The Effect of Maternal Diet on Fetal Outcomes

Maternal diet is critical for a successful pregnancy, as well as fetal health outcomes. Recent investigations reveal that dietary fats, such as omega-3 fatty acids, serve as substrates for the biosynthesis of specialized pro-resolving lipid mediators (SPM), which have anti-inflammatory and immune-stimulating effects. However, the relationship between maternal omega-3 fatty acid intake and maternal and cord plasma SPM levels in normal weight versus obese pre-pregnancy body mass index (BMI) deliveries is unclear. Pre-pregnancy obesity is associated with serious adverse pregnancy outcomes, including an increased risk of miscarriage, caesarean section, pre-eclampsia, and thromboembolism. Along with maternal risk, these complications lead to a four-fold increase in neonatal mortality, attributed to prematurity and macrosomia. Obesity-associated inflammation in early development, from intrauterine, peri-partum, and early childhood insults, may have lifelong impacts on the offspring. Studies are needed to identify modifiable factors in the intrauterine environment and developing fetus that can reduce inflammation and limit the negative consequences of obesity during pregnancy. Recent studies reveal certain omega-3 fatty acid derivatives actively attenuate and resolve pro-inflammatory processes. These SPMs may be key to the beneficial effects of omega-3 fatty acids. While the association between inflammation and obesity is clear, the protective mechanisms of SPMs against complicated birth in maternal-fetal health are a gap in the field. Currently, it is known that SPM production is dependent on intermediates of the omega-3 fatty acid metabolic pathway. However, it is unknown how material SPM production is related to omega-3 fatty acid intake. In recent studies, the Anderson Berry Lab has found strikingly low intakes of omega-3 fatty acids in pregnant woman. Thus, understanding the therapeutic value of omega-3 fatty acid intake and the role of SPMs in maternal-fetal outcomes addresses an unmet need. We hope to achieve two specific aims: 1) to identify the relationship between maternal omega-3 fatty acid intake and maternal and cord plasma SPM levels in normal weight pre-pregnancy BMI and obese pre-pregnancy BMI deliveries and 2) to evaluate similarities and differences in intakes, food security, and transportation security. Dr. Anderson Berry will provide review of the pathophysiology of adverse pregnancy outcomes, teach and assist in a literature search for relevant manuscripts to study, and provide quality assurance for accuracy throughout the data collection process. Over a 10-week period, the recruitment of additional subjects to augment current samples was successfully performed. Subject recruitment required the collection of informed consent, preparation of maternal and cord blood, preparation of placental tissue samples, and administration of a validated food frequency questionnaire. Over 100 new subjects were successfully enrolled in the study in this manner. Preliminary evaluation of differences in intakes, food security, and transportation security between obese and normal weight groups was completed. Due to technical equipment challenges and timing inconsistencies in data analysis, utilization of a targeted lipidomics approach to measure SPMs and determine the association between maternal omega-3 fatty acid dietary intake and maternal and cord plasma SPMs is in progress with the mass spectroscopy coil and protocol being fine-tuned on other, less valuable samples. In the future, we hope to employ a targeted lipidomics approach to measure SPM levels and determine the association between maternal omega-3 fatty acid dietary intake and maternal and cord plasma SPM levels at the time of delivery. We plan to analyze 80 existing samples (40 mother-infant pairs) consisting of maternal, cord, placental, and neonatal blood and breast milk, 32% of which had a pre-pregnancy BMI \u3e30. Clinical data from these subjects and dietary data measured via a validated food frequency questionnaire have been obtained. Dr. Nordgren will then determine SPM levels in plasma and placental samples via liquid chromatography-tandem mass spectrometry-mediated lipid identification. Key lipids and metabolites to be characterized will include 18- HEPE, 15-HETE, RvE1, RvD1, RvD2, RVD3, RvD5, 17(R)-RvD1, Maresin-1, and protectin-D1. This technique will also allow for determination of the association between maternal and cord serum concentrations of SPMs of obese pre-pregnancy BMI delivery. Levels and associations with clinical pregnancy outcomes will be analyzed. It is hypothesized that in the presence of obesity mediated inflammation, adequate omega-3 fatty acid intake provides a pool of substrates for increased SPM production, minimizing poor pregnancy outcomes.https://digitalcommons.unmc.edu/com_students_pres/1000/thumbnail.jp

Agricultural Dust Derived Bacterial Extracellular Vesicle Mediated Inflammation is Attenuated by DHA

Dietary long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and their pro-resolving metabolites are protective against atherosclerotic disease, and ameliorate systemic inflammatory conditions including lupus erythematosus, psoriasis, and bronchial asthma. Organic bioaerosol inhalation is a common and injurious hazard associated with agricultural occupations such as work in swine concentrated animal feeding operations (CAFOs) and is known to increase the risk for developing respiratory conditions such as asthma and COPD. Nearly all cells secrete membrane-bound vesicles (extracellular vesicles, EVs) that have the capacity to transmit protein, nucleic acid, and lipid signaling mediators between cells. Using a polymer-based isolation technique (ExoQuick, PEG) followed by ultracentrifugation, EVs were isolated from CAFO dust extracts, and were quantified and partially characterized. Here, we investigated the role of the n-3 PUFA docosahexaenoic acid (DHA) as a component of n-6 to n-3 PUFA mixtures used to recapitulate physiologically relevant dietary ratios in the resolution of inflammatory injury caused by exposure to EVs carried by agricultural organic dust in vitro. Primary human bronchial epithelial cells, fibroblasts and monocyte-derived macrophages were exposed to EVs isolated from swine CAFO dust. Cells were treated with mixtures of n-6 and n-3 PUFA during recovery from the EV-induced injury. CAFO dust extract (DE) was found to contain EVs that contributed significantly to the overall consequences of exposure to complete DE. DHA-rich PUFA ratios inhibited DE-derived EV-induced proinflammatory cytokine release dose-dependently. DHA-rich PUFA ratios also reversed the damaging effects of EVs on recellularization of lung matrix scaffolds, accelerated wound healing, and stimulated the release of pro-resolution mediators. These results underscore the importance of n-3 PUFA as anti-inflammatory compounds during recovery from EV-laden environmental dust exposure in the context of cellular responses in vitro, warranting future translational studies

The omega-3 fatty acid docosahexaenoic acid attenuates organic dust-induced airway inflammation.

Workers exposed to organic dusts from concentrated animal feeding operations (CAFOs) are at risk for developing airway inflammatory diseases. Available preventative and therapeutic measures for alleviating dust-induced lung disease are inadequate. Because omega-3 fatty acids can mitigate inflammatory processes, we aimed to determine whether nutritional supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA) could reduce the airway inflammatory consequences of exposures to organic dust. Aqueous extracts of organic dusts from swine CAFOs (ODE) were utilized. In DHA-pretreated human bronchial epithelial cells, lung fibroblasts, monocyte cell cultures, and precision-cut murine lung slices, we found that DHA pretreatment dose-dependently decreased ODE-induced inflammatory cytokine production. To determine the in vivo significance of DHA, C57BL/6 mice were orally administered DHA for seven days prior to treatment with intranasal ODE or saline inhalations. Animals treated with 2 mg DHA demonstrated significant reductions in ODE-induced bronchial alveolar lavage neutrophil influx and pro-inflammatory cytokine/chemokine production compared to mice exposed to ODE alone. Collectively, these data demonstrate that DHA affects several lung cells to reduce the airway inflammatory response to organic dust exposures. Dietary supplementation with DHA may be an effective therapeutic strategy to reduce the airway inflammatory consequences in individuals exposed to agriculture dust environments

Saturated Fat Intake Is Associated with Lung Function in Individuals with Airflow Obstruction: Results from NHANES 2007⁻2012

Nutritional status is a well-recognized prognostic indicator in chronic obstructive pulmonary disease (COPD); however, very little is known about the relationship between lung function and saturated fat intake. We used data from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) to assess the relationship between saturated fatty acid (SFA) intake and lung function in the general US adult population. Adults in NHANES (2007⁻2012) with pre-bronchodilator spirometry measurements and dietary SFA intake were included. Primary outcomes were lung function including forced expiratory volume in one second (FEV₁

Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust

BACKGROUND: Exposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin-1 (MaR1), in reducing organic dust-associated airway inflammation. METHODS: As bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0–200 nM MaR1, followed by 1–24 hour treatment with 5% hog confinement facility-derived organic dust extract (HDE). Alternatively, a mouse lung slice model was utilized in supportive cytokine studies. Supernatants were harvested and cytokine levels determined via enzyme-linked immunosorbent assays. Epithelial cell protein kinase C (PKC) isoforms α and ϵ, and PKA activities were assessed via radioactivity assays, and NFκB and MAPK-related signaling mechanisms were investigated using luciferase vector reporters. RESULTS: MaR1 dose-dependently reduced IL-6 and IL-8 production following HDE treatment of BECs. MaR1 also reduced HDE-stimulated cytokine release including TNF-α in a mouse lung slice model when given before or following HDE treatment. Previous studies have established that HDE sequentially activates epithelial PKCα and PKCϵ at 1 and 6 hours, respectively that regulated TNF-α, IL-6, and IL-8 release. MaR1 pretreatment abrogated these HDE-induced PKC activities. Furthermore, HDE treatment over a 24-hour period revealed temporal increases in NFκB, AP-1, SP-1, and SRE DNA binding activities, using luciferase reporter assays. MaR1 pretreatment did not alter the activation of NFκB, AP-1, or SP-1, but did reduce the activation of DNA binding at SRE. CONCLUSIONS: These observations indicate a role for MaR1 in attenuating the pro-inflammatory responses of BECs to organic dust extract, through a mechanism that does not appear to rely on reduced NFκB, AP-1, or SP-1-related signaling, but may be mediated partly through SRE-related signaling. These data offer insights for a novel mechanistic action of MaR1 in bronchial epithelial cells, and support future in vivo studies to test MaR1’s utility in reducing the deleterious inflammatory effects of environmental dust exposures

A High Docosahexaenoic Acid Diet Alters the Lung Inflammatory Response to Acute Dust Exposure

Agricultural workers are at risk for the development of acute and chronic lung diseases due to their exposure to organic agricultural dusts. A diet intervention using the omega-3 fatty acid docosahexaenoic acid (DHA) has been shown to be an effective therapeutic approach for alleviating a dust-induced inflammatory response. We thus hypothesized a high-DHA diet would alter the dust-induced inflammatory response through the increased production of specialized pro-resolving mediators (SPMs). Mice were pre-treated with a DHA-rich diet 4 weeks before being intranasally challenged with a single dose of an extract made from dust collected from a concentrated swine feeding operation (HDE). This omega-3-fatty-acid-rich diet led to reduced arachidonic acid levels in the blood, enhanced macrophage recruitment, and increased the production of the DHA-derived SPM Resolvin D1 (RvD1) in the lung following HDE exposure. An assessment of transcript-level changes in the immune response demonstrated significant differences in immune pathway activation and alterations of numerous macrophage-associated genes among HDE-challenged mice fed a high DHA diet. Our data indicate that consuming a DHA-rich diet leads to the enhanced production of SPMs during an acute inflammatory challenge to dust, supporting a role for dietary DHA supplementation as a potential therapeutic strategy for reducing dust-induced lung inflammation