Increased Disease Susceptibility Research Articles

Using Peromyscus leucopus as a biomonitor to determine the impact of heavy metal exposure on the kidney and bone mineral density: results from the Tar Creek Superfund Site.

Human population growth and industrialization contribute to increased pollution of wildlife habitats. Heavy metal exposure from industrial and environmental sources is still a threat to public health, increasing disease susceptibility. In this study, I investigated the effects of heavy metals (cadmium (Cd), lead (Pb), and zinc (Zn)) on kidney and bone density. This study aims to determine the concentrations of Cd, Pb, and Zn in soil and compare them to the levels of the same metals in Peromyscus leucopus kidney tissue. Furthermore, the study seeks to investigate the impact of heavy metals on bone density and fragility using the fourth lumbar vertebra (L4) of P. leucopus. Cd, Pb, and Zn concentrations in soil specimens collected from Tar Creek Superfund Site (TCSFS), Beaver Creek (BC), and two reference sites (Oologah Wildlife Management Area (OWMA) and Sequoyah National Wildlife Refuge (SNWR)). Heavy metal concentrations were analyzed using inductively coupled plasma-mass spectroscopy (ICP-MS). Micro-computed tomography (µCT) was used to assess the influence of heavy metals on bone fragility and density. On the one hand, soil samples revealed that Pb is the most common pollutant in the sediment at all of the investigated sites (the highest contaminated site with Pb was TCSFS). Pb levels in the soil of TCSFS, BC, OWMA, and SNWR were found to be 1,132 ± 278, 6.4 ± 1.1, and 2.3 ± 0.3 mg/kg in the soil of TCSFS, BC and OWMA and SNWR, respectively. This is consistent with the fact that Pb is one of the less mobile heavy metals, causing its compounds to persist in soils and sediments and being barely influenced by microbial decomposition. On the other hand, the kidney samples revealed greater Cd levels, even higher than those found in the soil samples from the OWMA and SNWR sites. Cd concentrations in the kidney specimens were found to be 4.62 ± 0.71, 0.53 ± 0.08, and 0.53 ± 0.06 µg/kg, respectively. In addition, micro-CT analysis of L4 from TCSFS showed significant Pearson's correlation coefficients between Cd concentrations and trabecular bone number (-0.67, P ≤ 0.05) and trabecular separation (0.72, P ≤ 0.05). The results showed no correlation between bone parameters and metal concentrations at reference sites. This study is one of the few that aims to employ bone architecture as an endpoint in the field of biomonitoring. Furthermore, this study confirmed some earlier research by demonstrating substantial levels of heavy metal contamination in soil samples, kidney samples, and P. leucopus L4 trabecular bone separations from TCSFS. Moreover, this is the first study to record information regarding bone microarchitecture parameters in P. leucopus in North America.

Rheumatoid arthritis and the risk of preterm birth.

During pregnancy, many diseases are correlated with different adverse outcomes. In turn, pregnancy affects the body, leading to increased disease susceptibility. This interplay between diseased states and pregnancy outcomes is illustrated in the effect of the chronic autoimmune disorder, rheumatoid arthritis (RA), and the adverse outcome, preterm birth (PTB). RA is a systemic disorder characterized by inflammation of the joints and other body organs. Joint pain and swelling are the most prominent manifestations of RA during pregnancy. However, the exact role of RA on PTB among pregnant women has yet to be established. This review highlighted the immunologic mechanisms involved in PTB in pregnant patients with RA. The immune cell population in pregnant women with RA exhibited higher activity of macrophages, dendritic cells, neutrophils, helper T (Th) 1 cells, and Vδ1 cells, but lower activity of CD4+CD25high T regulatory (CD24+CD25high Treg ), Th2, and Vδ2 cells. Increased pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ and decreased anti-inflammatory cytokines IL-12 and IL-10 are also exhibited by pregnant patients with RA. This review also discussed factors that may predict the risk of PTB in RA. These include disease activity and severity of RA, laboratory parameters (cytokines and immune cell population), and sociodemographic factors such as ethnicity, smoking, alcohol intake, and the level of education. Current findings on the underlying immunological mechanisms of RA can help identify possible strategies to prevent PTB.

Abstract 10615: The Effects of Maternal Hypothyroidism on Progeny Cardiac Development and Disease Susceptibility

Introduction: Maternal hypothyroidism (MH) is a common clinical condition with high prevalence. MH is thought to have adverse effects on progeny's cardiac development and disease susceptibility. Hypothesis: MH impacts progeny's postnatal cardiac development and the susceptibility to adverse cardiac disease responses as adults. Methods: MH model was induced by thyroidectomy (TX) with total thyroxine (TT4) under 1ng/dl after surgery. Offspring of mice that underwent TX or Sham surgery was termed THD (Deficient) and THN (Normal) animals. Hearts were collected from THD and THN animals to determine heart weight, cardiomyocyte (CM) size, and CM proliferation. Transverse Aortic Constriction (TAC) was performed to induce pressure overload-induced cardiac hypertrophy and/or heart failure (HF) model in adult THD and THN mice. ECHO (in-vivo) and histological (in-vitro) were performed at specific times after TAC. RNA-seq was performed at embryo day (E) 18.5 and Postnatal day 5 (P5) using heart tissue. Results: The postnatal TT4 level was not different between the THD and THN mice. The heart weight (HW) to body weight (BW) ratio was similar between the two groups on P7, P14, and P60, but the THD mice had larger CM sizes. EdU+, Ki67+, and PH3+ CMs were lower in THD progenies on P0, P5, and P13. RNA-seq data showed that the genes related to cell division and DNA replication were downregulated in THD mice on E18.5 and P5, respectively. In adult animals six weeks after TAC, the THD mice had a greater HW/BW ratio and lung weight(LW) to BW ratio, consistent with more severe cardiac hypertrophy and HF than the THN mice. After TAC, THD mice had a lower LVEF, higher absolute E/e' ratio, greater end-diastolic pressure, and more severe LV fibrosis than THN mice. Conclusions: Alterations in CM proliferation during fetal and early postnatal development results in fewer adult CMs in animals from MH mothers. These changes are associated with increased disease susceptibility in adult MH progeny.

MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil.

Although aging correlates with a worse prognosis for Covid-19, super elderly still unvaccinated individuals presenting mild or no symptoms have been reported worldwide. Most of the reported genetic variants responsible for increased disease susceptibility are associated with immune response, involving type I IFN immunity and modulation; HLA cluster genes; inflammasome activation; genes of interleukins; and chemokines receptors. On the other hand, little is known about the resistance mechanisms against SARS-CoV-2 infection. Here, we addressed polymorphisms in the MHC region associated with Covid-19 outcome in super elderly resilient patients as compared to younger patients with a severe outcome. SARS-CoV-2 infection was confirmed by RT-PCR test. Aiming to identify candidate genes associated with host resistance, we investigated 87 individuals older than 90 years who recovered from Covid-19 with mild symptoms or who remained asymptomatic following positive test for SARS-CoV-2 as compared to 55 individuals younger than 60 years who had a severe disease or died due to Covid-19, as well as to the general elderly population from the same city. Whole-exome sequencing and an in-depth analysis of the MHC region was performed. All samples were collected in early 2020 and before the local vaccination programs started. We found that the resilient super elderly group displayed a higher frequency of some missense variants in the MUC22 gene (a member of the mucins' family) as one of the strongest signals in the MHC region as compared to the severe Covid-19 group and the general elderly control population. For example, the missense variant rs62399430 at MUC22 is two times more frequent among the resilient super elderly (p = 0.00002, OR = 2.24). Since the pro-inflammatory basal state in the elderly may enhance the susceptibility to severe Covid-19, we hypothesized that MUC22 might play an important protective role against severe Covid-19, by reducing overactive immune responses in the senior population.

Effects of a 24-Week Exercise Program on Functional Fitness, Oxidative Stress, and Salivary Cortisol Levels in Elderly Subjects.

Background and Objectives: Aging is a biological and irreversible process characterized by physiological alterations resulting in a progressive decline in biological functions, decreased resistance or adaptability to stress, and increased disease susceptibility. A decline in functional fitness, imbalance between pro- and antioxidant capacity, and/or hormonal dysregulation adversely impact physical capacity, emotional status, and overall quality of life, especially within the elderly population. On the other hand, regular physical activity is considered an effective strategy to prevent and reduce those changes associated with primary aging and concurrent chronic disease, while slowing age-related physical degeneration. However, there is still limited evidence-based information regarding both the intensity and interval of effective interventions on physical functioning in older adults. Thus, the aim of the study was to assess the effects of a 24-week regular multimodal exercise program on functional fitness, oxidative stress, salivary cortisol level, and self-perceived quality of life in a group of eighteen physically active elderly subjects (mean age 72.8 ± 7.5 years). Materials and Methods: A set of anthropometric and physical measurements (grip strength, chair sit to stand, sit and reach and back scratch) assessing the functional fitness performance were evaluated. Moreover, biochemical markers (derived-reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) tests, and salivary cortisol levels) and the EuroQoL 5-Dimension 3-Level (EuroQoL 5-D 3-L) self-perceived questionnaire of quality of life were measured before and after the intervention program. All measurements were normally distributed as assessed by D’Agostino and Pearson’s omnibus normality test. Student’s t-tests were used to evaluate the differences in all the parameters measured at baseline (T0) and after the 24-week physical program (T1). Results: The results showed that an age-tailored structured intervention exercise program (1 h per session, twice per week, for 24 weeks) was effective in improving flexibility and other biomechanical parameters, such as muscle strength and the dynamic balance fitness component, which are key to performing daily tasks independently. Moreover, biochemical analyses demonstrate that the proposed intervention program has beneficial effects on the balance between plasma ROS production and their neutralization. Conclusions: The results confirm the benefits of regular physical activity in older adults resulting in improved physical strength and flexibility in the functional fitness parameters, and in regulating anti- and pro-oxidant activity and cortisol (stress hormone) levels.

Impaired immune response drives age-dependent severity of COVID-19.

Severity of COVID-19 shows an extraordinary correlation with increasing age. We generated a mouse model for severe COVID-19 and show that the age-dependent disease severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) immunity. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity, and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice. Further, we show that therapeutic treatment with IFN-λ in adults and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1-/- mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity and clarify the nonredundant antiviral functions of type I, II, and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Our data suggest that highly vulnerable individuals could benefit from immunotherapy combining IFN-γ and IFN-λ.

Abstract P1121: Transposition Of Great Arteries - Genetics And Beyond

Background: Transposition of great arteries (TGA) is one of the most common severe congenital heart defects and neonatal cyanotic heart diseases. Given contribution of several molecular pathways involved in cardiac differentiation (Fig.1), the etiology governing morphogenesis of TGA remains largely unknown. There is greater insight into interactions and molecular variations culminating in aortic-pulmonary transposition. Clinical evidence and genetic sequencing has led to several polymorphic mutations demonstrating phylogenetic conservation of regulatory domains. Defects in transcription factors involved in nodal signaling, in addition to ZIC3 & PROSIT 240, are strongly implicated in arterial transposition. We reviewed current literature on the genetics determining TGA development and associated lateral syndromes Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar to identify listed keywords Body: TGA is now postulated as part of a spectrum of genetic disorders with familial recurrence, rather than sporadic defect. Evidence exists for TGA's correlation with genes involving lateralization defects, heterotaxy and asplenia. Evidence, albeit scarce, has surfaced depicting association of TGA with genetic syndromes like Trisomy 8, 18, VACTERL and CHARGE syndrome, Tuberous sclerosis, Deletion 11q, 18p, and other genetic syndromes like Digeorge, Turner’s, Noonan’s, Williams, and Marfan. Additional gene mutations causing TGA might include CFC-1, TRAP2, FOXH1, LEFTY2, PITX2, GDF1. The interrelation between mutations in ciliary genes contributing to both TGA and neurodevelopment disorder, prompts consideration of common ciliopathic pathogenies explaining association between TGA and neurodevelopmental disorders. Conclusion: The occurrence of mutations in a single gene, though a cause for TGA, does not correlate with 5-7% occurrence rate for TGA. Major research has focused on a single gene approach, neglecting the simultaneous screening for other susceptible targets. The multiple-hit model suggested by De Luca et al. (2010) is a promising approach for further understanding the contribution of multi-gene sequences. Minor genetic variations in several genes may have a cumulative effect that increases disease susceptibility in TGA and other congenital heart defects

Thermal cum lipopolysaccharide-induced stress challenge downregulates functional response of bovine monocyte-derived macrophages

Macrophages are considered to be key players in innate immunity and inflammatory responses. Domestic cattle with standard body size quickly reach their heat tolerance limit and are prone to heat stress. The combined effects of high temperature and endotoxemia on bovine monocyte-derived macrophages remain almost undisclosed. This study aims to unravel the molecular and functional responses of bovine monocyte-derived macrophages to thermal cum lipopolysaccharide induced stress challenge in vitro. The cells were incubated at 37 °C or 40 °C with lipopolysaccharide (1.0 μg/mL) for 24 h and 48 h. At the end of each treatment, cell viability, apoptotic rate, mitochondrial membrane potential, oxidative activity, phagocytosis, and autophagy functions were assessed and mRNA abundance of genes related to heat shock (HSP 70), inflammation (IL1β, IL6, IL 12, TNF, INF γ), cell signalling (TLR4), cell viability (Bax, Bcl2), nitric oxide synthesis (NOS2) and natural resistant associated macrophage protein were quantified by quantitative polymerase chain reaction (qPCR). The results revealed the increased apoptosis, reduced mitochondrial membrane potential, and cell viability, decreased oxidative and phagocytosis ability in cells co-stimulated with LPS and thermal stimuli. Upregulation of HSP 70 gene and downregulation of natural resistant associated macrophage protein, cell signalling, and inflammation related genes mRNA expressions were also identified due to these stressors. In conclusion, the observed thermal cum LPS stress induced dysregulation in macrophage functionality may be one facet of the increased disease susceptibility in dairy cattle during thermal stress.

Nanoplastics in Aquatic Environments: Impacts on Aquatic Species and Interactions with Environmental Factors and Pollutants.

Plastic production began in the early 1900s and it has transformed our way of life. Despite the many advantages of plastics, a massive amount of plastic waste is generated each year, threatening the environment and human health. Because of their pervasiveness and potential for health consequences, small plastic residues produced by the breakdown of larger particles have recently received considerable attention. Plastic particles at the nanometer scale (nanoplastics) are more easily absorbed, ingested, or inhaled and translocated to other tissues and organs than larger particles. Nanoplastics can also be transferred through the food web and between generations, have an influence on cellular function and physiology, and increase infections and disease susceptibility. This review will focus on current research on the toxicity of nanoplastics to aquatic species, taking into account their interactive effects with complex environmental mixtures and multiple stressors. It intends to summarize the cellular and molecular effects of nanoplastics on aquatic species; discuss the carrier effect of nanoplastics in the presence of single or complex environmental pollutants, pathogens, and weathering/aging processes; and include environmental stressors, such as temperature, salinity, pH, organic matter, and food availability, as factors influencing nanoplastic toxicity. Microplastics studies were also included in the discussion when the data with NPs were limited. Finally, this review will address knowledge gaps and critical questions in plastics’ ecotoxicity to contribute to future research in the field.

Pomegranate (Punica granatum) By-Product Extract Influences the Oxylipids Profile in Primary Bovine Aortic Endothelial Cells in a Model of Oxidative Stress

Aerobic metabolism produces reactive oxygen species (ROS) as a natural by-product that can play a significant role in cell signaling and homeostasis. Excessive and uncontrolled production of ROS, however, can lead to oxidative stress that causes damage to immune cells and is related to several diseases in dairy cattle. Endothelial cells are essential for optimal immune and inflammatory responses but are especially sensitive to the damaging effects of ROS. Accordingly, investigating antioxidant strategies that can mitigate the detrimental impact of ROS on endothelial functions could impact compromised host defenses that lead to increased disease susceptibility. The objective of this study was to test the antioxidant effect of different concentrations (20, 40, 60, 80 μg/ml) of pomegranate by-product extract (PBE) on bovine aortic endothelial cells (BAECs). A model of oxidative stress was developed using in vitro exposure of BAEC to 2,2′-azobis (2-amidinopropane) dihydrochloride (AAPH) to induce the formation of ROS. The BAEC were then analyzed for cell viability, ROS production, fatty acids profile, and oxylipids formation. The BAECs viability did not change after different concentrations of PBE and remained up to 80% over control; whereas, intracellular ROS showed a reduction passing from 20 to 50% with increasing PBE concentration from 20 to 80 μg/ml, respectively. The PBE extract clearly demonstrated efficacy in reducing the concentrations of pro-inflammatory oxylipids with a concomitant enhancement of anti-inflammatory oxylipids. In particular, the pro-inflammatory 13-hydroxyoctadecadienoic acid and its derived anti-inflammatory 13-hydroperoxoctadecaienoic acid were found lower and higher, respectively, in PBE+AAPH treated cells than AAPH treatment. Data from the present study support in vivo future experimental use of pomegranate by-product extract to study its potential beneficial effect against oxidative stress conditions in dairy cattle.

Discovery and Functional Characterization of Two Regulatory Variants Underlying Lupus Susceptibility at 2p13.1.

Genome-wide association studies have identified 2p13.1 as a prominent susceptibility locus for systemic lupus erythematosus (SLE)—a complex, multisystem autoimmune disease. However, the identity of underlying causal variant (s) and molecular mechanisms for increasing disease susceptibility are poorly understood. Using meta-analysis (cases = 10,252, controls = 21,604) followed by conditional analysis, bioinformatic annotation, and eQTL and 3D-chromatin interaction analyses, we computationally prioritized potential functional variants and subsequently experimentally validated their effects. Ethnicity-specific meta-analysis revealed striking allele frequency differences between Asian and European ancestries, but with similar odds ratios. We identified 20 genome-wide significant (p < 5 × 10−8) variants, and conditional analysis pinpointed two potential functional variants, rs6705628 and rs2272165, likely to explain the association. The two SNPs are near DGUOK, mitochondrial deoxyguanosine kinase, and its associated antisense RNA DGUOK-AS1. Using luciferase reporter gene assays, we found significant cell type- and allele-specific promoter activity at rs6705628 and enhancer activity at rs2272165. This is supported by ChIP-qPCR showing allele-specific binding with three histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), transcriptional coactivator p300, CCCTC-binding factor (CTCF), and transcription factor ARID3A. Transcriptome data across 28 immune cell types from Asians showed both SNPs are cell-type-specific but only in B-cells. Splicing QTLs showed strong regulation of DGUOK-AS1. Genotype-specific DGOUK protein levels are supported by Western blots. Promoter capture Hi-C data revealed long-range chromatin interactions between rs2272165 and several nearby promoters, including DGUOK. Taken together, we provide mechanistic insights into how two noncoding variants underlie SLE risk at the 2p13.1 locus.

213-LB: Combined Oral Contraceptives Drive Inactivity and Hepatic Mitochondrial Oxidative Stress in Female Mice

Background: It is well established that compared to age-matched men, pre-menopausal women are protected against metabolic disease (obesity, diabetes, hepatic steatosis) . However, both epidemiological data on menopause and pre-clinical ovariectomy models show that disruption of estrogen signaling increases disease susceptibility. Combined oral hormonal contraceptives (OC) induce loss of normal estrogen cycling, and despite widespread use, the impact of OCs on metabolic health and disease remains poorly understood. Methods: Female C57BL/6J mice (7-8 wks old) were treated with high-fat diet (HFD; CON) or HFD + OCs (2mg estradiol/kg HFD, 200mg progestin/kg HFD; OC) for 12 wks. In each treatment group, mice either remained sedentary or had access to voluntary running wheels (VWR; n=12 per group) . Liver and skeletal muscle mitochondrial function (respiratory capacity, H2O2, coupling) were measured along with body composition, glucose tolerance, energy expenditure, and intrahepatic triglyceride. Results: OCs decreased VWR, spontaneous physical activity, and total energy expenditure. OC treated mice had lower adiposity and hepatic triglyceride compared to CON mice, with no difference in glucose tolerance. Despite similar maximal respiratory capacity, OCs induced robust increases in hepatic mitochondrial H2O2 across all respiratory states and with both fat and carbohydrate-based substrates. There were no differences in muscle mitochondrial outcomes. Conclusions: When combined with HFD, OC use lowers physical activity and energy expenditure while inducing tissue-specific effects on mitochondrial function in mice. These data provide pause for use of OCs in the context of elevated metabolic disease risk. Future work should explore whether OC-induced changes in physical activity blunts the ability of exercise to prevent or treat insulin resistance and steatosis and whether prolonged OC exposure leads to liver injury via elevated oxidative stress. Disclosure K. Fuller: None. C. S. Mccoin: None. H. Stierwalt: None. J. P. Thyfault: None. Funding AHA (20PRE35120098) , VA Merit Review Grant (1I01BX002567-01)

Metagenomic signatures of transportation stress in the early life stages of cobia (Rachycentron canadum) to aid in mitigation strategies

Cobia (Rachycentron canadum) is a high-value marine aquaculture species. Knowledge of the microbial dynamics in various aquaculture operations is crucial for developing suitable management practices. The present study revealed the critical dysbiotic events in the whole larval and juvenile-gut microbiome of cobia, through an inevitable aquaculture operation, viz. live transportation. The results through both culture-dependent and independent techniques demonstrated the sensitivity of the cobia microbiome during early life, where live transport is inevitable. In detail, there was a significant change in the microbial composition and reduction in the cultivable load of all the life stages. Further, a significant reduction in functional metagenomics along with an increase in taxonomic metagenomics was recorded in the L21 stage. Significant reductions of the putative healthy microbiota, viz., Proteobacteria and Actinobacteria were remarkable in the whole larval microbiome. The analysis through linear discriminant analysis effect size revealed that the opportunistic fish pathogens, viz., Vibrio spp., Arcobacter spp., and Acinetobacter spp. were increased whereas, Pseudomonas spp. was decreased in larvae following transportation. The significant reduction in the taxonomic diversity measures was noteworthy in the juvenile-gut microbiome. Transportation promoted Serratia spp., Enterobacter spp., an unidentified genus in Flavobacteriaceae, Pseudoalteromonas spp., Alteromonas spp., and Enterovibrio spp., and inhibited Empedobacter spp. in the juvenile gut. Collectively, the results provide the prospective metagenomic signatures of health and stress in the early life stages of cobia and novel possible explanations for increased disease susceptibility post-transportation. The study warrants future research on the microbes which were found to be decreased following transportation, as potential probiotics to mitigate the stress in the marine aquaculture practices. The metagenomic signatures revealed through the study can be further applied for evaluating different husbandry practices to mitigate stress during live transportation.

The effects of dietary zinc supplement on intracellular zinc concentration in bovine immune cells

Abstract Zinc (Zn) is one of the most abundant metals in our body and is critical for innate and adaptive immune functions. In humans and mice, Zn deficiency may lead to immunodeficiency, reduced reproductive health, and increased disease susceptibility. However, trace mineral requirements and evidence of Zn dysregulation are poorly defined in cattle. This study aimed to evaluate intracellular Zn concentrations in immune cells from young growing steers with different Zn dietary supplements. Eighteen Angus crossbred steers were stratified by body weight and randomly assigned to two dietary treatments groups: 1) control, no supplemental Zn, or 2) high Zn; 150 ppm of Zn delivered in premixes in total mixed rations. To evaluate the intracellular Zn concentration of immune cells, whole blood cells were loaded with FluoZinTM-3, a fluorescent cell-permeant Zn indicator, then stimulated with Zn pyrithione (100 μM) or TPEN [N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine] (50 μM) to measure maximum and minimum mean fluorescent intensity. Cells were stained with surface antibodies to identify immune cell populations and data were collected by flow cytometry. The intracellular Zn concentrations of circulating CD8 T cells and γδ T cells, but not other populations, differed significantly between treatment groups. These results indicate that intracellular Zn concentration can be influenced by dietary Zn intake, and that certain immune populations are differentially affected by Zn status. This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2020-06540 from the USDA National Institute of Food and Agriculture.

Gut Microbiome Alterations Associated with Diabetes in Mexican Americans in South Texas.

ABSTRACTMexican Americans have a high prevalence of diabetes and burden of diabetes-related complications, highlighting the need for novel preventive strategies and noninvasive predictors of diabetes risk tailored to this population. Changes in the gut microbiome have the potential to predict diabetes. Here, we aimed to identify alterations in the gut microbiome associated with diabetes in the high-risk population of Mexican Americans in South Texas. Stool samples were collected from 216 subjects from the population-based Cameron County Hispanic Cohort. Among them, 75 had type 2 diabetes. Taxonomic and functional profiling of the stool samples were assessed by 16S and shotgun metagenomic sequencing, and the influence of genetic factors was explored. The gut microbiome of subjects with diabetes was enriched with proinflammatory Proteobacteria members (Enterobacteriaceae, Escherichia-Shigella) and depleted of butyrate-producing Clostridiales members (Faecalibacterium prausnitzii, Peptostreptococcaceae, and Clostridium sensu stricto 1). The accompanying metagenomic changes in subjects with diabetes suggested dysregulated amino acid metabolism, reduced galacturonate and glucuronate catabolism (correlating with Faecalibacterium prausnitzii abundance), and enriched heme biosynthesis (correlating with Enterobacteriaceae abundance). Polymorphism rs7129790 near MMP27 was strongly associated with high Proteobacteria abundance and was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. In conclusion, Mexican Americans in South Texas with diabetes display distinct gut microbiome and metagenomic signatures. These signatures may have utility in risk modeling and disease prevention in this high-risk population.IMPORTANCE The gut microbiome composition varies across ethnicities and geographical locations, yet studies on diabetes-associated microbiome changes specific to high-risk Mexican Americans are lacking. Here, we aimed to identify specific alterations associated with diabetes in this population, as well as host genetic factors that may explain increased disease susceptibility in this ethnic group. Using samples from a population-based cohort of Mexican Americans with a high prevalence of obesity and diabetes, we confirmed findings from studies on other ethnicities that suggested promotion of a chronic proinflammatory environment, loss of butyrate production, and compromised intestinal barrier integrity. High abundance of proinflammatory Proteobacteria was associated with a polymorphism that was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. Validation of microbiome-based risk models for diabetes should be evaluated in prospective cohort studies.

Prolonged diet-induced obesity modifies DNA methylation and gene expression in the hippocampus

Obesity and age independently have negative effects on the brain, increasing the risk of neurodegenerative events. How these events synergize to increase disease susceptibility remains poorly understood. To better understand the epigenetic implications of poor diet with increased age, we sought to determine CpG methylation changes in the dorsal hippocampus attributable to age and/or diet-induced obesity. Male C57BL/6J mice were fed either normal chow or an obesogenic diet until six or 14 months of age. Hippocampus was analyzed by Reduced Representation Bisulfite Sequencing. In total, 107 differentially methylated regions (DMRs) were identified across all four conditions; older obese mice accounted for 63% of those DMRs. Gene ontology analysis showed two affected pathways, nervous system development and regulation of multicellular organismal process, in older obese mice only. From the RRBS results, five genes were selected for qPCR quantification: Bridging Integrator 1 (BIN1), Histone Deacetylase 5 (HDAC5), Folliculin Interacting Protein 2 (FNIP2), Proline, Glutamate and Leucine Rich Protein 1 (PELP1), and Protein Tyrosine Phosphatase Non-Receptor Type 1 (PTPN1). Generally, DMR changes aligned with mRNA expression changes in BIN1, HDAC5, FNIP2, PELP1, and PTPN1. Notably BIN1 decreased and HDAC5 increased due to obesity and age. In summary, obesity interacts with aging to significantly affect the hippocampal methylome, changing the expression of genes implicated in neurodegeneration and metabolism.

2011 Role of Maternal Micronutrients

Two thirds of all deaths in the world are due to non-communicable diseases (NCDs), and 80% of NCD deaths occur in low- and middle-income countries. Cardiovascular diseases, obesity and type 2 diabetes (T2D) are the major contributors to the global burden of NCDs. Studies in the life course evolution of these chronic diseases have highlighted an etiological role for factors which govern intrauterine and post-natal growth. Research in this field could off er a novel solution to the “primordial” prevention of conditions which are the most prominent killers in today’s world. These novel ideas arose from a series of studies by David Barker and his colleagues in the UK. They proposed that intrauterine undernutrition initiated a number of adaptations in the fetus which increased disease susceptibility in later life, especially when post-natal nutrition tended to be “excessive”. A developing fetus has the ability to grow in different ways depending on the surrounding (intrauterine) environment; this ability is called the “plasticity”. An unfavorable environment restricts the ability of the fetus to grow “wildly” and causes a permanent structural or functional change, known as “programming”. India is the world’s capital of low birth weight (lBW) babies, while at the same time it is evolving into one of the economic powers of the world. It was clear that research in India would shed important light on these new and exciting ideas.

Early life adversity drives sex-specific anhedonia and meningeal immune gene expression through mast cell activation

Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- dura mater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on sucrose preference behavior, dura mater expression of inflammatory markers and mast cell histology in adult male and female C57Bl/6 mice. We found that NMSEW alone does not affect sucrose preference behavior in males or females, but it increases the dura mater expression of the genes coding for mast cell protease CMA1 (cma1) and the inflammatory cytokine TNF alpha (tnf alpha) in females. When NMSEW is combined with an adult mild stress (that does not affect behavior or gene expression in NH animals) females show reduced sucrose preference and even greater increases in meningeal cma1 levels. Interestingly, systemic administration of the mast cell stabilizer Ketotifen before exposure to adult stress prevents both, reduction in sucrose preference an increases in cma1 expression in NMSEW females, but facilitates stress-induced sucrose anhedonia in NMSEW males and NH females. Finally, histological analyses showed that, compared to males, females have increased baseline activation levels of mast cells located in the transverse sinus of the dura mater, where the meningeal lymphatics run along, and that, in males and females exposed to adult stress, NMSEW increases the number of mast cells in the interparietal region of the dura mater and the levels of mast cell activation in the sagittal sinus regions of the dura mater. Together, our results indicate that ELA induces long-term meningeal immune gene changes and heightened sensitivity to adult stress-induced behavioral and meningeal immune responses and that these effects could mediated via mast cells.

Effects of Long-Term Enclosed Environment on Human Health Based on the Analysis of Salivary Microbiota and Cytokines.

ABSTRACTThe long-term exposure to enclosed environments may lead to chronic stress in crewmembers and affect their physical and mental state. Salivary microbiome and biomarkers of immune function are increasingly used in human health research. The “Lunar Palace 365” project, which was a 370-day, multicrew, enclosed experiment carried out in a ground-based bioregenerative life support system platform named Lunar Palace 1 (LP1). We investigated the temporal dynamics of the salivary microbiota and cytokines in the third phase of the “Lunar Palace 365” experiment, including 1 month before entering LP1 and 1 month after leaving Lp1. Results reveal no regular temporal change pattern in these parameters (highly abundant phyla and genera) during the experiment. Although the crewmembers’ oral microbiota temporally changed, it recovered quickly after the study subjects left the enclosed environment. The levels of IL-6, IL-10, and TNF-α in crewmembers’ saliva decreased after leaving the normal environment for the enclosed environment, indicating that their oral inflammatory response level was reduced. There were significant individual differences in crewmembers’ salivary microbiota, however, the shared living space reduced these differences. Moreover, air microbiota might have also played a significant role in reducing the individual differences. In summary, the enclosed environment did not result in persistent changes in human salivary microbiota and oral immunity. This study provides some insights for studying the effect of enclosed controlled environments on human immunity and microbiome.IMPORTANCE Long-term exposure to space environments may influence the human microbiome, the human immune system, and the intricate balance between the two, causing impaired immunity and increased disease susceptibility. It was previously believed that the main potential factors of long-term spaceflight on human health were microgravity and radiation. However, the effects of long-term enclosed environments on human health were unclear. Bioregenerative life support systems (BLSS) is a good experimental model for studying the effects of enclosed environments on human systemic microbiota and immune disorders. We monitored the microbiota and cytokines in the saliva of crewmembers before they entered BLSS, during their stay in BLSS, and after leaving BLSS. The results indicated long-term closed environment will not cause persistent changes in human salivary microbiota and immunity.

Altered Differentiation and Inflammation Profiles Contribute to Enhanced Innate Responses in Severe COPD Epithelium to Rhinovirus Infection.

BackgroundRespiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The consequences of the persisting inflammation and differentiation status in virus associated severe disease is not fully understood. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses.MethodsWell-differentiated primary bronchial epithelial cells (WD-PBECs) derived from severe COPD patients and age-matched healthy controls were cultured in the air-liquid interface (ALI) model. The differentiation phenotype, epithelial barrier integrity, pathological response and cytokine secreting profile of these cultures before and after HRV infection were investigated.ResultsWD-PBECs derived from severe COPD patients showed aberrant epithelium differentiation with a decreased proportion of ciliated cells but increased numbers of club cells and goblet cells compared with healthy controls. Tight junction integrity was compromised in both cultures following HRV infection, with heightened disruptions in COPD cultures. HRV induced increased epithelial cell sloughing, apoptosis and mucus hypersecretion in COPD cultures compared with healthy controls. A Th1/Th2 imbalance and a strong interferon and pro-inflammatory cytokine response was also observed in COPD cultures, characterized by increased levels of IFNγ, IFNβ, IP-10, IL-10 and decreased TSLP and IL-13 cytokine levels prior to HRV infection. Significantly enhanced basolateral secretion of eotaxin 3, IL-6, IL-8, GM-CSF were also observed in both mock and HRV infected COPD cultures compared with corresponding healthy controls. In response to HRV infection, all cultures displayed elevated levels of IFNλ1 (IL-29), IP-10 and TNFα compared with mock infected cultures. Interestingly, HRV infection dramatically reduced IFNλ levels in COPD cultures compared with healthy subjects.ConclusionAn altered differentiation phenotype and cytokine response as seen in severe COPD WD-PBECs may contribute to increased disease susceptibility and an enhanced inflammatory response to HRV infection.