Biology subjects

Jasarevic, E.

Publications and source records attributed to Jasarevic, E..

10 recordsLinked to original sources

bioRxiv2025

Phylosymbiosis in the making: Host-associated microbiota and host gene expression profiles exhibit discordant timing of phylogenetic congruence over early mammalian development

Gut microbial communities often mirror host phylogenetic relationships, an eco-evolutionary pattern known as phylosymbiosis. While phylosymbiosis is well documented in adult mammals, the developmental timing and mechanisms underlying its emergence remain unknown. Here, we use four captive-bred species of Peromyscus mice, a powerful model for studying natural variation in animal biology, to investigate the assembly of the intestinal microbiota and the emergence of phylosymbiotic signatures from birth through weaning. We combine 16S rRNA microbiome profiling with whole-tissue transcriptomics across three developmental stages (newborn, pre-weaning, and weaning) to test when during development the microbiome and host transcriptome exhibit evolutionary signatures. While parental feces and maternal mammary skin harbored phylosymbiotic communities, the intestines of newborn pups did not. Phylosymbiosis only emerged in pups at the pre-weaning stage of development and was sustained through weaning. Gut microbial diversity increased with age across species, and developmental stage was a stronger driver of community composition than host species identity, with a 1.5-2x larger effect size. Strikingly, host gene expression profiles showed the opposite pattern: transcriptome-based dendrograms were congruent with host phylogeny only at birth, not at later stages. Gene co-expression modules that showed correlation with host phylogenetic distance at birth were mainly enriched for metabolic pathways, such as lysosome activity, fat and vitamin digestion and absorption, and glycan metabolism. This work provides the first evidence, to our knowledge, in vertebrates that phylosymbiosis is not a fixed property of host-microbiome systems, but an emergent feature with distinct developmental dynamics in both the microbiome and the host transcriptome. Our results begin to reveal the complex and dynamic nature by which mammalian host-microbiome relationships are established and maintained across both evolutionary and developmental and time scales.

evolutionary biology↗

bioRxiv2025

Adolescent girls at familial risk for depression with more advanced adrenarche have altered gut microbiota

ObjectivesRates of adolescent depression are rising, especially among girls, with children of depressed parents facing a three times higher risk. Emerging evidence suggests a link between gut microbiota, neural function, and depression risk, possibly through pathways that involve brain-body interactions, including the vagus nerve. During adolescence, sex-specific changes in the microbiota align with pubertal development, although their connection to depression vulnerability remains unclear. We compared gut microbiota in adolescents at high and low familial risk for depression and explored whether differences are affected by vagal activity and pubertal stage. MethodsWe collected clinical assessments, physiological data, and stool samples from 52 adolescents (aged 9-15, including 31 females), consisting of 27 high-risk and 25 low-risk individuals. We used 16S rRNA marker gene sequencing to analyze the diversity, structure, composition, and predicted function of the microbial community. A laboratory stressor task was employed to examine changes in vagally mediated heart rate variability (stress reactivity). Regressions were used to assess the relationship between depression risk, gut microbiota, and cardiovascular stress reactivity indices. Exploratory analyses investigated the effects of sex, age, and pubertal stage (adrenarche and gonarche). ResultsHigh-risk adolescents exhibited a distinct gut microbiota profile compared to low-risk adolescents, with this effect primarily driven by female participants. This profile was characterized by a higher abundance of Prevotella, which was 2-fold higher in high-risk females, and lower levels of other beneficial genera. High-risk females were also significantly more advanced in adrenarcheal development; the link between depression risk and adrenarcheal development was mediated by gut microbiota in females. Cardiovascular stress reactivity did not differ between groups and was not linked to gut microbiota. ConclusionsOur results reveal sex-specific links between depression risk, adrenarcheal development, and gut microbiota in adolescence. The increase of Prevotella in high-risk females suggests inflammation-related pathways may connect familial vulnerability to mood disorders. Future long-term studies examining hormones, microbiota, and mood during pubertal changes are essential to determine causality and develop targeted treatments.

neuroscience↗

bioRxiv2024

The microbiota extends the reproductive lifespan by safeguarding the ovarian reserve

Infertility is a devastating condition affecting one in six people globally. In many cases, the underlying causes are unknown. Emerging evidence suggests that the microbiota influences reproduction, yet the mechanistic link between the microbiota, ovarian function, and length of the fertile lifespan remain unexplored. Here we report that the microbiota controls the length of the reproductive lifespan by maintaining the primordial follicle pool, a process mediated by microbiota-derived short chain fatty acids modulating gene regulatory networks crucial for the survival of the ovarian reserve. Dietary perturbation of the microbiota during a critical developmental window is sufficient to diminish the ovarian reserve, reduce oocyte retrieval, and impair preimplantation embryo viability, mirroring challenges in human fertility treatments. Targeted interventions to restore microbiota improve assisted reproductive outcomes, particularly when implemented early. These findings reveal a novel contribution of host-microbe interactions in mammalian reproduction and demonstrate that the microbiota impacts ovarian function and fertility.

developmental biology↗

bioRxiv2023

Modeling an ultra-rare epilepsy variant in wildtype mice with in utero prime editing

Generating animal models that mirror a patients seizures within clinically-useful timeframes is an important step toward advancing precision medicine for genetic epilepsies. Here we report a somatic cell genome editing approach that rapidly incorporated a patients genomic variant into mice, which developed seizures recapitulating elements of the patients pathology. This approach offers a versatile in vivo platform for clinical, preclinical, and basic research applications, including tailoring pharmacotherapy, assessing variants of uncertain significance, and screening compounds to develop drugs for rare epilepsies. As proof-of-principle, we modeled an epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A using prime editing in utero directly in the developing brain of wild-type mice. This methodology achieved high-fidelity genome editing in vivo sufficient to induce frequent spontaneous seizures without necessitating germline modification or extensive breeding. Leveraging the speed and versatility of this approach, we propose a generalizable workflow to generate bedside-to-bench animal models of individual patients within weeks. This advance holds promise for providing a cost-effective, expedient in vivo testing platform that reduces barriers to access for precision medicine, and accelerates drug development for rare and neglected neurological conditions.

neuroscience↗

bioRxiv2023

Diet influences community dynamics following vaginal group B Streptococcus colonization

The vaginal microbiota plays a pivotal role in reproductive, sexual, and perinatal health and disease. Unlike the well-established connections between diet, metabolism, and the intestinal microbiota, parallel mechanisms influencing the vaginal microbiota and pathogen colonization remain overlooked. In this study, we combine a mouse model of Streptococcus agalactiae strain COH1 (GBS) vaginal colonization with a mouse model of pubertal-onset obesity to assess diet as a determinant of vaginal microbiota composition and its role in colonization resistance. We leveraged culture-dependent assessment of GBS clearance and culture-independent, sequencing-based reconstruction of the vaginal microbiota in relation to diet, obesity, glucose tolerance, and microbial dynamics across time scales. Our findings demonstrate that excessive body weight gain and glucose intolerance are not associated with vaginal GBS density or timing of clearance. Diets high in fat and low in soluble fiber are associated with vaginal GBS persistence, and changes in vaginal microbiota structure and composition due to diet contribute to GBS clearance patterns in nonpregnant mice. These findings underscore a critical need for studies on diet as a key determinant of vaginal microbiota composition and its relevance to reproductive and perinatal outcomes. IMPORTANCEThis work sheds light on diet as a key determinant influencing the composition of vaginal microbiota and its involvement in group B Streptococcus (GBS) colonization in a mouse model. The study shows that dietary components, such as dietary fat and soluble fiber, impact GBS density and timing of clearance in the female reproductive tract. These findings are particularly significant given clear links between GBS and adverse reproductive and neonatal outcomes, advancing our understanding by identifying critical connections between dietary components, factors originating from the intestinal tract, vaginal microbiota, and reproductive outcomes.

microbiology↗

bioRxiv2022

The magnitude of sex differences in host-microbe interactions are time-of-day dependent

Circadian rhythms dynamically regulate sex differences in metabolism and immunity, and circadian disruption increases the risk of metabolic disorders. We investigated the role of sex-specific microbial circadian rhythms in host metabolism using germ-free and conventionalized female and male mice, dietary manipulations, coupled with a systems biology approach. Sex differences in circadian rhythms of genes involved in immunity and metabolism are dependent on oscillations in the microbiota, microbial metabolic functions, and microbial metabolites. Further, dietary factors modify the magnitude of sex differences in host-microbe circadian dynamics. We show that consuming an obesogenic high-fat, low-fiber diet produced sex-specific changes in circadian rhythms in microbiota, metabolites, and host gene expression, which were linked to sex differences in the severity of metabolic dysfunction. These results reveal that microbial circadian rhythms contribute to sex differences in metabolism, emphasizing the need to consider sex as a biological variable in research on microbial contributions to metabolic dysfunction. HIGHLIGHTSO_LIMicrobial circadian rhythms differ by sex. C_LIO_LISex-specific rhythms in host transcriptional networks are microbiome-dependent. C_LIO_LIDiet-induced obesity entrains new sex-specific rhythms in microbiome and host genes. C_LIO_LITiming of data collection influences magnitude of sex differences. C_LI

systems biology↗

bioRxiv2021

Colonization at birth with human CST IV cervicovaginal microbiota alters development and increases neonatal mortality in mice

Profound racial health disparities contribute to maternal-infant morbidity and mortality. An emergent risk factor is the maternal microbiota, whereby compositional alterations impact maternal health and offspring development during pregnancy and beyond. The presence of a nonoptimal CST IV cervicovaginal microbiota, more common in Black and Hispanic women, is associated with increased risk of preterm birth and adverse birth outcomes. Through examination of the biological mechanisms by which vertical transmission of microbiota from mother to offspring influences postnatal development, we found that exposing cesarean delivered mice with CST IV cervicovaginal microbiota from pregnant women produced lasting effects on offspring metabolic, immune, and neural outcomes. We then examined how compounding effects of a typical high-risk, proinflammatory in utero environment, characterized by a maternal obesogenic state and the presence of G. vaginalis, would affect the offspring response to CST IV microbial gut colonization. The resultant developmental immaturity, coupled with an exaggerated immune response induced by exposure to risk-associated maternal microbiota, resulted in a profound increase in neonatal mortality, supporting the critical importance of elucidating the multifactorial biological mechanisms involved in high-risk pregnancies. HighlightsO_LIGut colonization by nonoptimal human cervicovaginal microbiota had sex-specific effects on postnatal development. C_LIO_LIA high-risk in utero environment increased offspring mortality risk. C_LIO_LIHeightened innate immune response associated with mortality risk. C_LIO_LIDevelopmental immaturity, premature birth, and exposure to CST IV contribute to increased offspring mortality risk. C_LI

systems biology↗

bioRxiv2019

It’s the fiber, not the fat: Significant effects of dietary challenge on the gut microbiome

BackgroundDietary effects on the gut microbiome has been shown to play a key role in the pathophysiology of behavioral dysregulation, inflammatory disorders, metabolic syndrome, and obesity. Often overlooked is that experimental diets vary significantly in the proportion and source of dietary fiber. Commonly, treatment comparisons are made between animals that are fed refined diets that lack soluble fiber and animals fed vivarium-provided chow diet that contain a rich source of soluble fiber. Despite the well-established role of soluble fiber on metabolism, immunity, and behavior via the gut microbiome, the extent to which measured outcomes may be driven by differences in dietary fiber is unclear. Further, the significant impact of sex and age in response to dietary challenge is likely important and should also be considered.\n\nResultsWe compared the impact of transitioning young and aged male and female mice from a chow diet to a refined low soluble fiber diet on body weight and gut microbiota. Then, to determine the contribution of dietary fat, we examined the impact of transitioning a subset of animals from refined low fat to refined high fat diet. Serial tracking of body weights revealed that consumption of low fat or high fat refined diet increased body weight in young and aged adult male mice. Young adult females showed resistance to body weight gain, while high fat diet-fed aged females had significant body weight gain. Transition from a chow diet to low soluble fiber refined diet accounted for most of the variance in community structure and composition across all groups. This dietary transition was characterized by a loss of taxa within the phylum Bacteroidetes and a concurrent bloom of Clostridia and Proteobacteria in a sex- and age-specific manner. Most notably, no changes to gut microbiota community structure and composition were observed between mice consuming either low- or high-fat diet, suggesting that transition to the refined diet that lacks soluble fiber is the primary driver of gut microbiota alterations, with limited additional impact of dietary fat on gut microbiota.\n\nConclusionCollectively, our results show that the choice of control diet has a significant impact on outcomes and interpretation related to body weight and gut microbiota. These data also have broad implications for rodent studies that draw comparisons between refined high fat diets and chow diets to examine dietary fat effects on metabolic, immune, behavioral, and neurobiological outcomes.

systems biology↗

bioRxiv2018

Antidepressant treatment modulates the gut microbiome and metabolome during pregnancy and lactation in rats with a depressive-like phenotype

BackgroundUp to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during and after pregnancy to manage mood disorders, with possible implications for the developing offspring. The microbiota within the gastrointestinal tract contributes to the regulation of serotonin synthesis. However, the interaction between maternal depression, SSRI use, bacterial community composition, and availability of microbiota-derived metabolites during pregnancy and lactation is not clear and may be consequential to the long-term health of mother and offspring. To determine the impact of SSRI treatment on maternal microbial community dynamics, we conducted these studies in a rat model of maternal vulnerability (MV). All MV females are on a background of genetic vulnerability, where rats exposed to early life stress (sMV) develop a depressive-like phenotype. In adulthood, sMV- and control (cMV) females were treated with either the SSRI fluoxetine (FLX) or the vehicle (Veh) throughout pregnancy and lactation. High-resolution 16S ribosomal RNA gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively.\n\nResultsThe diversity, structure, and composition of the fecal bacterial community differed between pregnancy and lactation. Shifts in microbiota composition were accompanied by changes in fecal metabolite availability. FLX altered some key features of the transition from pregnancy to lactation, but only in females exposed to early life stress (sMV-Veh vs sMV-FLX). For instance, sMV-FLX females had lower fecal availability of the amino acids serine, proline, and aspartic acid than sMV-Veh females. These metabolite concentrations correlated negatively with the relative abundance of bacterial taxa Prevotella, Ruminococcus, and Oscillospira.\n\nConclusionsOur studies demonstrate an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in sMV rats, possibly through parallel changes in the maternal gut microbiome. Since maternal microbial metabolites contribute to health outcomes in offspring, insults to the maternal microbiome by SSRIs might have inter-generational consequences.

microbiology↗

bioRxiv2018

Epididymal glucocorticoid receptors promote intergenerational transmission of paternal stress

Paternal preconception exposures and insults, including stress, dietary challenge and drugs of abuse, can shape offspring health and disease risk outcomes, as evidenced from retrospective human studies and more recent animal models1-16. Mechanistic examination has implicated small noncoding RNA populations in sperm, including microRNA (miRs), as carriers of paternal environmental information that consequently influence offspring development15,17-21. However, the cellular mechanisms by which these paternal signals are relayed to sperm and how they may persist remain unknown. Here, using our previously established paternal stress mouse model we identify caput epididymal epithelial glucocorticoid receptors as crucial upstream mediators of long-lasting germ cell programming. We show that glucocorticoid treatment of caput epididymal epithelial cells results in increased glucocorticoid receptor levels and enduring changes to the miR content of secreted extracellular vesicles (EVs), or epididymosomes, known to interact with sperm and alter their RNA content22,23. Further, significant changes were detected in the caput epididymal histone code long after stress ended, both in vitro and in vivo, as a potential mechanism whereby stress programmed enduring changes to EV miRs. Genetic targeting to reduce caput epididymal epithelial-specific glucocorticoid receptors reversed stress-induced chromatin remodeling and promoted cellular resilience to paternal stress, ultimately rescuing transmission of a stress dysregulated offspring phenotype. Taken together, these studies identify glucocorticoid receptor regulation of EV miRs in the caput epididymis as a key contributor in the intergenerational transmission of paternal environmental stress experiences.

neuroscience↗