Dietary approaches for normalizing dysbiosis induced by high-fat, obesogenic diets.

PURPOSE OF REVIEW: Given the world-wide problem of obesity, this review considers what types of dietary changes can be utilized to minimize the adverse effects of an obesogenic diet on the intestinal microbiota. RECENT FINDINGS: In rodents fed high-fat diets containing lard or Western blend fats to induce obesity, switching to high-fat diets formulated to contain higher amounts of fiber or fiber-containing foods, plant extracts, omega-3 fatty acids or whole grains has beneficial effects on body weight, metabolic alterations, and the intestinal microbiota. Several studies show that the intestinal microbiota has a role in mediating the beneficial health effects of these dietary factors. Many aspects of the microbiota observed in animals when healthful dietary components were added to the feed have also been observed in humans who follow healthful dietary patterns. SUMMARY: The data shows that specific foods and macronutrients can normalize the obesity-associated microbiota and improve metabolic health. These findings support the design of dietary interventions that would allow individuals to focus on diet quality independently of weight loss to mitigate the adverse sequelae of obesity.

Proton Pump Inhibitor Use and Obesity-Associated Cancer in the Women's Health Initiative.

Proton pump inhibitors (PPIs) have off-target activity on fatty acid synthase (FASN), a critical enzyme in energy balance and cancer growth. We evaluated risk of common obesity-related cancers: breast, colorectal (CRC), and endometrial, with use of PPI and histamine-2 receptor antagonists (H2RA) in 124,931 postmenopausal women enrolled in the Women's Health Initiative. Incident cancer cases were physician-adjudicated. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for cancer incidence after year 3. There were 7956 PPI ever users and 9398 H2RA only users. Ever use of either PPI or H2RA was not associated with risk of breast cancer (n = 9186) nor risk of endometrial cancer (n = 1231). The risk of CRC (n = 2280) was significantly lower in PPI users (HR = 0.75, 95% CI = 0.61-0.92), but not in H2RA users (HR = 1.13, 95% CI = 0.97-1.31). The association of PPI use with CRC was apparent regardless of BMI or NSAID use, and was stronger with longer PPI duration (p = 0.006) and potency (p = 0.005). The findings that PPI use, but not H2RA use, demonstrate an inverse dose-response relationship with risk of CRC is consistent with preclinical data showing FASN inhibition prevents colon cancer progression and supports a role of PPI in CRC prevention.

A New Score for Quantifying Adherence to a Cancer-Preventive Mediterranean Diet.

Herein a Mediterranean Cancer Preventive Diet Score (MCAP Score) is proposed to quantify adherence to both traditional Mediterranean fat intakes and the current dietary recommendations for cancer prevention. The scoring uses research-backed cutoff values, unlike other scores that are based on a population-specific median value. The MCAP score awards positive points for seven preventive food categories, including Mediterranean fats (monounsaturated fats, ω-3 fatty acids) associated with reduced adiposity, and negative points for four food categories associated with increased cancer risk, including ultra-processed foods. In a randomized trial of 120 persons at increased risk of colon cancer, the baseline MCAP Score averaged seven of 20 possible points. Counseling for a Healthy Diet or a Mediterranean Diet improved the score to either 11 or 13 points, respectively, and the highest score observed in any individual was 20 points. The MCAP Score was correlated with serum carotenoids and serum ω-3 fatty acids, and improvements in the score were associated with weight loss over six months of study. The MCAP Score is therefore proposed as a new method to assess adherence to a Mediterranean type of diet for cancer prevention using absolute criteria that will facilitate comparisons of dietary intakes across studies.

Changes in Serum, Red Blood Cell, and Colonic Fatty Acids in a Personalized Omega-3 Fatty Acid Supplementation Trial.

This study evaluated changes in fatty acids from sera, red blood cells, and colonic biopsies from a phase Ib clinical trial of personalized ω-3 fatty acid dosing in 47 healthy volunteers. The trial aimed to reduce colonic prostaglandin E2 (PGE2), a pro-inflammatory product of arachidonic acid (AA) oxidation. The personalized doses ranged 2-10 grams/day (54% eicosapentaenoic acid, EPA, 24% other ω-3 fatty acids). In colon, increases in ω-3 highly unsaturated fatty acids (HUFA) and EPA:AA ratios each were correlated with decreases in PGE2. Changes in either colonic EPA:AA ratios or ω-3 HUFA were significantly correlated with changes in the same fatty acid measures in red blood cells or serum. The only blood-based measure significantly correlated with changes in colonic PGE2 was change in red blood cell ω-3 HUFA (ρ = -0.39), and the increase in red blood cell ω-3 HUFA was significantly greater in participants who had at least a median reduction in colonic PGE2 vs. those who did not. In summary, fatty acid changes in blood did reflect fatty acid changes in the colon, but additional factors will be needed for optimizing dosing models that seek to predict the anti-inflammatory effects of ω-3 fatty acids on the colon.

Increases in Colonic Bacterial Diversity after ω-3 Fatty Acid Supplementation Predict Decreased Colonic Prostaglandin E2 Concentrations in Healthy Adults.

BACKGROUND: The intestinal microbiome is an important determinant of inflammatory balance in the colon that may affect response to dietary agents. OBJECTIVE: This is a secondary analysis of a clinical trial, the Fish Oil Study, to determine whether interindividual differences in colonic bacteria are associated with variability in the reduction of colonic prostaglandin E2 (PGE2) concentrations after personalized supplementation with ω-3 (n-3) fatty acids. METHODS: Forty-seven healthy adults (17 men, 30 women, ages 26-75 y) provided biopsy samples of colonic mucosa and luminal stool brushings before and after personalized ω-3 fatty acid supplementation that was based on blood fatty acid responses. Samples were analyzed using 16S ribosomal RNA sequencing. The data analyses focused on changes in bacterial community diversity. Linear regression was used to evaluate factors that predict a reduction in colonic PGE2. RESULTS: At baseline, increased bacterial diversity, as measured by the Shannon and Inverse Simpson indexes in both biopsy and luminal brushing samples, was positively correlated with dietary fiber intakes and negatively correlated with fat intakes. Dietary supplementation with ω-3 fatty acids increased the Yue and Clayton community dis-similarity index between the microbiome in luminal brushings and colon biopsy samples post-supplementation (P = 0.015). In addition, there was a small group of individuals with relatively high Prevotella abundance who were resistant to the anti-inflammatory effects of ω-3 fatty acid supplementation. In linear regression analyses, increases in diversity of the bacteria in the luminal brushing samples, but not in the biopsy samples, were significant predictors of lower colonic PGE2 concentrations post-supplementation in models that included baseline PGE2, baseline body mass index, and changes in colonic eicosapentaenoic acid-to-arachidonic acid ratios. The changes in bacterial diversity contributed to 6-8% of the interindividual variance in change in colonic PGE2 (P = 0.001). CONCLUSIONS: Dietary supplementation with ω-3 fatty acids had little effect on intestinal bacteria in healthy humans; however, an increase in diversity in the luminal brushings significantly predicted reductions in colonic PGE2. This trial was registered at www.clinicaltrials.gov as NCT01860352.

Effect of prenatal EPA and DHA on maternal and umbilical cord blood cytokines.

BACKGROUND: Investigators have hypothesized that omega-3 fatty acid supplementation may modulate the immune response. However, available evidence is conflicting. We performed this study to investigate the effect of prenatal eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-rich fish oil supplementation on maternal and fetal cytokine production. METHODS: This study is a secondary analysis of a randomized controlled trial designed to assess whether prenatal EPA- or DHA-rich fish oil supplementation would prevent perinatal depressive symptoms among women at risk. Enrolled participants received EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA) or soy oil placebo. Maternal venous blood was collected at enrollment (12-20 weeks gestation) and after supplementation (34-36 weeks gestation). Umbilical cord blood was collected at delivery. We analyzed stored plasma specimens for 16 human cytokines using multiplex immunoassays. Maternal and cord blood cytokine levels were compared among the treatment groups. Associations of serum DHA and EPA with maternal and cord blood cytokines were explored via regression analysis. RESULTS: We enrolled 126 women, of whom 118 completed the trial. Prenatal supplementation with EPA-rich fish oil significantly lowered maternal IL6, IL15, and TNFα concentrations. However, supplementation with DHA-rich fish oil had no significant effect on maternal cytokine profiles. Maternal serum DHA fraction was significantly associated with IL1α, and maternal serum DHA and EPA fractions were significantly associated with IL 10 concentrations after supplementation. Compared with placebo, supplementation with EPA- or DHA-rich fish oils had no significant effect on cord blood cytokine concentrations. CONCLUSIONS: Prenatal supplementation with EPA-rich fish oil significantly reduced levels of several inflammatory cytokines in maternal plasma, while prenatal DHA-rich fish oil had no significant effect on cytokine concentrations. Supplementation with EPA- and DHA- rich fish oil had no significant effect on umbilical cord blood cytokine concentrations. TRIAL REGISTRATION: Clinical Trial Registration: registration number NCT00711971 7/7/2008.

Fatigue reduction diet in breast cancer survivors: a pilot randomized clinical trial.

PURPOSE: Fatigue is a prevalent and burdensome effect of breast cancer. Fatigue has been linked to chronic inflammation, and diets high in antioxidant nutrients have been associated with lesser prevalence and severity of fatigue. Studies are needed, however, to test if antioxidant-rich diets could improve fatigue. METHODS: Pilot, randomized, trial conducted between January 2014 and April 2015, to investigate if a 3-month diet rich in fruit, vegetables, whole grains, and omega-3 fatty acid-rich foods, named the fatigue reduction diet (FRD), improved fatigue and sleep compared to an attention control, named the general health curriculum (GHC). 30 stage 0 to III breast cancer survivors, who had completed cancer treatments, were randomized: 15 receiving the FRD and 15 the GHC. Primary outcome was change in fatigue, as measured by the brief fatigue Inventory, from baseline to 3 months analyzed using linear mixed models. Secondary analyses were changes in sleep quality, serum carotenoids, and fatty acids. RESULTS: From baseline to 3-month fatigue improved by 44 ± 39% in FRD compared to 8 ± 34% in GHC (p = 0.01); sleep quality improved by 2.5 ± 3.3 points in FRD, and diminished by 0.9 ± 2.3 in GHC (p = 0.03); serum total carotenoids (p < 0.01), ß-cryptoxanthin (p = 0.02), lutein (p = 0.05), zeaxanthin (p = 0.01), lycopene (p = 0.05), omega-3 fatty acids (p < 0.01), and ratio of omega-3:omega-6 fatty acids (p = 0.02) were significantly increased, and percent saturated fatty acids were decreased (p = 0.04) in FRD; γ-tocopherol was significantly increased in GHC (p = 0.03), and there was a significant visit by group difference for α-carotene between the study groups (p = 0.05). CONCLUSIONS: The FRD intervention improved fatigue and sleep in breast cancer survivors compared to the GHC. FRD diet could provide a non-toxic treatment strategy for persistent fatigue.

Nutritional Correlates of Human Oral Microbiome.

BACKGROUND: Despite many potential effects of the oral microbiome on oral and systemic health, scant information is available regarding the associations between diet and the oral microbiome. METHODS: Oral rinse DNA samples from 182 participants in a population-based case-control study for colorectal cancer were used to amplify a V3-V4 region of bacterial 16S rRNA gene. The amplicons were sequenced using Illumina MiSeq paired end chemistry on 2 runs, yielding approximately 33 million filtered reads that were assigned to bacterial classes. Relative abundances of each class and family as well microbial diversity/richness indices were correlated with selected dietary intakes from a food frequency questionnaire. RESULTS: Saturated fatty acids (SFAs) and vitamin C intakes were consistently correlated with alpha (within-subjects) diversity indexes in both richness and diversity. SFA intake was positively correlated with relative abundance of betaproteobacteria and fusobacteria. Vitamin C and other vitamins with correlated intakes-for example, the B vitamins and vitamin E-exhibited positive correlations with fusobacteria class, its family Leptotrichiaceae and a clostridia family Lachnospiraceae. In addition, glycemic load was positively correlated with Lactobacillaceae abundance. CONCLUSION: The observed associations in this study were modest. However, the results suggest that the effects of diets are likely to be habitat specific, and observations from the gut microbiome are not transferrable to the oral microbiome. Further studies are warranted, incorporating a range of host biomarkers, such as cytohistological, molecular, or biochemical measurements, in order to address biological consequences of these dietary intakes in human oral health.

Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet, Predict Prostaglandin E2 in Normal Human Colon Tissue.

Prostaglandin E2 (PGE2) in the colon is a pro-inflammatory mediator that is associated with increased risk of colon cancer. In this study, expression of genes in the PGE2 pathway were quantified in colon biopsies from a trial of a Mediterranean versus a Healthy Eating diet in 113 individuals at high risk for colon cancer. Colon biopsies were obtained before and after 6 months of intervention. Quantitative, real-time PCR was used to measure mRNA expression of prostaglandin H synthases (PTGS1 and 2), prostaglandin E synthases (PTGES1 and 3), prostaglandin dehydrogenase (HPGD), and PGE2 receptors (PTGER2, PTGER4). The most highly expressed genes were HPGD and PTGS1. In multivariate linear regression models of baseline data, both colon saturated fatty acid concentrations and PTGS1 expression were significant, positive predictors of colon PGE2 concentrations after controlling for nonsteroidal anti-inflammatory drug use, gender, age, and smoking status. The effects of dietary intervention on gene expression were minimal with small increases in expression noted for PTGES3 in both arms and in PTGER4 in the Mediterranean arm. These results indicate that short-term dietary change had little effect on enzymes in the prostaglandin pathway in the colon and other factors, such as differences in fatty acid metabolism, might be more influential.

Markers of systemic exposures to products of intestinal bacteria in a dietary intervention study.

PURPOSE: Systemic exposures to intestinal bacteria may play a role in the etiology of the chronic, low-grade inflammation that is associated with western diets. Production of lipopolysaccharide-binding protein (LBP) is one biomarker of increased exposures to intestinal bacteria. This study evaluated whether changes in diet quality could affect serum LBP. METHODS: This was a randomized, controlled trial of Mediterranean and Healthy Eating diets over 6 months in 120 healthy subjects at increased risk of colon cancer. Blood samples obtained before and after intervention were analyzed for LBP, branched-chain fatty acids characteristic of intestinal bacteria, micronutrients and cytokines. Data were analyzed for changes in LBP over time and for predictors of LBP. RESULTS: Serum concentrations of branched-chain bacterial fatty acids declined significantly in both diet groups. However, there was no significant change in mean serum LBP concentrations with either diet intervention. In serum, LBP was positively associated with CRP and negatively associated with carotenoids both before and after intervention. After intervention, LBP was predicted positively by both CRP and bacterial fatty acid concentrations in serum, and negatively by serum carotenoids and the ω3/ω6 fatty acid ratio. This model accounted for 30 % of the inter-individual variation in serum LBP after intervention. CONCLUSIONS: These results indicate that dietary intervention over 6 months was insufficient to alter serum LBP. The relationships with inflammation-related markers, however, indicate that anti-inflammatory strategies other than changes in diet quality, such as weight loss or improved fitness, may have more potential for reducing systemic markers of LPS exposures in well-nourished populations.

Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer.

Colorectal cancer (CRC) remains a significant cause of mortality. Inhibitors of cyclooxygenase (COX) and thus prostaglandin E2, are promising CRC preventives, but have significant toxicities. Ginger has been shown to inhibit COX, to decrease the incidence and multiplicity of adenomas, and decrease PGE2 concentrations in subjects at normal risk for CRC. This study was conducted to determine the effects of 2.0 g/d of ginger given orally on the levels of PGE2, leukotriene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-, 12-, & 15-hydroxyeicosatetraenoic acid, in the colonic mucosa of subjects at increased risk for CRC. We randomized 20 subjects to 2.0 g/d ginger or placebo for 28 d. At baseline and Day 28, a flexible sigmoidoscopy was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per amount of protein or free arachidonic acid (AA). There was a significant decrease in AA between baseline and Day 28 (P = 0.05) and significant increase in LTB4 (P = 0.04) when normalized to protein, in subjects treated with ginger versus placebo. No other changes in eicosanoids were observed. There was no difference between the groups in total adverse events (AE; P = 0.06). Ginger lacks the ability to decrease eicosanoid levels in people at increased risk for CRC. Ginger did appear to be both tolerable and safe; and could have chemopreventive effects through other mechanisms. Further investigation should focus on other markers of CRC risk in those at increased CRC risk.

Effects of vitamin E from supplements and diet on colonic α- and γ-tocopherol concentrations in persons at increased colon cancer risk.

The available evidence indicates that γ-tocopherol has more potential for colon cancer prevention than α-tocopherol, but little is known about the effects of foods and supplements on tocopherol levels in human colon. This study randomized 120 subjects at increased colon cancer risk to either a Mediterranean or a Healthy Eating diet for 6 mo. Supplement use was reported by 39% of the subjects, and vitamin E intake from supplements was twofold higher than that from foods. Serum α-tocopherol at baseline was positively predicted by dietary intakes of synthetic vitamin E in foods and supplements but not by natural α-tocopherol from foods. For serum γ-tocopherol, dietary γ-tocopherol was not a predictor, but dietary α-tocopherol was a negative predictor. Unlike with serum, the data supported a role for metabolic factors, and not a direct effect of diet, in governing concentrations of both α- and γ-tocopherol in colon. The Mediterranean intervention increased intakes of natural α-tocopherol, which is high in nuts, and decreased intakes of γ-tocopherol, which is low in olive oil. These dietary changes had no significant effects on colon tocopherols. The impact of diet on colon tocopherols therefore appears to be limited.

Effects of a Mediterranean Diet Intervention on Anti- and Pro-Inflammatory Eicosanoids, Epithelial Proliferation, and Nuclear Morphology in Biopsies of Normal Colon Tissue.

This randomized trial evaluated the effects of intervention with either a Healthy Eating or a Mediterranean diet on colon biomarkers in 120 healthy individuals at increased colon cancer risk. The hypothesis was that eicosanoids and markers of proliferation would be favorably affected by the Mediterranean diet. Colon epithelial biopsy tissues and blood samples were obtained at baseline and after 6 mo of intervention. Colonic eicosanoid concentrations were evaluated by HPLC-MS-MS, and measures of epithelial proliferation and nuclear morphology were evaluated by image analysis of biopsy sections. There was little change in proinflammatory eicosanoids and in plasma cytokine concentrations with either dietary intervention. There was, however, a 50% increase in colonic prostaglandin E3 (PGE3), which is formed from eicosapentanoic acid, in the Mediterranean arm. Unlike PGE2, PGE3, was not significantly affected by regular use of non-steroidal anti-inflammatory drugs at baseline, and normal weight subjects had significantly higher colon PGE3 than overweight or obese subjects. Increased proliferation in the colon at baseline, by Ki67 labeling, was associated with morphological features that defined smaller nuclei in the epithelial cells, lower colon leukotriene concentrations and higher plasma cytokine concentrations. Dietary intervention had little effect on measures of epithelial proliferation or of nuclear morphology. The increase in PGE3 with a Mediterranean diet indicates that in normal colon, diet might affect protective pathways to a greater extent than proinflammatory and proliferative pathways. Hence, biomarkers from cancer models might not be relevant in a true prevention setting.

Diet and proinflammatory cytokine levels in head and neck squamous cell carcinoma.

BACKGROUND: Proinflammatory cytokine levels may be associated with cancer stage, recurrence, and survival. The objective of this study was to determine whether cytokine levels were associated with dietary patterns and fat-soluble micronutrients in patients with previously untreated head and neck squamous cell carcinoma (HNSCC). METHODS: This was a cross-sectional study of 160 patients with newly diagnosed HNSCC who completed pretreatment food frequency questionnaires (FFQs) and health surveys. Dietary patterns were derived from FFQs using principal component analysis. Pretreatment serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) were measured using an enzyme-linked immunosorbent assay, and serum carotenoid and tocopherol levels were measured by high-performance liquid chromatography. Multivariable ordinal logistic regression models examined associations between cytokines and quartiles of reported and serum dietary variables. RESULTS: Three dietary patterns emerged: whole foods, Western, and convenience foods. In multivariable analyses, higher whole foods pattern scores were significantly associated with lower levels of IL-6, TNF-α, and IFN-γ (P ≤ .001, P = .008, and P = .03, respectively). Significant inverse associations were reported between IL-6, TNF-α, and IFN-γ levels and quartiles of total reported carotenoid intake (P = .006, P = .04, and P = .04, respectively). There was an inverse association between IFN-γ levels and serum α-tocopherol levels (P = .03). CONCLUSIONS: Consuming a pretreatment diet rich in vegetables, fruit, fish, poultry, and whole grains may be associated with lower proinflammatory cytokine levels in patients with HNSCC.

The Effect of an mHealth Self-Monitoring Intervention (MI-BP) on Blood Pressure Among Black Individuals With Uncontrolled Hypertension: Randomized Controlled Trial.

BACKGROUND: Hypertension is one of the most important cardiovascular disease risk factors and affects >100 million American adults. Hypertension-related health inequities are abundant in Black communities as Black individuals are more likely to use the emergency department (ED) for chronic disease-related ambulatory care, which is strongly linked to lower blood pressure (BP) control, diminished awareness of hypertension, and adverse cardiovascular events. To reduce hypertension-related health disparities, we developed MI-BP, a culturally tailored multibehavior mobile health intervention that targeted behaviors of BP self-monitoring, physical activity, sodium intake, and medication adherence in Black individuals with uncontrolled hypertension recruited from ED and community-based settings. OBJECTIVE: We sought to determine the effect of MI-BP on BP as well as secondary outcomes of physical activity, sodium intake, medication adherence, and BP control compared to enhanced usual care control at 1-year follow-up. METHODS: We conducted a 1-year, 2-group randomized controlled trial of the MI-BP intervention compared to an enhanced usual care control group where participants aged 25 to 70 years received a BP cuff and hypertension-related educational materials. Participants were recruited from EDs and other community-based settings in Detroit, Michigan, where they were screened for initial eligibility and enrolled. Baseline data collection and randomization occurred approximately 2 and 4 weeks after enrollment to ensure that participants had uncontrolled hypertension and were willing to take part. Data collection visits occurred at 13, 26, 39, and 52 weeks. Outcomes of interest included BP (primary outcome) and physical activity, sodium intake, medication adherence, and BP control (secondary outcomes). RESULTS: We obtained consent from and enrolled 869 participants in this study yet ultimately randomized 162 (18.6%) participants. At 1 year, compared to the baseline, both groups showed significant decreases in systolic BP (MI-BP group: 22.5 mm Hg decrease in average systolic BP and P<.001; control group: 24.1 mm Hg decrease and P<.001) adjusted for age and sex, with no significant differences between the groups (time-by-arm interaction: P=.99). Similar patterns where improvements were noted in both groups yet no differences were found between the groups were observed for diastolic BP, physical activity, sodium intake, medication adherence, and BP control. Large dropout rates were observed in both groups (approximately 60%). CONCLUSIONS: Overall, participants randomized to both the enhanced usual care control and MI-BP conditions experienced significant improvements in BP and other outcomes; however, differences between groups were not detected, speaking to the general benefit of proactive outreach and engagement focused on cardiometabolic risk reduction in urban-dwelling, low-socioeconomic-status Black populations. High dropout rates were found and are likely to be expected when working with similar populations. Future work is needed to better understand engagement with mobile health interventions, particularly in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02955537; https://clinicaltrials.gov/study/NCT02955537. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/12601.

Partial associations of dietary iron, smoking and intestinal bacteria with colorectal cancer risk.

Smoking and high red meat intake have been associated with colorectal cancer (CRC) risk. Increased iron exposure may be a common factor, favoring the colonization of certain bacterial pathogens that preferentially grow in an iron-rich luminal environment. We analyzed the data from a population-based case-control study of CRC and measured antibody levels against flagelin of Salmonella (FliC), one of the irontrophic bacteria, in 2 independent blood collections. The risk of CRC synergistically increased by combined exposures to heme iron intake and pack-yr (PY) of cigarette smoking (P value for the interaction = 0.039 on the continuous scale). There was a marginally significant interaction between heme iron intake and PY in increasing FliC antibody in the U.S. control subjects (P = 0.055), although no iron or smoking data were available for Dutch samples. Furthermore, FliC antibody levels were significantly higher in patients with colorectal polyps and cancer than in controls in both Dutch (3.93 vs. 2.23) (P = 0.014) and U.S. samples (6.65 vs. 4.37) (P < 0.001). Potential roles of iron from cigarette smoking and dietary heme in CRC through altering irontrophic luminal bacterial population may warrant further investigation.

Developmental programming for allergy: a secondary analysis of the Mothers, Omega-3, and Mental Health Study.

OBJECTIVE: Fetal dysregulation of T helper cell pathways may predispose to allergy, as high cord blood T helper 2/T helper 1 ratios have been shown to precede development of allergic diseases. We aimed to determine whether prenatal eicosapentaenoic acid and docosahexaenoic acid supplementation reduces T helper 2 to T helper 1-associated chemokine ratios. We also explored the effect of mode of delivery on T helper 2/T helper 1 ratios. STUDY DESIGN: We conducted a secondary analysis of a randomized placebo controlled trial initially performed to assess the effects of docosahexaenoic acid or eicosapentaenoic acid supplementation on pregnancy-related depressive symptoms among 126 participants. Cord plasma specimens from 98 newborns were assayed for chemokines associated with T helper 2 (thymus and activation-regulated chemokine [CCL17], macrophage-derived chemokine [CCL22], eotaxin [CCL 11]) and T helper 1 (interferon-inducible protein-10 [CXCL 10]) by enzyme-linked immunosorbent assay and Multiplex immunoassays. Ratios of log-transformed chemokines macrophage-derived chemokine/interferon-inducible protein-10 and thymus and activation-regulated chemokine/interferon-inducible protein-10 were compared between groups by analyses of variance. Multiple linear regression was performed to examine associations between treatments and chemokine ratios, adjusting for covariates. RESULTS: After adjusting for gestational age at delivery, birthweight, and mode of delivery, both omega-3 supplementation groups were associated with lower macrophage-derived chemokine/interferon-inducible protein-10 ratios than placebo (eicosapentaenoic acid: coefficient -1.8; 95% confidence interval [CI], -3.6 to -0.05; P = .04; docosahexaenoic acid: -2.0; 95% CI, -3.9 to -0.07; P = .04). Similar associations were found for thymus and activation-regulated chemokine/interferon-inducible protein-10 (eicosapentaenoic acid: -1.5; 95% CI, -3.0 to 0.06; P = .06; docosahexaenoic acid -2.2; 95% CI, -3.8 to -0.52; P = .01). Cesarean delivery was associated with higher macrophage-derived chemokine/interferon-inducible protein-10 (1.6; 95% CI, 0.01-3.3; P = .049) and thymus and activation-regulated chemokine/interferon-inducible protein-10 (1.5; 95% CI, 0.1-2.9; P = .042) ratios than vaginal delivery. CONCLUSION: Prenatal supplementation with eicosapentaenoic acid and docosahexaenoic acid resulted in decreased cord blood T helper 2/T helper 1 chemokine ratios. Cesarean delivery was associated with a pronounced T helper 2 deviation at birth.

The Mothers, Omega-3, and Mental Health Study: a double-blind, randomized controlled trial.

OBJECTIVES: Maternal deficiency of the omega-3 fatty acid, docosahexaenoic acid (DHA), has been associated with perinatal depression, but there is evidence that supplementation with eicosapentaenoic acid (EPA) may be more effective than DHA in treating depressive symptoms. This trial tested the relative effects of EPA- and DHA-rich fish oils on prevention of depressive symptoms among pregnant women at an increased risk of depression. STUDY DESIGN: We enrolled 126 pregnant women at risk for depression (Edinburgh Postnatal Depression Scale score 9-19 or a history of depression) in early pregnancy and randomly assigned them to receive EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA), or soy oil placebo. Subjects completed the Beck Depression Inventory (BDI) and Mini-International Neuropsychiatric Interview at enrollment, 26-28 weeks, 34-36 weeks, and at 6-8 weeks' postpartum. Serum fatty acids were analyzed at entry and at 34-36 weeks' gestation. RESULTS: One hundred eighteen women completed the trial. There were no differences between groups in BDI scores or other depression endpoints at any of the 3 time points after supplementation. The EPA- and DHA-rich fish oil groups exhibited significantly increased postsupplementation concentrations of serum EPA and serum DHA respectively. Serum DHA- concentrations at 34-36 weeks were inversely related to BDI scores in late pregnancy. CONCLUSION: EPA-rich fish oil and DHA-rich fish oil supplementation did not prevent depressive symptoms during pregnancy or postpartum.

Association of dietary quercetin with reduced risk of proximal colon cancer.

Quercetin is a flavonol that appears to be protective against several cancers, but its possible role in prevention of colorectal cancer is not yet well studied. We evaluated dietary intakes of quercetin and risk of colorectal cancer in a large case-control study conducted in metropolitan Detroit, Michigan (N = 2664). The protective effects of quercetin intake, as assessed by a food frequency questionnaire, were confined to risk of proximal colon cancer. Stratified analyses showed that the protective effects of quercetin on risk of proximal colon cancer were significant only when fruit intake or the Healthy Eating Index score was high, or when tea intake was low, with odds ratios (OR) for the highest vs. the lowest quartile of 0.49, 0.44, and 0.51, respectively. Increased quercetin intake had no protective effects when tea intake was high. Interestingly, increased intake of quercetin was associated with increased risk of distal colon cancer when total fruit intake was low (OR for the highest vs. the lowest quartile = 1.99). These results suggest that quercetin can have disparate effects on colon cancer risk depending on whether dietary intakes of fruit or tea are high, and that quercetin had protective effects only on proximal, not distal, colon cancer.

Effect of fish oil on levels of R- and S-enantiomers of 5-, 12-, and 15-hydroxyeicosatetraenoic acids in mouse colonic mucosa.

The balance of putative pro- and antiinflammatory lipoxygenase (LOX)-derived S-hydroxyeicosatetraenoic acids (S-HETEs) in colon mucosa is a potential target for modulating colon cancer risk and progression. The biological effects of S-HETEs and R-hydroxyeicosatetraenoic acids (produced by distinct pathways) may differ, but levels of these compounds in the colon are unknown. The objective of this study was to develop chiral methods to characterize hydroxyeicosatetraenoic (HETE) enantiomers in colonic mucosa and evaluate the effects of fish oil on HETE formation. C57BL/6 mice (COX-1 null, COX-2 null, wild-type) were fed a diet supplemented with either olive oil or menhaden oil for 11 wk, and R-/S-HETEs in colonic mucosa were quantified by chiral LC-MS/MS. The R-enantiomer comprised 60-72% of 5-HETE, 18-58% of 15-HETE, and 1-16% of 12-HETE in colonic mucosa, suggesting that non-LOX sources contribute to HETE profiles. Fish oil reduced levels of both R- and S-HETEs, and increased the preponderance of the R-enantiomers (particularly 12- and 15-HETEs). There was apparent shunting of arachidonic acid to 12-/15-LOX in the COX-1 null animals. This is the first report of the enantiomeric composition of HETEs in the colon in vivo and shows large effects of fish oil in the normal colon.