| 1. |
- Bashir, Zahra, et al.
(författare)
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Investigations of microbiota composition and neuroactive pathways in association with symptoms of stress and depression in a cohort of healthy women
- 2024
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite mounting evidence of gut-brain involvement in psychiatric conditions, functional data remain limited, and analyses of other microbial niches, such as the vaginal microbiota, are lacking in relation to mental health. This aim of this study was to investigate if the connections between the gut microbiome and mental health observed in populations with a clinical diagnosis of mental illness extend to healthy women experiencing stress and depressive symptoms. Additionally, this study examined the functional pathways of the gut microbiota according to the levels of psychological symptoms. Furthermore, the study aimed to explore potential correlations between the vaginal microbiome and mental health parameters in young women without psychiatric diagnoses.Methods: In this cross-sectional study, 160 healthy Danish women (aged 18-40 years) filled out questionnaires with validated scales measuring symptoms of stress and depression and frequency of dietary intake. Fecal and vaginal microbiota samples were collected at the beginning of the menstrual cycle and vaginal samples were also collected at cycle day 8-12 and 18-22. Shotgun metagenomic profiling of the gut and vaginal microbiome was performed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for functional profiling and 56 Gut Brain Modules were analyzed in the fecal samples.Results: The relative abundance in the gut of the genera Escherichia, Parabacteroides, and Shigella was higher in women with elevated depressive symptoms. Women with high perceived stress showed a tendency of increased abundance of Escherichia, Shigella, and Blautia. Amongst others, the potentially pathogenic genera, Escherichia and Shigella correlate with alterations in the neuroactive pathways such as the glutamatergic, GABAeric, dopaminergic, and Kynurenine pathways. Vaginosis symptoms were more prevalent in women reporting high levels of stress and depressive symptoms.Conclusions: The findings of this study support the concept of a microbiota-associated effect on the neuroactive pathways even in healthy young women. This suggest, that targeting the gut microbiome could be a promising approach for future psychiatric interventions.
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| 2. |
- Bradley, Frideborg, et al.
(författare)
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Multi-omics analysis of the cervical epithelial integrity of women using depot medroxyprogesterone acetate
- 2022
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 18:5
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Tidskriftsartikel (refereegranskat)abstract
- Depot medroxyprogesterone acetate (DMPA) is an injectable hormonal contraceptive used by millions of women worldwide. However, experimental studies have associated DMPA use with genital epithelial barrier disruption and mucosal influx of human immunodeficiency virus (HIV) target cells. We explored the underlying molecular mechanisms of these findings. Ectocervical biopsies and cervicovaginal lavage (CVL) specimens were collected from HIV-seronegative Kenyan sex workers using DMPA (n = 32) or regularly cycling controls (n = 64). Tissue samples were assessed by RNA-sequencing and quantitative imaging analysis, whereas protein levels were measured in CVL samples. The results suggested a DMPA-associated upregulation of genes involved in immune regulation, including genes associated with cytokine-mediated signaling and neutrophil-mediated immunity. A transcription factor analysis further revealed DMPA-associated upregulation of RELA and NFKB1 which are involved in several immune activation pathways. Several genes significantly downregulated in the DMPA versus the control group were involved in epithelial structure and function, including genes encoding keratins, small proline-rich proteins, and cell-cell adhesion proteins. Pathway analyses indicated DMPA use was associated with immune activation and suppression of epithelium development, including keratinization and cornification processes. The cervicovaginal microbiome composition (Lactobacillus dominant and non-Lactobacillus dominant) had no overall interactional impact on the DMPA associated tissue gene expression. Imaging analysis verified that DMPA use was associated with an impaired epithelial layer as illustrated by staining for the selected epithelial junction proteins E-cadherin, desmoglein-1 and claudin-1. Additional staining for CD4(+) cells revealed a more superficial location of these cells in the ectocervical epithelium of DMPA users versus controls. Altered protein levels of SERPINB1 and ITIH2 were further observed in the DMPA group. Identification of specific impaired epithelial barrier structures at the gene expression level, which were verified at the functional level by tissue imaging analysis, illustrates mechanisms by which DMPA adversely may affect the integrity of the genital mucosa. Author summarySexual transmission accounts for the majority of all new HIV infections in women, and alterations to the mucosal environment of the female genital tract have been associated with an increase in the risk of acquiring HIV. Observational epidemiological studies have implied that the use of the injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with increased HIV-acquisition. However, a prospective clinical study has not confirmed this association and the controversial findings are currently evaluated in the context of international reproductive health policies. Several studies using various model systems indicate that DMPA affects the integrity of the genital epithelial barrier as well as the mucosal immune system, but the exact mechanisms remain largely unknown. To characterize the effect of DMPA on the genital mucosal environment, we used a multi-omics approach to assess paired genital secretions and cervical tissue samples from long-term regular DMPA users living in Kenya. This unique cohort represents a population at risk of HIV infection in which DMPA is one of the most commonly used hormonal contraceptives. We identified impaired cervical epithelial barrier structures, including DMPA-associated reduction in the expression of cell-cell adhesion molecules, keratins, small proline-rich proteins and a thinner upper epithelial layer with more superficially located CD4(+) cells. Gene set enrichment pathway analyses indicated DMPA use was associated with immune activation and suppression of epithelium development including keratinization and cornification pathways. Protein analysis identified altered levels of selected anti-proteases. Our findings illustrate mechanisms by which DMPA adversely may affect the integrity of the genital mucosa.
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| 3. |
- Edfeldt, Gabriella, et al.
(författare)
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Distinct cervical tissue-adherent and luminal microbiome communities correlate with mucosal host gene expression and protein levels in Kenyan sex workers
- 2023
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Ingår i: Microbiome. - : Springer Nature. - 2049-2618. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The majority of studies characterizing female genital tract microbiota have focused on luminal organisms, while the presence and impact of tissue-adherent ectocervical microbiota remain incompletely understood. Studies of luminal and tissue-associated bacteria in the gastrointestinal tract suggest that these communities may have distinct roles in health and disease. Here, we performed a multi-omics characterization of paired luminal and tissue samples collected from a cohort of Kenyan female sex workers.Results We identified a tissue-adherent bacterial microbiome, with a higher alpha diversity than the luminal microbiome, in which dominant genera overall included Gardnerella and Lactobacillus, followed by Prevotella, Atopobium, and Sneathia. About half of the L. iners-dominated luminal samples had a corresponding Gardnerella-dominated tissue microbiome. Broadly, the tissue-adherent microbiome was associated with fewer differentially expressed host genes than the luminal microbiome. Gene set enrichment analysis revealed that L. crispatus-dominated tissue-adherent communities were associated with protein translation and antimicrobial activity, whereas a highly diverse microbial community was associated with epithelial remodeling and pro-inflammatory pathways. Tissue-adherent communities dominated by L. iners and Gardnerella were associated with lower host transcriptional activity. Tissue-adherent microbiomes dominated by Lactobacillus and Gardnerella correlated with host protein profiles associated with epithelial barrier stability, although with a more pro-inflammatory profile for the Gardnerella-dominated microbiome group. Tissue samples with a highly diverse composition had a protein profile representing cell proliferation and pro-inflammatory activity.Conclusion We identified ectocervical tissue-adherent bacterial communities in all study participants of a female sex worker cohort. These communities were distinct from cervicovaginal luminal microbiota in a significant proportion of individuals. We further revealed that bacterial communities at both sites correlated with distinct host gene expression and protein levels. The tissue-adherent bacterial community could possibly act as a reservoir that seed the lumen with less optimal, non-Lactobacillus, bacteria.
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| 4. |
- Edfeldt, Gabriella
(författare)
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Epithelial barrier protection : implications for HIV susceptibility
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The majority of HIV infections today occur through sexual HIV transmission. The female genital mucosa offers a barrier against incoming pathogens. Although, studies show that the vaginal microbiome, co-current infections and local inflammation, the use of hormonal contraceptives and microbicides, can weaken this protective lining. In this thesis in situ digital image analysis workflows were developed and used together with protein profiling, to characterize the effects of such factors on the genital mucosal barrier integrity and the immune cells therein. Topically applied microbicides can protect against HIV. In paper I we introduced image analysis as a refined tool for evaluation of microbicide safety. We confirmed that a promising microbicide candidate, Q-GRFT, had no negative effect on the rectal epithelium while causing a small, but probably biologically negligible, increase in CD4+ HIV target cells. We also discovered potential effects of multiple biopsy sampling that should be considered when designing pre-clinical studies. Specific tissue resident immune cells with an effector memory phenotype have a rapid response against re-infections and may be important against HIV infection. In paper II, we observed that HIV infected women had increased levels of CD103-CD8+ tissue resident memory cells compared to uninfected women, and that this may be due to a recent influx of these effector cells that have not yet upregulated the CD103 retention molecule. In paper III we revealed that women taking the hormonal contraceptive DMPA, had a thinner superficial layer of the female genital mucosa. Lack of this protective layer in combination with having more HIV target cells located closer to the vaginal lumen, could contribute to the increased HIV risk in women taking DMPA. In paper IV we discovered that Lactobacillus non-iners dominated women had a more intact epithelium, and Gardnerella dominated women had a different spatial localization of CD4+ cells in the epithelium. Secreted protein profiles from Lactobacillus dominant women had elevated levels of anti-inflammatory and epithelial barrier proteins compared to non-Lactobacillus dominant women. These factors may contribute to reduced HIV risk in Lactobacillus-dominant women. The results of this thesis highlight the benefits of using digital image analysis as a tool for studying spatial and structural changes in the mucosal tissue barrier and the immune cell landscape therein. We showed potential mechanisms in how different factors increase the HIV risk. These findings will support development of interventions aimed to strengthen the mucosal barrier, and thereby reduce transmission of sexually transmitted infections.
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| 5. |
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| 6. |
- Edfeldt, Gabriella, et al.
(författare)
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Regular Use of Depot Medroxyprogesterone Acetate Causes Thinning of the Superficial Lining and Apical Distribution of Human Immunodeficiency Virus Target Cells in the Human Ectocervix
- 2022
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 225:7, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with an increased risk of acquiring human immunodeficiency virus (HIV). We hypothesize that DMPA use influences the ectocervical tissue architecture and HIV target cell localization.MethodsQuantitative image analysis workflows were developed to assess ectocervical tissue samples collected from DMPA users and control subjects not using hormonal contraception.ResultsCompared to controls, the DMPA group exhibited a significantly thinner apical ectocervical epithelial layer and a higher proportion of CD4+CCR5+ cells with a more superficial location. This localization corresponded to an area with a nonintact E-cadherin net structure. CD4+Langerin+ cells were also more superficially located in the DMPA group, although fewer in number compared to the controls. Natural plasma progesterone levels did not correlate with any of these parameters, whereas estradiol levels were positively correlated with E-cadherin expression and a more basal location for HIV target cells of the control group.ConclusionsDMPA users have a less robust epithelial layer and a more apical distribution of HIV target cells in the human ectocervix, which could confer a higher risk of HIV infection. Our results highlight the importance of assessing intact genital tissue samples to gain insights into HIV susceptibility factors.
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| 10. |
- Günaydin, Gökce, et al.
(författare)
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Impact of Q-Griffithsin anti-HIV microbicide gel in non-human primates : In situ analyses of epithelial and immune cell markers in rectal mucosa
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin(+) cells, CD4(+) cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin(+) cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4(+) cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4(+) cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4(+) lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4(+) rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa.
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