Interaction of mediators and effector cells in cashew nut-induced anaphylaxis
Background: The underlying mechanisms of an immediate food-induced allergic reaction involve mast-cell degranulation and recruitment of other effector cells, such as lymphocytes, eosinophils, and basophils. How the interaction of various mediators and cells results in anaphylaxis is not fully understood. Objective: To evaluate changes in platelet-activating factor (PAF), platelet-activating factor acetylhydrolase (PAF-AH), tryptase, eosinophils, basophils, and eosinophil cationic protein (ECP) in cashew nut-induced anaphylaxis. Methods: Open cashew nut challenges were performed on 106 children (aged 1-16 years), sensitized to cashew nut, with earlier allergic reaction to cashew nut or no known exposure. PAF, PAF-AH, tryptase, ECP, eosinophils, and basophils were measured at four timepoints. Results: 34/72 (47%) positive challenges were defined as anaphylactic. Eosinophil count decreased progressively during an anaphylactic reaction at all four timepoints (P< .005*) compared to baseline. Although significant PAF elevation was observed 1 hour from moderate-to-severe reaction (P= .039*), PAF seemed to peak especially in anaphylaxis but did not achieve statistical significance. PAF peak ratio (peak PAF/baseline PAF) was significantly greater in anaphylactic reactions compared to the no-anaphylaxis group (P= .008*). Maximal percentage change in eosinophils revealed negative correlation to severity score and PAF peak ratio (Spearman's rho -0.424 and -0.516, respectively). Basophils decreased significantly in moderate-to-severe reactions and in anaphylaxis (P< .05*) compared to baseline. Delta-tryptase (peak tryptase minus baseline) did not differ significantly between anaphylaxis and the no-anaphylaxis subgroups (P= .05). Conclusion: PAF is a specific anaphylaxis biomarker. Marked decline of eosinophils during anaphylaxis may be related to robust secretion of PAF reflecting migration of eosinophils to target tissues. https://doi.org/10.1016/j.anai.2023.04.014
Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy
Background: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. Methods: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. Results: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. Conclusions: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.). https://doi.org/10.1056/NEJMoa2212895
Use of a Liver-Targeting Immune-Tolerogenic mRNA Lipid Nanoparticle Platform to Treat Peanut-Induced Anaphylaxis by Single- and Multiple-Epitope Nucleotide Sequence Delivery
While oral desensitization is capable of alleviating peanut allergen anaphylaxis, long-term immune tolerance is the sought-after goal. We developed a liver-targeting lipid nanoparticle (LNP) platform to deliver mRNA-encoded peanut allergen epitopes to liver sinusoidal endothelial cells (LSECs), which function as robust tolerogenic antigen-presenting cells that induce FoxP3+ regulatory T-cells (Tregs). The mRNA strand was constructed by including nucleotide sequences encoding for nonallergenic MHC-II binding T-cell epitopes, identified in the dominant peanut allergen, Ara h2. These epitopes were inserted in the mRNA strand downstream of an MHC-II targeting sequence, further endowed in vitro with 5′ and 3′ capping sequences, a PolyA tail, and uridine substitution. Codon-optimized mRNA was used for microfluidics synthesis of LNPs with an ionizable cationic lipid, also decorated with a lipid-anchored mannose ligand for LSEC targeting. Biodistribution to the liver was confirmed by in vivo imaging, while ELISpot assays demonstrated an increase in IL-10-producing Tregs in the spleen. Prophylactic administration of tandem-repeat or a combination of encapsulated Ara h2 epitopes induced robust tolerogenic effects in C3H/HeJ mice, sensitized to and subsequently challenged with crude peanut allergen extract. In addition to alleviating physical manifestations of anaphylaxis, there was suppression of Th2-mediated cytokine production, IgE synthesis, and mast cell release, accompanied by increased IL-10 and TGF-β production in the peritoneum. Similar efficacy was demonstrated during LNP administration postsensitization. While nondecorated particles had lesser but significant effects, PolyA/LNP-Man lacked protective effects. These results demonstrate an exciting application of mRNA/LNP for treatment of food allergen anaphylaxis, with the promise to be widely applicable to the allergy field. https://doi.org/10.1021/acsnano.2c12420
The protective effect of moderate maternal peanut consumption on peanut sensitization and allergy
Background: The Learning Early About Peanut Allergy or LEAP trial found that the early introduction of peanuts in the diet of infants at risk for peanut allergies prevents peanut allergy. The effect of maternal consumption of peanuts on subsequent peanut sensitization or peanut allergy in the LEAP trial has not been studied to date. Objective: To determine whether maternal consumption of peanut protein while breastfeeding protects against peanut-allergic outcomes in the absence of peanut consumption in infants. Methods: We performed an analysis of the data from the peanut avoidance arm of the LEAP study to discern the effects of maternal consumption of peanuts while pregnant and breastfeeding on an infant's peanut-allergic outcomes. Results: Of the 303 infants in the avoidance group, 31 mothers consumed more than 5 g of peanut per week, 69 consumed less than 5 g of peanut per week and 181 did not consume peanut while breastfeeding. Peanut sensitization (P = .03) and peanut allergy (P = .07) occurred less frequently in infants whose mothers consumed a moderate amount of peanuts while breastfeeding when compared with those who either did not consume peanuts while breastfeeding or those who consumed a large amount of peanuts when breastfeeding. Ethnicity (odds ratio [OR], 0.47; P = .046, 95% confidence interval [CI], 0.22-0.99), baseline peanut skin prick test stratum (OR, 4.87; P < .001, 95% CI, 2.13-11.12), no maternal peanut consumption while breastfeeding (OR, 3.25; P = .008, 95% CI, 1.36-7.77), and baseline SCORing Atopic Dermatitis greater than 40 (OR, 2.78; P = .007, 95% CI, 1.32-5.85) were all significant contributors to peanut sensitization or allergy at 60 months of age. Conclusion: Moderate consumption (<5 grams per week) of peanuts while breastfeeding provides a significant protective effect against peanut sensitization and a noticeable but not statistically significant protective effect against peanut allergy later on in life in high-risk infants in the context of delayed peanut introduction. https://doi.org/10.1016/j.anai.2023.04.012
A Pecan-Enriched Diet Reduced Postprandial Appetite Intensity and Enhanced Peptide YY Secretion: A Randomized Control Trial
Background & aims: Tree nuts have been shown to have satiating qualities; however, little is known concerning the effect of pecans on measures of appetite. The purpose of this study was to examine the impact of a pecan-enriched diet on subjective, physiological, and direct measures of appetite in older adults. Methods: This was a randomized, controlled trial in which healthy older adults (50–75 y) were randomized to either consume 68 g of pecans/day (pecan; n = 21) or avoid all nuts (control; n = 23) for 4 weeks. At pre- (V1) and post-diet (V2) visits body weight (BW) and body fat percentage (BF) were assessed and actual change in these outcomes for pecan were compared to theoretical changes if pecans were consumed without compensation. Subjective appetite was measured using visual analog scale (VAS), and blood was collected to assess changes in physiological appetite before and every 30 min for 4 h following a high-fat meal. Energy intake (EI) at a buffet meal was then assessed in the laboratory (“in-lab”). VAS assessments continued hourly for the next 7 h and EI (“at-home”) was self-reported. Results: BW and BF did not change for pecan or control across the intervention and theoretical change in BW (theoretical: 2.2 ± 0.1 vs. actual: 0.4 ± 0.2 kg; p < 0.0001) and BF (theoretical: 0.4 ± 0.04 vs. actual: 0.2 ± 0.2%; p < 0.0001) was significantly greater than actual change for pecan. From V1 to V2, there was an increase in fasting (pecan: 77.0 ± 4.6 to 93.5 ± 6.1 vs control: 76.0 ± 5.0 to 72.5 ± 5.0 pg/mL; p = 0.01) and postprandial peptide YY for pecan vs. control (p = 0.04); however, fasting and postprandial cholecystokinin and ghrelin did not differ (p > 0.05). There were no differences in the change in subjective appetite ratings at fasting, following the high-fat meal (in-lab), at-home, or across the full day between groups (p > 0.05 for all). However, there was a significant suppression of peak desire to eat ratings for pecan vs. control (pecan: 67.9 ± 4.6 to 57.1 ± 5.2 vs. control: 61.9 ± 4.2 to 60.6 ± 4.3 mm; p = 0.04). Combined, buffet meal, and at-home EI did not differ significantly within pecan and control; however, there was a trend (p = 0.11) for a between group difference in buffet meal EI driven by increased EI for control (+137 ± 86 kcal) vs. decreased EI for pecan (−45 ± 77 kcal). Conclusion: A 4-week pecan-enriched diet led to enhanced satietogenic metrics compared to a diet void of all nuts. As weight remained stable during the intervention, adding pecans to the daily diet may be beneficial to appetite control and weight maintenance in a healthy older population. https://doi.org/10.1016/j.clnesp.2023.05.002
The role of intestinal microbiota and microRNAs in the anti-inflammatory effects of cranberry: from pre-clinical to clinical studies
Cranberries have known anti-inflammatory properties, which extend their benefits in the context of several chronic diseases. These benefits highly rely on the polyphenol profile of cranberries, one of few foods rich in A-type proanthocyanidin (PAC). A-type PAC comprises flavan-3-ol subunits with an additional interflavan ether bond in the conformational structure of the molecule, separating them from the more commonly found B-type PAC. PACs with a degree of polymerization higher than three are known to reach the colon intact, where they can be catabolyzed by the gut microbiota and biotransformed into lower molecular weight organic acids that are available for host absorption. Gut microbiota-derived metabolites have garnered much attention in the past decade as mediators of the health effects of parent compounds. Though, the mechanisms underlying this phenomenon remain underexplored. In this review, we highlight emerging evidence that postulates that polyphenols, including ones derived from cranberries, and their metabolites could exert anti-inflammatory effects by modulating host microRNAs. Our review first describes the chemical structure of cranberry PACs and a pathway for how they are biotransformed by the gut microbiota. We then provide a brief overview of the benefits of microbial metabolites of cranberry in the intestinal tract, at homeostasis and in inflammatory conditions. Finally, we discuss the role of microRNAs in intestinal health and in response to cranberry PAC and how they could be used as targets for the maintenance of intestinal homeostasis. Most of this research is pre-clinical and we recognize that conducting clinical trials in this context has been hampered by the lack of reliable biomarkers. Our review discusses the use of miRNA as biomarkers in this context. https://doi.org/10.3389/fnut.2023.1092342
Tree Nut and Peanut Consumption and Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
CVD is the leading cause of death globally. Habitual consumption of tree nuts and peanuts is associated with cardioprotective benefits. Food-based dietary guidelines globally recommend nuts as a key component of a healthy diet. This systematic review and meta-analysis were conducted to examine the relationship between tree nut and peanut consumption and risk factors for CVD in randomized controlled trials (RCTs). MEDLINE, PubMed, CINAHL, and Cochrane Central databases were searched up to 26 September, 2021. All RCT studies that assessed the effects of tree nut or peanut consumption of any dose on CVD risk factors were included. Review Manager software was used to conduct a random effect meta-analysis for CVD outcomes from RCTs. Forest plots were generated for each outcome, between-study heterogeneity was estimated using the I2 test statistic and funnel plots and Egger's test for outcomes with ≥10 strata. The quality assessment used the Health Canada Quality Appraisal Tool, and the certainty of the evidence was assessed using grading of recommendations assessment, development, and evaluation (GRADE). A total of 153 articles describing 139 studies (81 parallel design and 58 cross-over design) were included in the systematic review, with 129 studies in the meta-analysis. The meta-analysis showed a significant decrease for LDL cholesterol, total cholesterol (TC), TG, TC:HDL cholesterol, LDL cholesterol:HDL cholesterol, and apoB following nut consumption. However, the quality of evidence was "low" for only 18 intervention studies. The certainty of the body of evidence for TC:HDL cholesterol, LDL cholesterol:HDL cholesterol, and apoB were "moderate" because of inconsistency, for TG were "low," and for LDL cholesterol and TC were "very low" because of inconsistency and the likelihood of publication bias. The findings of this review provide evidence of a combined effect of tree nuts and peanuts on a range of biomarkers to create an overall CVD risk reduction. PROSPERO (CRD42022309156). https://doi.org/10.1016/j.advnut.2023.05.004
Believe It or ‘Nut’: Why It Is Time to Set the Record Straight on Nut Protein Quality: Pistachio (Pistacia vera L.) Focus
There are growing public health movements to transition towards diets that are plant-based. However, confusion exists with concerns that plant-based proteins (including nuts) may be inferior with respect to protein quality. The present publication evaluates the evolution of protein quality concepts and explains the protein science related to pistachios. Pistachio nuts are a plant-based complete protein providing all nine EAAs in addition to an array of nutrients and phytochemicals. They have a PDCAAS of 73 and 81%, (raw and roasted pistachios, respectively), higher than that of many other tree nuts. From an environmental perspective transitioning towards plant-based diets (including nuts) could have potential to reduce total/green water footprints. Dietary guidelines are evolving yet nuts such as pistachios do not always have a clear place within these. Now appears to be a pertinent time to look at protein quality from the perspective of whole daily diets and dietary patterns, factoring in both health and environmental outcomes. Given updated modes of thinking, nuts such as pistachios have an important role to play in terms of providing ready-to-eat, good-quality, plant-based protein within daily diets. https://doi.org/10.3390/nu15092158
Antioxidant and Anti-Inflammatory Properties of Walnut Constituents: Focus on Personalized Cancer Prevention and the Microbiome
Walnuts have been lauded as a ‘superfood’, containing a remarkable array of natural constituents that may have additive and/or synergistic properties that contribute to reduced cancer risk. Walnuts are a rich source of polyunsaturated fatty acids (PUFAs: alpha-linolenic acid, ALA), tocopherols, antioxidant polyphenols (including ellagitannins), and prebiotics, including fiber (2 g/oz). There is a growing body of evidence that walnuts may contribute in a positive way to the gut microbiome, having a prebiotic potential that promotes the growth of beneficial bacteria. Studies supporting this microbiome-modifying potential include both preclinical cancer models as well as several promising human clinical trials. Mediated both directly and indirectly via its actions on the microbiome, many of the beneficial properties of walnuts are related to a range of anti-inflammatory properties, including powerful effects on the immune system. Among the most potent constituents of walnuts are the ellagitannins, primarily pedunculagin. After ingestion, the ellagitannins are hydrolyzed at low pH to release ellagic acid (EA), a non-flavonoid polyphenolic that is subsequently metabolized by the microbiota to the bioactive urolithins (hydroxydibenzo[b,d]pyran-6-ones). Several urolithins, including urolithin A, reportedly have potent anti-inflammatory properties. These properties of walnuts provide the rationale for including this tree nut as part of a healthy diet for reducing overall disease risk, including colorectal cancer. This review considers the latest information regarding the potential anti-cancer and antioxidant properties of walnuts and how they may be incorporated into the diet to provide additional health benefits. https://doi.org/10.3390/antiox12050982
Higher versus lower nut consumption and changes in cognitive performance over two years in a population at risk of cognitive decline: a cohort study
Background: Tree nuts and peanuts (henceforth, nuts) are nutrient-dense foods rich in neuroprotective components; thus, their consumption could benefit cognitive health. However, evidence to date is limited and inconsistent regarding the potential benefits of nuts for cognitive function. Objective: To prospectively evaluate the association between nut consumption and 2-year changes in cognitive performance in older adults at cognitive decline risk. Methods: 6,630 participants aged 55-75 years (mean age 65.0±4.9 years, 48.4% women) with overweight/obesity and metabolic syndrome, completed a validated semi-quantitative food frequency questionnaire and a comprehensive battery of neuropsychological tests at baseline and after a 2-year follow-up. Composite cognitive scores were used to assess global, general, attention, and executive function domains. Nut consumption was categorized as <1, ≥1 to <3, ≥3 to <7, and ≥7 servings/week (1 serving=30 g). Multivariable-adjusted linear regression models were fitted to assess associations between baseline nut consumption and 2-year cognitive changes. Results: Nut consumption was positively associated with 2-year changes in general cognitive function (p-trend <0.001). Compared to participants consuming <1 serving/week of nuts, those categorized as consuming ≥3 to <7 and ≥7 servings/week showed more favorable changes in general cognitive performance (β z-score [95% CI]= 0.06 [0.00,0.12] and 0.13 [0.06,0.20], respectively). No significant changes were observed in the multivariable-adjusted models for other cognitive domains assessed. Conclusion: Frequent nut consumption was associated with smaller decline in general cognitive performance over a 2-year period in older adults at risk of cognitive decline. Randomized clinical trials to verify our findings are warranted. https://doi.org/10.1016/j.ajcnut.2023.05.032