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

198 results found

Grewal K, MacIntyre DA, Bennett PR, 2021, The reproductive tract microbiota in pregnancy., Biosci Rep, Vol: 41

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

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, ISSN: 2041-1723

Journal article

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

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

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

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

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

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

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Lactobacillus crispatus</jats:italic> or <jats:italic>L. iners</jats:italic>, with the latter associated with vaginal leukocyte presence. Women with high sialidase activity were enriched for bacterial vaginosis-associated genera including <jats:italic>Gardnerella, Atopobium</jats:italic> and <jats:italic>Prevotella</jats:italic>. 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.</jats:p><jats:sec><jats:title>Importance</jats:title><jats:p>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 <jats:italic>Lactobacillus crispatus</jats:italic> or <jats:italic>L. iners<

Journal article

Whelan E, Kalliala I, Semertzidou A, Raglan O, Bowden S, Markozannes G, Cividini S, Kechagias K, McNeish I, Marchesi J, MacIntyre D, Bennett P, Tsilidis K, Kyrgiou Met al., 2021, Risk factors for ovarian cancer: an umbrella review of the literature, Publisher: WILEY, Pages: 71-71, ISSN: 1470-0328

Conference paper

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 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

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

MacIntyre D, Bennett P, 2020, Chapter 3 - Microbial signatures of preterm birth, The Human Microbiome in Early Life Implications to Health and Disease, Publisher: Academic Press, ISBN: 9780128180976

Preterm birth remains the primary cause of death in children under the age of 5 years worldwide. A causal relationship between infection and preterm birth has long been recognized. However, recent applications of molecular-based profiling techniques have provided new insights into the relationship between specific bacterial compositions of the lower reproductive tract and subsequent preterm birth risk. In this chapter, we investigate evidence for “microbial signatures” of preterm birth and examine mechanisms by which shifts in microbiome composition could contribute to an infectious etiology of preterm birth. Despite high levels of heterogeneity between studies, vaginal depletion of Lactobacillus spp. and high-diversity communities enriched for potentially pathogenic bacteria are frequently associated with preterm birth, whereas Lactobacillus spp. dominant communities appear to confer protection against preterm birth, particularly when dominated by Lactobacillus crispatus. Strategies focused toward promoting optimal microbial signatures during pregnancy may help reduce rates of preterm birth and improve maternal and neonatal outcomes.

Book chapter

Paraskevaidi M, Cameron SJS, Whelan E, Bowden S, Tzafetas M, Mitra A, Semertzidou A, Athanasiou A, Bennett P, MacIntyre D, Takats Z, Kyrgiou Met al., 2020, Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening, EBioMedicine, Vol: 60, ISSN: 2352-3964

BackgroundThe introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed.MethodsIn this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening.FindingsIn a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease.InterpretationThis automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme.

Journal article

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., 2020, Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome, Publisher: Nature Research

<jats:title>Abstract</jats:title><jats:p>Bacteria use protein receptors called lectins to anchor to specific host surface sugars. The role of lectins in the vaginal microbiome, and their involvement in reproductive tract pathophysiology is poorly defined. Here we establish a classification system based on taxonomy and protein 3D structure to identify 109 lectin classes. Hidden Markov Model (HMM) profiles for each class were used to search bacterial genomes, resulting in the prediction of &gt;100 000 bacterial lectins available at unilectin.eu/bacteria. Genome screening of 90 isolates from 21 vaginal bacterial species showed that potential pathogens produce a larger variety of lectins than commensals indicating increased glycan-binding potential. Both the number of predicted bacterial lectins, and their specificities for carbohydrates correlated with pathogenicity. This study provides new insights into potential mechanisms of commensal and pathogen colonisation of the reproductive tract that underpin health and disease states.</jats:p>

Working paper

Bayar E, Bennett PR, Chan D, Sykes L, MacIntyre Det al., 2020, The pregnancy microbiome and preterm birth, Springer Seminars in Immunopathology, Vol: 42, Pages: 487-499, ISSN: 1863-2297

Preterm birth is a global health concern and continues to contribute to substantial neonatal morbidity and mortality despite advances in obstetric and neonatal care. The underlying aetiology is multi-factorial and remains incompletely understood. In this review, the complex interplay between the vaginal microbiome in pregnancy and its association with preterm birth is discussed in depth. Advances in the study of bacteriology and an improved understanding of the human microbiome have seen an improved awareness of the vaginal microbiota in both health and in disease.

Journal article

Tzafetas M, Mitra A, Paraskevaidi M, Bodai Z, Kalliala I, Bowden S, Lathouras K, Rosini F, Szasz M, Savage A, Manoli E, Balog J, McKenzie J, Lyons D, Bennett P, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2020, The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease (vol 117, pg 7338, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 18892-18892, ISSN: 0027-8424

Journal article

Rasheed ZBM, Lee YS, Kim SH, Rai RK, Ruano CSM, Anucha E, Sullivan MHF, MacIntyre DA, Bennett PR, Sykes Let al., 2020, Differential response of gestational tissues to TLR3 viral priming prior to exposure to bacterial TLR2 and TLR2/6 agonists, Frontiers in Immunology, Vol: 11, Pages: 1-27, ISSN: 1664-3224

Background: Infection/inflammation is an important causal factor in spontaneous preterm birth (sPTB). Most mechanistic studies have concentrated on the role of bacteria, with limited focus on the role of viruses in sPTB. Murine studies support a potential multi-pathogen aetiology in which a double or sequential hit of both viral and bacterial pathogens leads to a higher risk preterm labour. This study aimed to determine the effect of viral priming on bacterial induced inflammation in human in vitro models of ascending and haematogenous infection.Methods: Vaginal epithelial cells, and primary amnion epithelial cells and myocytes were used to represent cell targets of ascending infection while interactions between peripheral blood mononuclear cells (PBMCs) and placental explants were used to model systemic infection. To model the effect of viral priming upon the subsequent response to bacterial stimuli, each cell type was stimulated first with a TLR3 viral agonist, and then with either a TLR2 or TLR2/6 agonist, and responses compared to those of each agonist alone. Immunoblotting was used to detect cellular NF-κB, AP-1, and IRF-3 activation. Cellular TLR3, TLR2, and TLR6 mRNA was quantified by RT-qPCR. Immunoassays were used to measure supernatant cytokine, chemokine and PGE2 concentrations.Results: TLR3 (“viral”) priming prior to TLR2/6 agonist (“bacterial”) exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased m

Journal article

Mitra A, MacIntyre D, Ntritsos G, Smith A, Tsilidis K, Marchesi J, Bennett P, moscicki A-B, Kyrgiou Met al., 2020, The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions, Nature Communications, Vol: 11, Pages: 1-13, ISSN: 2041-1723

Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.

Journal article

MacIntyre D, Beagley K, 2020, The immune system of the genitourinary tract, Principles of Mucosal Immunology, Publisher: Garland Science, ISBN: 9781000754490

The human genitourinary tract is characterized by a complex system of compartmentalized, highly integrated tissues, finely tuned hormonal regulation, and an immune system that has some similarities to, but also distinct differences from, the gastrointestinal immune system. Innate and adaptive immune defenses in the genitourinary tract influence, and are influenced by, the composition of commensal microbial communities, which provide a degree of protection against sexually transmitted diseases. The mucosal immune system in the female reproductive tract contains an array of protective mechanisms that are under hormonal control. Immune cell organization varies with tissue and stage of the menstrual cycle. Sex hormones also regulate immune-cell function in tissues of the female reproductive tract as the immune system faces the unique challenge of protecting tissues that are changing shape, thickness, and vascularity. The mucosal immune system in the male and female human reproductive tracts has evolved to meet the unique requirements of procreation and host defense against genital tract pathogens.

Book chapter

Tzafetas M, Mitra A, Paraskevaidi M, Bodai Z, Kalliala I, Bowden S, Lathouras K, Rosini F, Szasz M, Savage A, Balog J, McKenzie J, Lyons D, Bennett P, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2020, The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 7338-7346, ISSN: 0027-8424

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.

Journal article

Grewal K, Lee YS, Smith A, Al-Memar M, Bourne T, MacIntyre DA, Bennett Pet al., 2020, Euploid Miscarriage is Associated with Lactobacillus spp. Deplete Vaginal Microbial Composition and Local Inflammation., 67th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SPRINGER HEIDELBERG, Pages: 65A-65A, ISSN: 1933-7191

Conference paper

Budwig L, Brown R, Lee YS, Adan M, Bayar E, MacIntyre DA, Bennett PR, Sykes Let al., 2020, The Use of Peripheral Blood Neutrophil Counts in the Prediction of Funisitis Following Preterm Prelabour Rupture of Membranes., 67th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SPRINGER HEIDELBERG, Pages: 212A-212A, ISSN: 1933-7191

Conference paper

Hua R, Edey LF, O'Dea KP, Howe L, Herbert BR, Cheng W, Zheng X, MacIntyre DA, Bennett PR, Takata M, Johnson MRet al., 2020, CCR2 mediates the adverse effects of LPS in the pregnant mouse, Biology of Reproduction, Vol: 102, Pages: 445-455, ISSN: 0006-3363

In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10-μg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild-type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta, and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 h in both groups of mice. At 7 h post-injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung, and liver. At 7 h post-LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation were similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.

Journal article

Al-Memar M, Bobdiwala S, Fourie H, Manino R, Lee YS, Smith A, Marchesi JR, Timmerman D, Bourne T, Bennett PR, MacIntyre DAet al., 2020, The association between vaginal bacterial composition and miscarriage: a nested case-control study, BJOG: an International Journal of Obstetrics and Gynaecology, Vol: 127, Pages: 264-274, ISSN: 1470-0328

OBJECTIVE: To characterise vaginal bacterial composition in early pregnancy and investigate its relationship with first and second trimester miscarriages. DESIGN: Nested case-control study. SETTING: Queen Charlotte's and Chelsea Hospital, Imperial College Healthcare NHS Trust, London. POPULATION: 161 pregnancies; 64 resulting in first trimester miscarriage, 14 in second trimester miscarriage and 83 term pregnancies. METHODS: Prospective profiling and comparison of vaginal bacteria composition using 16S rRNA gene-based metataxonomics from 5 weeks gestation in pregnancies ending in miscarriage or uncomplicated term deliveries matched for age, gestation and body-mass index. MAIN OUTCOME MEASURES: Relative vaginal bacteria abundance, diversity and richness. Pregnancy outcomes defined as first or second trimester miscarriage, or uncomplicated term delivery. RESULTS: First trimester miscarriage associated with reduced prevalence of Lactobacillus spp.-dominated vaginal microbiota classified using hierarchical clustering analysis (65.6% vs. 87·7%; P=0·005), higher alpha diversity (mean Inverse Simpson Index 2.5 (95% confidence interval 1.8-3.0) vs. 1.5 (1.3-1.7), P=0·003) and higher richness 25.1 (18.5-31.7) vs. 16.7 (13.4-20), P=0·017), compared to viable pregnancies. This was independent of vaginal bleeding and observable before first trimester miscarriage diagnosis (P=0·015). Incomplete/complete miscarriage associated with higher proportions of Lactobacillus spp.-deplete communities compared to missed miscarriage. Early pregnancy vaginal bacterial stability was similar between miscarriage and term pregnancies. CONCLUSIONS: These findings associate the bacterial component of vaginal microbiota with first trimester miscarriage and indicate suboptimal community composition is established in early pregnancy. While further studies are required to elucidate the mechanism, vaginal bacterial composition may represent a modifiable risk factor fo

Journal article

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