Project description:The hormonal contraceptive medroxyprogesterone acetate (MPA) is associated with increased risk of human immunodeficiency virus (HIV), via incompletely understood mechanisms. Increased diversity in the vaginal microbiota modulates genital inflammation and is associated with increased HIV-1 acquisition. However, the effect of MPA on diversity of the vaginal microbiota is relatively unknown. In a cohort of female Kenyan sex workers, negative for sexually transmitted infections (STIs), with Nugent scores <7 (N=58 of 370 screened), MPA correlated with significantly increased diversity of the vaginal microbiota as assessed by 16S rRNA gene sequencing. MPA was also significantly associated with decreased levels of estrogen in the plasma, and low vaginal glycogen and α-amylase, factors implicated in vaginal colonization by lactobacilli, bacteria that are believed to protect against STIs. In a humanized mouse model, MPA treatment was associated with low serum estrogen, low glycogen and enhanced HIV-1 susceptibility. The mechanism by which the MPA mediated changes in the vaginal microbiota may contribute to HIV-1 susceptibility in humans appears to be independent of inflammatory cytokines and/or activated T cells. Altogether, these results suggest MPA-induced hypo-estrogenism may alter key metabolic components that are necessary for vaginal colonization by certain bacterial species including lactobacilli, and allow for greater bacterial diversity in the vaginal microbiota.
Project description:Human breast milk (BM) plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. BM contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). However, to date, most studies on BMEVs have been limited in sample size. We aimed to investigate BMEV-miRNA profiles in a human population cohort, characterize BMEV-miRNAs patterns, and assess potential pathways and ontology. We thus conducted the first study to describe the EV miRNA profile of BM in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1,523 miRNAs with ≥ one read in 70% of samples, and 447 miRNAs with ≥ one read in 100% of samples. Using hierarchical clustering, we determined five BMEV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster BMEV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. Future studies investigating determinants of BMEV-miRNAs and associated health outcomes are needed to elucidate the role of BMEV-miRNAs in health and disease.
Project description:In this study we performed data-independet mass-spectrometry analysis of blood plasma collected from a cohort consisting of people living with HIV-1, people living with HIV-2, and HIV seronegative individuals. The data was used to infer signs of damage to a wide array of tissues and cell types.
Project description:Human milk (HM) contains an array of regulatory biomolecules including miRNAs, the origin, properties, distribution and functional significance of which are still undetermined. In this study, we used the TaqMan OpenArray System to profile 681 human mature miRNAs in two fractions of HM (cells and lipids) collected from healthy mothers in month 2 of lactation (n=10). Comparisons were performed with maternal peripheral blood mononuclear cells (PBMCs) and plasma collected from the same individuals, as well as with a bovine- and a soy-based infant formulae. HM cells (292 miRNAs) and PBMCs (345 miRNAs) had higher miRNA content than HM lipids (242 miRNAs) and plasma (219 miRNAs), respectively (p<0.05). Despite the wide variation in miRNA profiles and expression between mothers, a strong association was found between HM cells and lipids within a mother, whilst PBMCs and plasma were distinctly different to the two milk fractions, with plasma displaying marked inter-individual variation. Considering the dominance of epithelial cells in mature milk of healthy women, these results suggest that HM cell and lipid miRNAs primarily originate from the mammary epithelium, whilst the maternal circulation may have a smaller contribution. Infant formulae contained very few human miRNA compared to HM. Our findings demonstrate that unlike infant formulae, human milk is a rich source of lactation-specific miRNA, which could be used as a biomarker of the performance and health status of the lactating gland. Given the recently identified stability and gene regulatory functions of food-derived miRNAs, HM miRNAs may contribute to infant protection and development.