Location: Immunity and Disease Prevention Research2014 Annual Report
The three objectives described here are linked by the overarching goal of examining the effect of diet and dietary components on inflammation. 1: Determine how diet quality (assessed using the Healthy Eating Index), nutritional status (assessed using biomarkers in a cross-sectional study) and adherence to a diet following Dietary Guidelines recommendations for intake of fat and fat-soluble vitamins affect immune function and inflammation. 1A: In the WHNRC Cross-Sectional Phenotyping Study of 396 healthy adults with a wide range of age and BMI, determine if diet quality is independently associated with systemic immune activation. 1B: In the WHNRC DGA Intervention Trial, an 8 wk, randomized, intervention trial of 80 adults (40 per group) with elevated BMI and other indicators of metabolic syndrome, determine (i) if following the DGA diet improves markers of systemic and intestinal inflammation relative to a typical American diet (based on NHANES data). We will also determine (ii) if the DGA diet moves the stool microbiome toward the healthy, low inflammation pattern identified in the Cross-Sectional Phenotyping Study, relative to the TAD. 2: Determine the degree of modulation and the mechanism of activation or inhibition of blood monocytes by different types of dietary fatty acids (including saturated fatty acids and docosahexaenoic acid) and by fruit-derived dietary polyphenols or their metabolites. 2A: Determine (1) whether the high fat/sugar challenge meal administered during the WHNRC Cross-Sectional Phenotyping Study induces postprandial monocyte activation; (2) whether this activation (assessed by IL-1ß release) is mediated by meal-derived saturated fatty acids (SFA); (3) whether and how the challenge meal-induced monocyte activation is suppressed by docosahexaenoic acid (DHA) in ex vivo experiments; and (4) in the WHNRC Intervention Trial, whether the DGA or TA diets affect challenge meal-induced monocyte activation relative to baseline and relative to the other diet. 2B: In a subset of subjects from the WHNRC Cross-Sectional Phenotyping Study, determine whether addition of DHA to the high fat/sugar challenge meal inhibits monocyte activation. 2C: In cell culture studies, determine whether selected bioactive phytochemicals known to inhibit TLR-derived signaling pathways, or their metabolites, also suppress SFA-induced monocyte activation. 3: Determine the mechanisms by which a diet rich in fruits affects inflammation and immune function by characterizing the effect of fruit-derived dietary polyphenols or their metabolites on cell surface receptor-mediated oxidation-reduction signaling. 3A: Determine whether a diet rich in fruit-derived dietary polyphenols modulates activation of leukocyte receptor tyrosine kinases (RTKs). 3B: Determine whether and how individual fruit-derived dietary polyphenols or their metabolites modulate activation of RTKs. 3C: Examine the relationships between leukocyte RTK activation and dietary and blood levels of fruit-derived dietary polyphenols or their metabolites, antioxidant status and oxidative stress.
Objective 1 will utilize samples exclusively from the two human studies, the Western Human Nutrition Research Center (WHNRC) Cross-Sectional Phenotyping Study and the WHNRC Dietary Guidelines for Americans (DGA) Intervention Trial. Thus the designs of these studies are described under Objective 1 and the sample size calculations given relate to the goals of Objective 1. 1A: Such activation takes several forms and we will differentiate among pathways defined by the activity of pro-inflammatory T-helper (Th) cells (Th1, Th2 and Th17) and T-regulatory (Treg) cells. We hypothesize that those with low diet quality (including high solid fat and added sugar [SOFA] and low n-3 polyunsaturated fatty acids [PUFA]), or low intake (or status) of key nutrients (including vitamin D) will have greater immune activation after adjustment for appropriate covariates (e.g., age, BMI and sex). In addition, we hypothesize that dysbiosis of the gut microbiota (e.g., high levels of Proteobacteria) will be associated with gut inflammation that, in turn, will be associated with systemic immune activation. Microbiota will be assessed in stool using 16S rRNA gene sequence and inflammation by stool calprotectin and neopterin levels. 1B: DGA diet is optimized to minimize inflammation by decreasing SOFA, and increasing vitamin D, n-3 PUFA, fruit and vegetable intake. Objectives 2 and 3 will also utilize samples from both of these studies. In addition, Objectives 2 and 3 will utilize cell culture methods to examine effects of dietary components on regulating cellular functions, including the effects of DHA (Objective 2B) and phytochemicals (Objectives 2C and 3B) on monocyte activation and insulin receptor (IR) function (Objective 3B).
This is a new project which began in January of 2014 and continues research from the previous project, “Dietary Modulation of Immune Function and Oxidative Stress”, 5306-51530-018-00D”. Please refer to the previous project for additional information. Data analysis continues on results from the vitamin A supplementation study conducted under Objective 1 of the preceding project. A publication should be submitted in 2015. In addition, work has continued on incoming and outgoing agreements that carried over from the previous project. In particular, work continues on a human feeding trial evaluating the bioavailability of beta-carotene, a provitamin A carotenoid, from a traditional African food (gari) prepared from standard or biofortified cassava. In addition, a manuscript is being prepared to report the results of the trial conducted in Bangladesh to examine the effects of newborn vitamin A supplementation in improving immune function. In addition a new study has begun with the same study volunteers to examine the effect of vitamin A supplementation on gut microbiota and vaccine response. Study visits for this study commenced in June and will continue for a year in Dhaka, Bangladesh. In addition, samples are arriving in our laboratory from several U.S. clinical sites participating in two studies examining the effect of vitamin D on bone health in both HIV-positive and HIV-negative adolescents and young adults taking the antiretroviral drug Tenofovir. Finally, samples are also arriving for analysis to characterize the association of serum vitamin D and parathyroid hormone levels with markers of bone health in HIV-infected and uninfected children.
1. Gut microbiota affects vaccine responses. The composition of the community of microbes that inhabits the human intestine is likely to have a profound influence on both infant and adult health. An ARS scientist from Davis, California, worked with collaborating scientists to conduct a study among healthy Bangladeshi infants up to 15 weeks of age to determine if the intestinal microbiota (as assessed from fecal samples using DNA-based methods) is associated with standard vaccine responses. The study demonstrated that a high abundance of intestinal bacteria from the phylum Actinobacteria (and particularly from the genus Bifidobacterium) was associated with higher responses to several vaccines, including the oral polio vaccine, the tetanus toxoid vaccine and the tuberculosis vaccine. Multiple measures of vaccine response were affected, including the systemic antibody response, the delayed-type hypersensitivity skin-test response, and the T-cell proliferative response. The implication of this finding is that interventions to promote a healthy microbial community using live bacteria or appropriate foods may improve the efficacy of vaccination programs.
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Bornhorst, G., Rutherfurd, S.M., Roman, M., Burri, B.J., Moughan, P.J., Singh, R. 2014. Gastric pH distribution and mixing of soft and rigid food particles in the stomach using a dual-marker technique. Food Biophysics. 9:292-300. DOI 10.1007/s11483-014-9354-3.
Havens, P.L., Hazra, R., Stephensen, C.B., Kiser, J., Flynn, P.M., Wilson, C.M., Rutledge, B., Bethel, J., Pan, C., Woodhouse, L.R., Van Loan, M.D., Lui, N., Lujan-Zilbermann, J., Baker, A., Kapogiannis, B.G., Gordon, C.M., Mulligan, K. 2014. Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate. Antiviral Therapy. DOI: 10.3851/IMP2755.
Havens, P.L., Hazra, R., Stephensen, C.B., Kiser, J., Flynn, P.M., Wilson, C.M., Rutledge, B., Bethel, J., Pan, C., Woodhouse, L.R., Van Loan, M.D., Lui, N., Lujan-Zilbermann, J., Baker, A., Kapogiannis, B.G., Gordon, C.M., Mulligan, K. 2014. Vitamin D Supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate. Antiviral Therapy. DOI: 10.3851/imp2755.