Metabolomic Markers of Response to Fish Oil Supplementation: We recently completed a study entitled “Variation in the ALOX5 gene and response to omega-3 fatty acid supplements” (R21 AT003411, C. Stephensen, PI; ClinicalTrials.gov Identifier, NCT00536185). A total of 116 subjects of African ancestry were randomized within ALOX5 promoter genotypes to 5 g/day fish oil concentrate or 5 g/day corn/soy placebo oil for a six week intervention; 98 subjects completed the trial. In brief, there was a significant, beneficial effect of fish oil supplementation on plasma lipid and lipoprotein profiles and on markers of inflammation. However, there was a wide range of responses for these variables. We hypothesize that accounting for variability in subject responses to fish oil intervention will increase our ability to see significant differences in markers of inflammation linked to development of chronic inflammatory diseases. In the current study we are using two markers of response to supplementation to quantify this variability. The first marker is the change in fatty acid composition of erythrocyte cell membranes in response to supplementation, focusing on arachadonic acid (AA) and the two principal omega-3 fatty acids from fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These data are available from the parent study. The second marker set will be developed from plasma concentrations of a panel of 18- to 20-carbon omega-3 and omega-6 fatty acid metabolites that will be measured along with an array of leukotrienes (LT), prostaglandins (PG) and thromboxanes (TX) for the study proposed here. We will determine if these erythrocyte or plasma biomarkers of omega-3 intake will predict changes in markers of inflammation by specific, highly purified cell types (monocyte, granulocyte, lymphocyte) more reliably than using the fish oil/placebo designation. Monocyte data are available from the parent study while granulocyte and lymphocyte samples saved from the parent study will be analyzed for this proposal. We will also determine if these biomarkers will predict changes in plasma markers of systemic inflammation, including plasma concentrations of LT, PG and TX measured for this study, and concentrations of multiple plasma protein markers of inflammation to be measured for this study, including cytokines, chemokines, soluble cell adhesion molecules, acute phase proteins, proteases and anti-proteases, and complement components. This study involves co-investigators, including Dr. Hooman Allayee of the
Fish oil to prevent asthma exacerbations in patients with ALOX5 polymorphisms: This proposal describes a clinical study that is designed to study the effects of the supplemental intake of enriched omega-3 polyunsaturated fatty acids in patients with moderate to severe asthma. It is a collaborative study with Dr. Nicholas Kenyon of the UC Davis Department of Medicine and Dr. Gertrud Schuster, UCD Nutrition Department. The study is based on the fact that the pro-inflammatory leukotriene family of molecules (produced from the precursor molecule, arachidonic acid) plays a significant role in the pathogenesis of asthma and their production can be inhibited by the omega-3 fatty acids found in fish oil. Inhibiting the detrimental effects of leukotrienes is a key goal of controller therapy using pharmaceutical agents in severe asthmatics. Some asthmatic patients appear to have specific mutations of the arachidonate 5-lipoxygenase (ALOX5) gene, one gene that regulates the production of the inflammatory leukotrienes. Omega-3 fatty acids can interfere with the arachidonic acid pathway and decrease the production of leukotrienes, and this may benefit moderate and severe asthma patients. The hypothesis of this study is that omega-3 fatty acid supplements, added on to a patient’s asthma medication regimen, can decrease the number of minor asthma exacerbations compared to patients who do not receive the supplement. Furthermore, we believe that asthma patients with specific ALOX5 gene mutations will benefit most. We will enroll 30 asthma subjects to take part in this trial. They will undergo genotyping of the ALOX5 gene and be treated with omega3-fatty acids and placebo over a nine month period. We expect that this strategy will allow us to discover which moderate and severe asthma patients will benefit most from supplements of omega-3 fatty acids. The study was funded by the UC Davis Center for Health and Nutrition Research. The clinical phase of the study is complete and laboratory work is in progress.
Vitamin D and Inflammation in Pregnancy: This is a collaborative study with Dr. Bryon Jacoby in the Department of Obstetrics and Gynecology at the UC Davis Medical Center (ClinicalTrials.gov Identifier, NCT01417351). The study is examining the effects of vitamin D supplementation during pregnancy on maternal health and immune function. The study hypothesis is that vitamin D supplementation at levels greater than the current recommendation is beneficial for maternal health during pregnancy. In particular, there is evidence that vitamin D deficiency during pregnancy puts women at greater risk for diseases like pre-eclampsia, which may be due to an imbalance in immune function that alters interaction with the placenta. Vitamin D may have an anti-inflammatory during normal pregnancy and vitamin D deficiency may disrupt this normal anti-inflammatory activity with potentially adverse consequences for the mother and infant. In the present study, pregnant women who participate in the study receive either 400 IU or 2,000 IU of vitamin D per day for the duration of their pregnancy. The investigators will collect blood at three time points during pregnancy (16-20 weeks, 26-28 weeks, 36 weeks gestation) for analysis of immune function and vitamin D status. The investigators are also collecting data on clinical parameters, such as blood pressure and glucose tolerance. The primary outcomes will be changes in the expression of inflammatory and regulatory cytokines measured in cultured lymphocytes by flow cytometry. Recruitment for this study is in progress.
Effect of Vitamin D Supplementation on Immune Function: In this study adult volunteers with vitamin D insufficiency (serum 25(OH)D 25-50 nmol/L) will be recruited and given one of three doses of vitamin D3 for 12 weeks: 400, 2,000 and 5,000 IU per day. The underlying hypothesis is that the higher doses will improve specific aspects of immune function that are impaired by vitamin D insufficiency (ClinicalTrials.gov Identifier, NCT01399151) in comparison with the 400 IU “control” dose. Volunteers will be given a booster immunization with the tetanus toxoid vaccine after 8 weeks of supplementation to examine effects on response to immunization. The specific objectives of this study are as follows: (1) Determine if supplements decrease the production of proinflammatory and increase the production of anti-inflammatory cytokines and chemokines by innate immune cells stimulated ex vivo. (2) Determine if supplements decrease serum markers of inflammation and autoimmune activity, and increase serum levels of defensive molecules. (3) Determine if supplements decrease blood levels of proinflammatory T-helper type 1 (Th1) and Th17 cells and increase levels of anti-inflammatory T-regulatory (Treg) and Th2 cells. (4) Determine if supplements increase expression of the anti-bacterial protein cathelicidin in granulocytes. Recruitment for this study is in progress.
Efficacy of Newborn Vitamin A Supplementation in Improving Immune Function: This project is being conducted in
Effect of vitamin A supplementation at birth on gut colonization with commensal microbiota and enteric pathogens: Vitamin A deficiency is common in developing countries and is associated with decreased innate and adaptive immunity at mucosal surfaces and as a result increased infections and death, particularly among infants and children. Many of the infections associated with vitamin A deficiency in infants are closely associated with the intestinal mucosa. The interplay between mucosal immunity and the intestinal microbiota in infection and many chronic diseases across the lifespan is an area of active research. A current study of early supplementation with high dose vitamin A shortly after birth in
Randomized, Placebo-Controlled Trial of the Safety and Effectiveness of Vitamin D Supplement to Improve Tubular Reabsorption of Phosphate and Decrease Bone Turnover in Adolescents and Young Adults with HIV Infection Being Treated with Antiretroviral Therapy Containing Tenofovir Compared to Those Being Treated with Antiretroviral Therapy Not Containing Tenofovir: Dr. Stephensen is a co-investigator on this trial being conducted by the Adolescent Trials Network (ATN) funded by NIH to examine clinical care issues in adolescents and young adults with HIV infection. This study examins the effect of vitamin D supplementation (50,000 IU vitamin D3 vs. placebo directly-observed therapy at 4 week intervals) in subjects receiving and not receiving tenofovir. Tenofovir therapy causes loss of bone mineral density and this loss may be ameliorated by vitamin D supplementation. Previous work has shown that subjects in the ATN have a high risk of vitamin D deficiency. Subjects will be enrolled and followed for 12 weeks. The primary objectives of the study are to compare the change in renal tubular reabsorption of phosphate (measured as TRP and TmP/GFR) and markers of bone turnover (BAP, NTX, and PTH) in adolescent and young adult patients with HIV being treated with tenofovir, to the change in values in those patients being treated with antiretrovirals other than tenofovir, and to measure the effect of vitamin D or placebo within and between the four study groups, during 12 weeks of treatment with vitamin D3, 50,000 IU administered once every four weeks. The principal investigator of the study is Dr. Peter Havens of the Medical College of Wisconsin.