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1.
Molecular Immune-Inflammatory Connections between Dietary Fats and Atherosclerotic Cardiovascular Disease: Which Translation into Clinics?
Mattavelli, E, Catapano, AL, Baragetti, A
Nutrients. 2021;(11)
Abstract
Current guidelines recommend reducing the daily intake of dietary fats for the prevention of ischemic cardiovascular diseases (CVDs). Avoiding saturated fats while increasing the intake of mono- or polyunsaturated fatty acids has been for long time the cornerstone of dietary approaches in cardiovascular prevention, mainly due to the metabolic effects of these molecules. However, recently, this approach has been critically revised. The experimental evidence, in fact, supports the concept that the pro- or anti-inflammatory potential of different dietary fats contributes to atherogenic or anti-atherogenic cellular and molecular processes beyond (or in addition to) their metabolic effects. All these aspects are hardly translatable into clinics when trying to find connections between the pro-/anti-inflammatory potential of dietary lipids and their effects on CVD outcomes. Interventional trials, although providing stronger potential for causal inference, are typically small sample-sized, and they have short follow-up, noncompliance, and high attrition rates. Besides, observational studies are confounded by a number of variables and the quantification of dietary intakes is far from optimal. A better understanding of the anatomic and physiological barriers for the absorption and the players involved in the metabolism of dietary lipids (e.g., gut microbiota) might be an alternative strategy in the attempt to provide a first step towards a personalized dietary approach in CVD prevention.
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Breast Milk Lipids and Fatty Acids in Regulating Neonatal Intestinal Development and Protecting against Intestinal Injury.
Ramiro-Cortijo, D, Singh, P, Liu, Y, Medina-Morales, E, Yakah, W, Freedman, SD, Martin, CR
Nutrients. 2020;(2)
Abstract
Human breast milk is the optimal source of nutrition for infant growth and development. Breast milk fats and their downstream derivatives of fatty acids and fatty acid-derived terminal mediators not only provide an energy source but also are important regulators of development, immune function, and metabolism. The composition of the lipids and fatty acids determines the nutritional and physicochemical properties of human milk fat. Essential fatty acids, including long-chain polyunsaturated fatty acids (LCPUFAs) and specialized pro-resolving mediators, are critical for growth, organogenesis, and regulation of inflammation. Combined data including in vitro, in vivo, and human cohort studies support the beneficial effects of human breast milk in intestinal development and in reducing the risk of intestinal injury. Human milk has been shown to reduce the occurrence of necrotizing enterocolitis (NEC), a common gastrointestinal disease in preterm infants. Preterm infants fed human breast milk are less likely to develop NEC compared to preterm infants receiving infant formula. Intestinal development and its physiological functions are highly adaptive to changes in nutritional status influencing the susceptibility towards intestinal injury in response to pathological challenges. In this review, we focus on lipids and fatty acids present in breast milk and their impact on neonatal gut development and the risk of disease.
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Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function.
Tan, BL, Norhaizan, ME
Nutrients. 2019;(11)
Abstract
Cognitive dysfunction is linked to chronic low-grade inflammatory stress that contributes to cell-mediated immunity in creating an oxidative environment. Food is a vitally important energy source; it affects brain function and provides direct energy. Several studies have indicated that high-fat consumption causes overproduction of circulating free fatty acids and systemic inflammation. Immune cells, free fatty acids, and circulating cytokines reach the hypothalamus and initiate local inflammation through processes such as microglial proliferation. Therefore, the role of high-fat diet (HFD) in promoting oxidative stress and neurodegeneration is worthy of further discussion. Of particular interest in this article, we highlight the associations and molecular mechanisms of HFD in the modulation of inflammation and cognitive deficits. Taken together, a better understanding of the role of oxidative stress in cognitive impairment following HFD consumption would provide a useful approach for the prevention of cognitive dysfunction.
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Assessment of effect of CYP3A inhibition, CYP induction, OATP1B inhibition, and high-fat meal on pharmacokinetics of the JAK1 inhibitor upadacitinib.
Mohamed, MF, Jungerwirth, S, Asatryan, A, Jiang, P, Othman, AA
British journal of clinical pharmacology. 2017;(10):2242-2248
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Abstract
AIMS: Upadacitinib (ABT-494) is a selective Janus kinase 1 inhibitor being developed for treatment of auto-immune inflammatory disorders. This work evaluated effects of high-fat meal, cytochrome P450 (CYP) 3A inhibition, CYP induction, and organic anion transporting polypeptide (OATP) 1B inhibition on upadacitinib pharmacokinetics. METHODS Two Phase 1 evaluations were conducted, each in 12 healthy subjects. In Study 1, using a randomized, two-sequence crossover design, a 3 mg dose of upadacitinib (immediate-release capsules) was administered alone under fasting conditions, after high-fat meal, or on Day 4 of a 6-day regimen of 400 mg once-daily ketoconazole. In Study 2, a 12 mg upadacitinib dose was administered alone, with the first, and with the eighth dose of a 9-day regimen of rifampin 600 mg once daily. Upadacitinib plasma concentrations were characterized. RESULTS Administration of upadacitinib immediate-release capsules after a high-fat meal decreased upadacitinib Cmax by 23% and had no impact on upadacitinib AUC relative to the fasting conditions. Ketoconazole (strong CYP3A inhibitor) increased upadacitinib Cmax and AUC by 70% and 75%, respectively. Multiple doses of rifampin (broad CYP inducer) decreased upadacitinib Cmax and AUC by approximately 50% and 60%, respectively. A single dose of rifampin (also an OATP1B inhibitor) had no effect on upadacitinib AUC. Upadacitinib was well tolerated when co-administered with ketoconazole, rifampin, or after a high-fat meal. CONCLUSIONS Strong CYP3A inhibition and broad CYP induction result in a weak and moderate effect, respectively, on upadacitinib exposures. OATP1B inhibition and administration of upadacitinib immediate-release formulation with food does not impact upadacitinib exposure.
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Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition.
Zhang, L, Voskuijl, W, Mouzaki, M, Groen, AK, Alexander, J, Bourdon, C, Wang, A, Versloot, CJ, Di Giovanni, V, Wanders, RJ, et al
PloS one. 2016;(5):e0155143
Abstract
OBJECTIVE Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis. DESIGN An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified. RESULTS On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower. CONCLUSION SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.
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The role of nutritional lipids and antioxidants in UV-induced skin cancer.
Black, HS
Frontiers in bioscience (Scholar edition). 2015;(1):30-9
Abstract
Two dietary tenets of the free radical theory of cancer require refinement. The first was dietary reduction of vulnerable free-radical targets, e.g., polyunsaturated lipids. The second was the addition of one or more antioxidants to the diet. Further, it was reported in 1939 that high levels of dietary fat exacerbated UV-carcinogenesis. Both lines of enquiry (dietary lipid and antioxidant effects on UV-carcinogenesis) were investigated. Both dietary lipids and antioxidants modified carcinogenic expression. Increasing levels of omega-6 polyunsaturated fatty acids (PUFA) exacerbated UV-carcinogenesis. However, omega-3 PUFA dramatically inhibited carcinogenic expression. It is probable that the action of omega-6 and-3 PUFA rests with differential metabolic intermediates, both tumor promoting and immune-modulating, that each PUFA generates through lipoxygenase and cyclooxygenase pathways. Antioxidant supplementation with butylated hydroxytoluene or beta-carotene demonstrated that each exerted its own specific antioxidant mechanism(s). When introduced into the complex milieu of the cell with its own intricate and complex antioxidant defense system, detrimental effects may ensue. These results point to oversimplification of these dietary suggestions to reduce cancer risk and the necessity to refine these dietary recommendations.
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Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.
Ananthakrishnan, AN, Khalili, H, Konijeti, GG, Higuchi, LM, de Silva, P, Fuchs, CS, Willett, WC, Richter, JM, Chan, AT
Gut. 2014;(5):776-84
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INTRODUCTION Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohn's disease (CD) and ulcerative colitis (UC) are limited and conflicting. METHODS We conducted a prospective study of women enrolled in the Nurses' Health Study cohorts. Diet was prospectively ascertained every 4 years using a validated semi-quantitative food frequency questionnaire. Self-reported CD and UC were confirmed through medical record review. We examined the effect of energy-adjusted cumulative average total fat intake and specific types of fat and fatty acids on the risk of CD and UC using Cox proportional hazards models adjusting for potential confounders. RESULTS Among 170,805 women, we confirmed 269 incident cases of CD (incidence 8/100,000 person-years) and 338 incident cases of UC (incidence 10/100,000 person-years) over 26 years and 3,317,338 person-years of follow-up. Cumulative energy-adjusted intake of total fat, saturated fats, unsaturated fats, n-6 and n-3 polyunsaturated fatty acids (PUFAs) were not associated with risk of CD or UC. However, greater intake of long-chain n-3 PUFAs was associated with a trend towards lower risk of UC (HR 0.72, 95% CI 0.51 to 1.01). In contrast, high long-term intake of trans-unsaturated fatty acids was associated with a trend towards an increased incidence of UC (HR 1.34, 95% CI 0.94 to 1.92). CONCLUSIONS A high intake of dietary long-chain n-3 PUFAs may be associated with a reduced risk of UC. In contrast, high intake of trans-unsaturated fats may be associated with an increased risk of UC.
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Diet-induced expansion of pathobionts in experimental colitis: implications for tailored therapies.
Devkota, S, Chang, EB
Gut microbes. 2013;(2):172-4
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Abstract
Evidence presented in our recent study and elsewhere suggests that the interplay of dietary macronutrients with the intestinal lumen alters the microbial environment, and thus host-microbe interactions, in ways that are not always in a favorable, mutualistic fashion. Specifically, in inflammatory bowel diseases (IBD), experimental and clinical observations have implicated a detrimental impact of environmental/microbial factors on the etiopathogenesis of IBD in individuals with a background of genetic susceptibility to the disease. Thus, now more than ever, we are realizing that specific intestinal microbes can metabolize and react to a wide array of dietary compositions that, in turn, markedly alter microbial populations. We aimed to understand if certain dietary fats that are prevalent in Western diets are capable of precipitating colonic inflammation through their actions on the enteric microbiota. On a background of genetic susceptibility, these microbial changes can impact host immune homeostasis and increase risk for disease. Here we elaborate on our findings and their potential implications for future medical care.
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A randomized trial to investigate the effects of pre-natal and infant nutritional supplementation on infant immune development in rural Gambia: the ENID trial: Early Nutrition and Immune Development.
Moore, SE, Fulford, AJ, Darboe, MK, Jobarteh, ML, Jarjou, LM, Prentice, AM
BMC pregnancy and childbirth. 2012;:107
Abstract
BACKGROUND Recent observational research indicates that immune development may be programmed by nutritional exposures early in life. Such findings require replication from trials specifically designed to assess the impact of nutritional intervention during pregnancy on infant immune development. The current trial seeks to establish: (a) which combination of protein-energy (PE) and multiple-micronutrient (MMN) supplements would be most effective; and (b) the most critical periods for intervention in pregnancy and infancy, for optimal immune development in infancy. METHODS/DESIGN The ENID Trial is a 2 x 2 x 2 factorial randomized, partially blind trial to assess whether nutritional supplementation to pregnant women (from < 20 weeks gestation to term) and their infants (from 6 to 12 months of age) can enhance infant immune development. Eligible pregnant women from the West Kiang region of The Gambia (pregnancy dated by ultrasound examination) are randomized on entry to 4 intervention groups (Iron-folate (FeFol = standard care), multiple micronutrients (MMN), protein-energy (PE), PE + MMN). Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination, including ultrasound. At delivery, cord blood and placental samples are collected, with detailed infant anthropometry collected within 72 hours. Infants are visited weekly thereafter for a morbidity questionnaire. From 6 to 12 months of age, infants are further randomized to a lipid-based nutritional supplement, with or without additional MMN. The primary outcome measures of this study are thymic development during infancy, and antibody response to vaccination. Measures of cellular markers of immunity will be made in a selected sub-cohort. Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age. DISCUSSION The proposed trial is designed to test whether nutritional repletion can enhance early immune development and, if so, to help determine the most efficacious form of nutritional support. Where there is evidence of benefit from a specific intervention/combination of interventions, future research should focus on refining the supplements to achieve the optimal, most cost-effective balance of interventions for improved health outcomes.
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Fat overload induces changes in circulating lactoferrin that are associated with postprandial lipemia and oxidative stress in severely obese subjects.
Fernández-Real, JM, García-Fuentes, E, Moreno-Navarrete, JM, Murri-Pierri, M, Garrido-Sánchez, L, Ricart, W, Tinahones, F
Obesity (Silver Spring, Md.). 2010;(3):482-8
Abstract
Lactoferrin is an innate immune system protein with anti-inflammatory and antioxidant activities. We aimed to evaluate circulating lactoferrin levels in association with lipid concentrations, and parameters of oxidative stress and inflammation in subjects with morbid obesity after an acute fat intake. The effects of a 60 g fat overload on circulating lactoferrin and antioxidant activities were evaluated in 45 severely obese patients (15 men and 30 women, BMI 53.4 +/- 7.2 kg/m(2)). The change in circulating lactoferrin after fat overload was significantly and inversely associated with the free fatty acid (FFA) change. In those subjects with the highest increase in lactoferrin (in the highest quartile), high-density lipoprotein (HDL)-cholesterol decreased after fat overload to a lesser extent (P = 0.03). In parallel to lipid changes, circulating lactoferrin concentrations were inversely linked to the variations in catalase (CAT) and glutathione reductase (GSH-Rd). Baseline circulating lactoferrin concentration was also inversely associated with the absolute change in antioxidant activity after fat overload, and with the change in C-reactive protein (CRP). Furthermore, those subjects with higher than the median value of homeostasis model assessment of insulin secretion (HOMA(IS)) had significantly increased lactoferrin concentration after fat load (885 +/- 262 vs. 700 +/- 286 ng/ml, P = 0.03). Finally, we further explored the action of lactoferrin in vitro. Lactoferrin (10 micromol/l) led to significantly lower triglyceride (TG) concentrations and lactate dehydrogenase activity (as expression of cell viability) in the media from adipose explants obtained from severely obese subjects. In conclusion, circulating lactoferrin concentrations, both at baseline and fat-stimulated, were inversely associated with postprandial lipemia, and parameters of oxidative stress and fat-induced inflammation in severely obese subjects.