Biology subjects

Bowdish, D. M. E.

Publications and source records attributed to Bowdish, D. M. E..

5 recordsLinked to original sources

bioRxiv2024

Maternal obesogenic diet disrupts mid-gestation decidual immune and vascular homeostasis without impairing spiral artery remodelling

Excess maternal adiposity (i.e., overweight and obesity) during pregnancy has been linked to impaired uteroplacental perfusion, compromised placental development, and a higher risk of adverse pregnancy outcomes. Owing to the nature of chronic inflammation and immune dysregulation accompanying excess adiposity, disruption of leukocyte-mediated tissue remodelling and immunoregulation within the decidua have emerged as likely drivers contributing to suboptimal placental function in pregnancies impacted by maternal overweight or obesity. However, the impacts of excess adiposity on major populations of innate lymphoid cells (ILCs) and macrophages which orchestrate these processes and the environment that these cells occupy remain vastly understudied. Here, we used a mouse model of chronic high-fat, high-sucrose (HFHS) diet-feeding to characterize the impacts of an obesogenic milieu on decidual immune dynamics during placental development at mid-gestation (E10.5). HFHS pregnancies exhibited marked increases in total decidual leukocyte abundance, driven by population-level increases in tissue-resident and conventional NK cells, and MHC-II+ macrophages. This was not associated with abnormalities in implantation site morphology or decidual spiral artery remodelling but was coincident with histological patterns of local inflammation. In line with this, expression of canonical proinflammatory cytokines and chemokines were moderately upregulated in bulk decidual tissue of HFHS dams. This was accompanied by more potent elevations in multiple mediators of angiogenesis, endothelial activation, and coagulation in HFHS decidual tissue. Collectively, these findings point towards pathological vascular inflammation and possibly dysregulated decidual angiogenesis in the first half of pregnancy as factors predisposing to reduced placental efficiency, malperfusion, and inflammation seen in pregnancies affected by maternal overweight and obesity.

developmental biology↗

bioRxiv2023

Maternal adaptations in mouse lactation are vulnerable to diet-induced excess adiposity

Lifetime maternal risk of obesity is increased by excess gestational weight gain, which alters maternal metabolic adaptations in pregnancy, but the effects of excess weight retention/adiposity in the early postpartum period have not been extensively studied. The pathophysiology of excess adiposity and its accompanying immunometabolic dysregulation are associated with impaired intestinal barrier function in both non-pregnant and pregnant contexts. Using a mouse model, we investigated effects of diet-induced excess adiposity on maternal physiological adaptations during lactation. We report that in lactation, excess adiposity altered maternal intestinal morphology, influenced local immune cell composition and phenotype, increased intestinal permeability, and altered whole-body glucose metabolism as well as peripheral inflammation and immune cell composition. Many of these effects persisted two months post-lactation in mice with excess adiposity. Our findings have important implications for the development of interventions for periconceptual/perinatal excess adiposity and emphasize that further studies are needed to better understand effects of excess adiposity on maternal postpartum health.

developmental biology↗

bioRxiv2022

Intestinal permeability and peripheral immune cell composition are altered by pregnancy and adiposity at mid- and late-gestation in the mouse

It is clear that the gastrointestinal tract influences metabolism and immune function. Most studies to date have used male test subjects, with a focus on effects of obesity and dietary challenges. Despite significant physiological adaptations that occur across gestation, relatively few studies have examined pregnancy-related gut function. In this study, we investigated the impacts of pregnancy and adiposity on maternal intestinal epithelium morphology, in vivo intestinal permeability, and peripheral blood immunophenotype, using control (CTL) and high-fat (HF) fed non-pregnant female mice and pregnant mice at mid-(embryonic day (E)14.5) and late (E18.5) gestation. We found that small intestine length increased between non-pregnant mice and dams at late-gestation, but ileum villus length, and ileum and colon crypt depths and goblet cell numbers remained similar. Compared to CTL-fed mice, HF-fed mice had reduced small intestine length, ileum crypt depth and villus length. Goblet cell numbers were only consistently reduced in HF-fed non-pregnant mice. Pregnancy increased in vivo gut permeability, with a greater effect at mid-versus late-gestation. Non-pregnant HF-fed mice had greater gut permeability, and permeability was also increased in HF-fed pregnant dams at mid but not late-gestation. The impaired maternal gut barrier in HF-fed dams at mid-gestation coincided with changes in maternal blood and bone marrow immune cell composition, including an expansion of circulating inflammatory Ly6Chigh monocytes. In summary, pregnancy has temporal effects on maternal intestinal structure and barrier function, and on peripheral immunophenotype, which are further modified by HF diet-induced maternal adiposity.

developmental biology↗

bioRxiv2021

Mouse models of immune dysfunction: Their neuroanatomical differences reflect their anxiety-behavioural phenotype

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging (MRI), we studied the neuroanatomical differences among 11 distinct genetically-modified mouse lines (n=371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures -- such as the corpus callosum, midbrain, and thalamus -- were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.

neuroscience↗

bioRxiv2019

Tertiary lymphoid tissue develops during normal aging in mice and humans

Aging has multifaceted effects on the immune system in the context of systemic responses to specific vaccines and pathogens, but how aging affects tissue-specific immunity is not well-defined. Chronic bladder inflammation is highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Here we report distinct, age-associated changes to the immune compartment in the otherwise normal female (but not in male) mouse urinary bladder and parallel changes in older women with chronic bladder inflammation. In aged mice, the bladder epithelium became more permeable, and the homeostatic immune landscape shifted from a limited, innate immune-predominant surveillance to an inflammatory, adaptive immune-predominant environment. Strikingly, lymphoid cells were organized into tertiary lymphoid tissues, hereafter named bladder tertiary lymphoid tissue (bTLT). Analogous bTLTs were found in older women, many of whom had a history of recurrent urinary tract infection (UTI). Aged mice responded poorly to experimental UTI, experiencing spontaneous recurrences at higher rates than young mice. However, bTLT formation was dependent on aging and independent of infection. Furthermore, bTLTs in aged mice played a role in de novo antibody responses and urinary IgA production by recruitment of naive B cells that form germinal centers and mature into IgA-secreting plasma cells. Finally, TNF was a key driver of bTLT formation, as aged TNF-/- mice lacked bTLTs. Both aged TNF-/- and wild type mice exhibited increased bladder permeability, suggesting that epithelial dysfunction may be an upstream mediator of chronic, age-associated bladder inflammation. Thus, bTLTs arise as a function of age and may underlie chronic, age-associated bladder inflammation. Our model establishes a platform for further investigation of age-association tissue inflammation and translation to new treatment strategies.\n\nOne Sentence SummaryMice develop bladder tertiary lymphoid tissue (bTLT) during aging that is dependent on TNF and independent of urinary tract infection.

immunology↗