammation and extracellular matrix remodelling collagenase: MMP-9 in pregnant women with HIV, a potential preterm birth mechanism warranting further exploration, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-14, ISSN: 2235-2988

Background: Pregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria. Material and Methods: Cervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, cART exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored. Results: CVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1b, IL-8, IL-12 and TNF-a in both trimesters compared to HUPW (p≤0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1b(r=0.61), IL-8(r=0.57) and TNF-a(r=0.64), p<

Journal article

MacIntyre D, Mirzayi C, Renson A, Zohra F, Elsafoury S, Geistlinger L, Kasselman L, Eckenrode K, van de Wijgert J, Loughman A, Marques FZ, STORMS Consortium, Genomic Standards Consortium, Massive Analysis and Quality Control 8 Society, Segata N, Huttenhower C, Dowd JB, Jones HE, Waldron Let al., 2021, Reporting guidelines for human microbiome research: the STORMS checklist, Nature Medicine, Vol: 27, Pages: 1885-1892, ISSN: 1078-8956

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called ‘Strengthening The Organization and Reporting of Microbiome Studies’ (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

Journal article

Mitra A, MacIntyre DA, Paraskevaidi M, Moscicki A-B, Mahajan V, Smith A, Lee YS, Lyons D, Paraskevaidis E, Marchesi JR, Bennett PR, Kyrgiou Met al., 2021, The vaginal microbiota and innate immunity after local excisional treatment for cervical intraepithelial neoplasia, Genome Medicine: medicine in the post-genomic era, Vol: 13, ISSN: 1756-994X

Background:Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines.Methods:We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls.Results:Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1β and IL-8 remained significantly elevated pre- (p < 0.0001 and p = 0.0014, respectively) and post-treatment (p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p < 0.0001); however, their levels remained lower than controls post-treatment.Conclusions:Women with CIN hav

Journal article

Pruski P, Dos Santos Correia G, Lewis H, Capuccini K, Inglese P, Chan D, Brown R, Kindinger L, Lee Y, Smith A, Marchesi J, McDonald J, Cameron S, Alexander-Hardiman K, David A, Stock S, Norman J, Terzidou V, Teoh TG, Sykes L, Bennett P, Takats Z, MacIntyre Det al., 2021, Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth, Nature Communications, Vol: 12, ISSN: 2041-1723

The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n = 160; 455 swabs; VMET II, n = 205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics.

Journal article

Mitra A, MacIntyre D, Paraskevaidi M, Moscicki A-B, Mahajan V, Smith A, Lyons D, Paraskevaidis E, Marchesi J, Bennett P, Kyrgiou Met al., 2021, The vaginal microbiota and innate Immunity after local excisional treatment for cervical intraepithelial neoplasia, Publisher: BioMed Central

Background: Vaginal microbiota (VMB) are altered in women with cervical intra-epithelial neoplasia (CIN) and associate with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This interventional study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMPs levels in matched vaginal secretions. Analyses were performed to compare bacterial composition and immune analyte levels before and after CIN excision and in healthy controls.Results: Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV: 21/103, 20% vs 1/39, 3%, p=0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV: 19/103, 20% vs 1/39, 3%, p=0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1 and IL-8 remained significantly elevated pre- (p<0.0001 and p=0.0014 respectively) and post-treatment compared to untreated controls (p<0.0001 and p=0.0035 respectively). Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p<0.0001), however their levels remained lower than controls post-treatment.Conclusions: Women with CIN have increased prevalence of Lactobacillus spp. depleted, high-diversity V

Working paper

Grewal K, MacIntyre DA, Bennett PR, 2021, The reproductive tract microbiota in pregnancy, Bioscience Reports: molecular and cellular biology of the cell surface, Vol: 41, ISSN: 0144-8463

The reproductive tract microbiota plays a crucial role in maintenance of normal pregnancy and influences reproductive outcomes. Microbe-host interactions in pregnancy remain poorly understood and their role in shaping immune modulation is still being uncovered. In this review, we describe the composition of vaginal microbial communities in the reproductive tract and their association with reproductive outcomes. We also consider strategies for manipulating microbiota composition by using live biotherapeutics, selective eradication of pathogenic bacteria with antibiotics and vaginal microbiota transplantation. Finally, future developments in this field and the need for mechanistic studies to explore the functional significance of reproductive tract microbial communities are highlighted.

Journal article

Fourie H, Al-Memar M, Smith A, Ng S, Lee Y, Timmerman D, Bourne T, MacIntyre D, Bennett Pet al., 2021, The relationship between systemic oestradiol and vaginal microbiota composition in miscarriage and normal pregnancy, Publisher: OXFORD UNIV PRESS, Pages: 311-312, ISSN: 0268-1161

Conference paper

Chan D, Bennett PR, Lee YS, Teoh TG, Adan M, Ahmed SM, Brown RG, David AL, Lewis H, Gimeno-Molina B, Norman JE, Stock SJ, Terzidou V, Kropf P, Botto M, MacIntyre DA, Sykes Let al., 2021, Microbial-Driven Preterm Labour Involves Crosstalk between the Innate and Adaptive Immune Response., Publisher: SPRINGER HEIDELBERG, Pages: 108A-109A, ISSN: 1933-7191

Conference paper

Grewal K, Lee YS, Smith A, Brosens JJ, Bourne T, Al-Memar M, Kundu S, MacIntyre DA, Bennett Pet al., 2021, Euploid Miscarriage Is Associated with Lactobacillus spp. Deplete Vaginal Microbial Composition and Local Inflammation., Publisher: SPRINGER HEIDELBERG, Pages: 77A-77A, ISSN: 1933-7191

Conference paper

Bayar E, Zarasvand S, Adan M, Sykes L, Lee Y, Parks T, Lee P, MacIntyre D, Bennett Pet al., 2021, Acceptability of live vaginal biotherapeutics in a cohort of pregnant women, Publisher: WILEY, Pages: E32-E33, ISSN: 1470-0328

Conference paper

Budwig L, Brown R, Lee YS, Mountain K, Gimeno-Molina B, Adan M, Bayar E, MacIntyre DA, Bennett PR, Sykes Let al., 2021, The Use of Peripheral Blood Neutrophil Counts in the Prediction of Funisitis Following Preterm Prelabour Rupture of Membranes., Publisher: SPRINGER HEIDELBERG, Pages: 116A-116A, ISSN: 1933-7191

Conference paper

Bonnardel F, Haslam SM, Dell A, Feizi T, Liu Y, Tajadura-Ortega V, Akune Y, Sykes L, Bennett PR, MacIntyre DA, Lisacek F, Imberty Aet al., 2021, Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome, npj Biofilms and Microbiomes, Vol: 7, Pages: 1-10, ISSN: 2055-5008

Bacteria use carbohydrate-binding proteins (CBPs), such as lectins and carbohydrate-binding modules (CBMs), to anchor to specific sugars on host surfaces. CBPs in the gut microbiome are well studied, but their roles in the vagina microbiome and involvement in sexually transmitted infections, cervical cancer and preterm birth are largely unknown. We established a classification system for lectins and designed Hidden Markov Model (HMM) profiles for data mining of bacterial genomes, resulting in identification of >100,000 predicted bacterial lectins available at unilectin.eu/bacteria. Genome screening of 90 isolates from 21 vaginal bacterial species shows that those associated with infection and inflammation produce a larger CBPs repertoire, thus enabling them to potentially bind a wider array of glycans in the vagina. Both the number of predicted bacterial CBPs and their specificities correlated with pathogenicity. This study provides new insights into potential mechanisms of colonisation by commensals and potential pathogens of the reproductive tract that underpin health and disease states.

Journal article

Mowla S, Bennett P, MacIntyre D, 2021, The vaginal microbiome, NEW GENETIC DIAGNOSTIC TECHNOLOGIES IN REPRODUCTIVE MEDICINE 2E, Editors: Simon, Rubio

There is now substantial evidence implicating the vaginal microbiome in reproductive tract health and disease. As technology has developed, our ability to characterise the composition of the vaginal microbiome has improved providing new insights into how commensal and pathogenic microbes interact with the host to protect against, or potentiate pathology and disease. In this chapter we discuss the current understanding of what shapes the structure of the vaginal microbiome throughout a woman’s life span, how it can be characterised and how specific microbiota-host interactions at the mucosal interface may influence reproductive success or failure.

Book chapter

Semertzidou A, MacIntyre D, Marchesi J, Bennett P, Kyrgiou Met al., 2021, The role of genital tract microbiota continuum in endometrial malignancy, Publisher: WILEY, Pages: 115-116, ISSN: 1470-0328

Conference paper

Raglan O, MacIntyre D, Mitra A, Lee Y, Smith A, Assi N, Nautiyal J, Purkayastha S, Gunter M, Gabra H, Marchesi J, Bennett P, Kyrgiou Met al., 2021, The association between obesity and weight loss after bariatric surgery on the vaginal microbiota, Microbiome, ISSN: 2049-2618

<h4>Background: </h4> Obesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery. <h4>Methods: </h4>: Vaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery. <h4>Results: </h4>: The bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of a Lactobacillus -dominant VMB and higher prevalence of a high diversity ( Lactobacillus spp., and Gardnerella - spp. depleted) VMB, compared with non-obese subjects (p<0.001). Obese women had higher relative abundance of Dialister species (p<0.001), Anaerococcus vaginalis (p=0.021) and Prevotella timonensis (p=0.020) and decreased relative abundance of Lactobacillus crispatus (p=0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α, and TNFα levels were all higher among obese women, however only IL-1β and IL-8 correlated with VMB species diversity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery, however 75% of these women remained obese at six months. Prior to surgery there was no relationship between body mass index (BMI) and VMB structure, however post-surgery women with a Lactobacillus -dominant VMB had a significantly lower BMI than those with a high diversity VMB. <h4>Conclusions: </h4>: Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compare

Journal article

Raglan O, MacIntyre D, Mitra A, Lee YS, Smith A, Assi N, Nautiyal J, Purkayastha S, Gunter MJ, Gabra H, Marchesi JR, Bennett P, Kyrgiou Met al., 2021, The association between obesity and weight loss after bariatric surgery on the vaginal microbiota, Microbiome, Vol: 9, Pages: 1-17, ISSN: 2049-2618

Background: Obesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery.Methods: Vaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery. Results: The bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of a Lactobacillus-dominant VMB and higher prevalence of a high diversity (Lactobacillus spp., and Gardnerella- spp. depleted) VMB, compared with non-obese subjects (p<0.001). Obese women had higher relative abundance of Dialister species (p<0.001), Anaerococcus vaginalis (p=0.021) and Prevotella timonensis (p=0.020) and decreased relative abundance of Lactobacillus crispatus (p=0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α, and TNFα levels were all higher among obese women, however only IL-1β and IL-8 correlated with VMB species diversity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery, however 75% of these women remained obese at six months. Prior to surgery there was no relationship between body mass index (BMI) and VMB structure, however post-surgery women with a Lactobacillus-dominant VMB had a significantly lower BMI than those with a high diversity VMB.Conclusions: Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compared to non-obese women. Bariatric surgery does not change the VMB, however, those with the greatest

Journal article

Quenby S, Gallos I, Dhillon-Smith R, Podesek M, Stephenson M, Fisher J, Brosens J, Brewin J, Ramhorst R, Lucas E, McCoy R, Anderson R, Daher S, Regan L, Al-Memar M, Bourne T, MacIntyre D, Rai R, Christiansen O, Sugiura-Ogasawara M, Odendaal J, Devall A, Bennett P, Petrou S, Coomarasamy Aet al., 2021, Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss, The Lancet, Vol: 397, Pages: 1658-1667, ISSN: 0140-6736

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need

Journal article

Semertzidou A, Macintyre D, Marchesi J, Bennett P, Kyrgiou Met al., 2021, THE ROLE OF GENITAL TRACT MICROBIOTA CONTINUUM IN ENDOMETRIAL MALIGNANCY, Publisher: BMJ PUBLISHING GROUP, Pages: A135-A135, ISSN: 1048-891X

Conference paper

Short C-E, Brown R, Quinlan R, Lee Y, Smith A, Marchesi J, Shattock R, Bennett P, Taylor G, MacIntyre Det al., 2021, Lactobacillus-depleted vaginal microbiota in pregnant women living with HIV-1 infection are associated with increased local inflammation and preterm birth, Frontiers in Cellular and Infection Microbiology, Vol: 10, ISSN: 2235-2988

Background: Pregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.Methods: Prospective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.Findings: There was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.Interpretation: There is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.

Journal article

Kim SH, MacIntyre D, Binkhamis R, Cook J, Sykes L, Bennett P, Terzidou Vet al., 2020, Maternal plasma miRNAs as potential biomarkers for detecting risk of small-for-gestational-age births, EBioMedicine, Vol: 62, ISSN: 2352-3964

BackgroundSmall-for-gestational-age fetuses (SGA) (birthweight <10th centile) are at high risk for stillbirth or long-term adverse outcomes. Here, we investigate the ability of circulating maternal plasma miRNAs to determine the risk of SGA births.MethodsMaternal plasma samples from 29 women of whom 16 subsequently delivered normally grown babies and 13 delivered SGA (birthweight <5th centile) were selected from a total of 511 women recruited to form a discovery cohort in which expression data for a total of 800 miRNAs was determined using the Nanostring nCounter miRNA assay. Validation by RT-qPCR was performed in an independent cohort.FindingsPartial least-squares discriminant analysis (PLS-DA) of the Nanostring nCounter miRNA assay initially identified seven miRNAs at 12–14+6 weeks gestation, which discriminated between SGA cases and controls. Four of these were technically validated by RT-qPCR. Differential expression of two miRNA markers; hsa-miR-374a-5p (p = 0•0176) and hsa-let-7d-5p (p = 0•0036), were validated in an independent population of 95 women (SGA n = 12, Control n = 83). In the validation cohort, which was enriched for SGA cases, the ROC AUCs were 0•71 for hsa-miR-374a-5p, and 0•74 for hsa-let-7d-5p, and 0•77 for the two combined.InterpretationWhilst larger population-wide studies are required to validate their performance, these findings highlight the potential of circulating miRNAs to act as biomarkers for early prediction of SGA births.

Journal article

Bennett PR, Brown RG, MacIntyre DA, 2020, Vaginal microbiome in preterm rupture of membranes, Obstetrics and Gynecology Clinics of North America, Vol: 47, Pages: 503-521, ISSN: 0889-8545

Journal article

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