Biology subjects

Sferruzzi-Perri, A.

Publications and source records attributed to Sferruzzi-Perri, A..

5 recordsLinked to original sources

bioRxiv2024

Maternal gut Bifidobacterium breve modifies fetal brain metabolism in mice

In recent years, our understanding of the gut microbiomes impact on host physiology and metabolism has grown exponentially. Yet, the specific role of certain microorganisms in regulating gestational health and fetal development remains largely unexplored. During pregnancy, Bifidobacterium represents a key beneficial microbiota genus that provides multiple benefits, including changes in placental development and fetal glycaemia. In this study, using germ-free mice colonized with or without Bifidobacterium breve UCC2003 during pregnancy, we demonstrated that this bacterium is important for controlling fetal brain metabolism. In particular, presence of maternal Bifidobacterium led to reduced levels of ten metabolites (including citrate, 3-hydroxyisobutyrate, and carnitine) in the fetal brain, with concurrent elevated abundance of transporters involved in glucose and branched-chain amino acid uptake. B. breve supplementation was also associated with increased expression of critical metabolic and cellular pathways, including the PI3K-AKT, AMPK, STAT5 and Wnt-{beta}-catenin (including its receptor Frizzled-7) in the fetal brain. Furthermore, maternal-associated Bifidobacterium resulted in HIF-2 protein stabilization and altered a number of https://pubmed.ncbi.nlm.nih.gov/38269505/ genes and proteins involved in cellular growth, axogenesis, and mitochondrial function. These findings highlight that Bifidobacterium breve colonisation of the maternal gut is important for the metabolism and growth of the fetal brain.

developmental biology↗

bioRxiv2023

Obesogenic diet in mice leads to inflammation and oxidative stress in the mother in association with sex-specific changes in fetal development, inflammatory markers and placental transcriptome

IntroductionObesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study in mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. MethodsFemale mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to and during pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox state. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. ResultsHFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and activation of pro-inflammatory pathways (p38-MAPK) along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-, IL-6 and IFN-{gamma}). Morphology of the placenta Lz was modified by a HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. DiscussionThis study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important given the marked consequences and the rising rates of obesity worldwide.

physiology↗

bioRxiv2021

Placental mitochondrial function, nutrient transporters, metabolic signalling and steroid metabolism relate to fetal size and sex in mice

Fetal growth depends on placental function, which requires energy from mitochondria. Here we investigated whether mitochondrial function in the placenta relates to growth of the lightest and heaviest fetuses of each sex within the litter of mice. Placentas from the lightest and heaviest fetuses were taken to evaluate placenta morphology (stereology), mitochondrial energetics (high-resolution respirometry), and mitochondrial regulators, nutrient transporters, hormone handling and signalling pathways (qPCR and western blotting). We found that mitochondrial complex I and II oxygen consumption rate was greater for placentas supporting the lightest female fetuses, although placental complex I abundance of the lightest females and complexes III and V of the lightest males were decreased compared to their heaviest counterparts. Expression of mitochondrial biogenesis (Nrf1) and fission (Drp1 and Fis1) genes was lower in the placenta from the lightest females, whilst biogenesis-related gene Tfam was greater in the placenta of the lightest male fetuses. Additionally, placental morphology and steroidogenic gene (Cyp17a1 and Cyp11a1) expression was aberrant for the lightest females, but glucose transporter (Glut1) expression was lower in only the lightest males versus their heaviest counterparts. Differences in intra-litter placental phenotype were related to sex-dependent changes in the expression of hormone responsive (androgen receptor) and metabolic signalling (AMPK, AKT, PPAR{gamma}) pathways. Thus, in normal mouse pregnancy, placental structure, function and mitochondrial phenotype are differentially responsive to growth of the female and the male fetus. This study may inform the design of sex- specific therapies for placental insufficiency and fetal growth abnormalities with life-long benefits for the offspring.

developmental biology↗

bioRxiv2020

Unbiased placental secretome characterization identifies candidates for pregnancy complications

Pregnancy requires adaptation of maternal physiology to enable normal fetal development. These adaptations are driven, in part, by the production of placental hormones. Failures in maternal adaptation and placental function lead to pregnancy complications including abnormal birthweight and gestational diabetes. However, we lack information on the full identity of hormones secreted by the placenta that mediate changes in maternal physiology. This study used an unbiased approach to characterise the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones that are important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed using mass spectrometry on cultured primary trophoblast and fluorescence-activated sorted endocrine cells from pregnant mouse dams, and a placenta secretome map containing 319 proteins was generated. Gene ontology analyses showed that a high proportion of placental secretome proteins are involved in metabolic and immune modulation, signalling and growth. The majority of proteins identified are also expressed by human placenta and several have been reported to be dysregulated in pregnancy complications. Moreover, in proof of concept studies, we found that the relative abundance of secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) was increased in women at 12 weeks of pregnancy, prior to diagnosis of gestational diabetes. Finally, we identified several transcription factors that may be important for controlling hormone production by the placenta and associate with pregnancy outcome. Thus, our observations suggest that analysis of the placental secretome could lead to the identification of new placental biomarkers of pregnancy complications.

physiology↗

bioRxiv2017

C-terminal truncation of Pik3r1 in mice models human lipodystrophic insulin resistance uncoupled from dyslipidemia

Heterodimeric class IA phosphatidylinositol-3-kinases (PI3K) transduce signals from many receptor tyrosine kinases including the insulin receptor. PI3K recruitment to phosphotyrosines is mediated by Pik3r1 gene products including the most intensely studied PI3K regulatory subunit, p85, which also binds and regulates the PIP3 phosphatase Pten, and the lipogenic transcription factor Xbp1. Mutations in human PIK3R1 cause SHORT syndrome, featuring lipodystrophy and severe insulin resistance which, uniquely, are uncoupled from fatty liver and dyslipidemia. We describe a novel mouse model of SHORT syndrome made by knock in of the Pik3r1 Y657X mutation. Homozygous embryos die at E11.5, while heterozygous mice exhibit pre-and postnatal growth impairment with diminished placental vascularity. Adipose tissue accretion on high fat feeding was reduced, however adipocyte size was unchanged and preadipocyte differentiation ex vivo unimpaired. Despite severe insulin resistance, heterozygous mice were hypolipidemic, and plasma adiponectin, liver weight, cholesterol, glycogen and triglyceride content were unchanged. Mild downregulation of lipogenic Srebp1, Srebp2 and Chrebp transcriptional activity but no suppression of Xbp1 target genes was seen after fasting. These findings give new insights into the developmental role of Pik3r1, and establish a model of lipodystrophic insulin resistance dissociated from dyslipidemia as seen in SHORT syndrome.

biochemistry↗