Predispose, precipitate, perpetuate, and protect: how diet and the gut influence mental health in emerging adulthood.

Medicine often employs the 4Ps of predisposing, precipitating, perpetuating, and protective factors to identify salient influences on illness states, and to help guide patient care. Mental illness is a significant cause of morbidity and mortality worldwide. Mental health is a complex combination of biological, psychological, environmental, and social factors. There is growing interest in the gut-brain-microbiome (GBM) axis and its impact on mental health. We use the medical model of the 4Ps to explore factors involving the connection between nutrition and the GBM axis and their associated risks with mental health problems in emerging adults (EAs), a life stage when mental illness onset is the most common. We review the impact of current dietary trends on the GBM and on mental health, and the role that gut microbiome-based interventions can have in modulating the GBM axis of EAs. We discuss the implications of gut health on the GBM and areas for clinical intervention.

Carriers of autosomal recessive conditions: are they really 'unaffected?'

Mendel's Law of Dominance suggests that recessive disease expression requires the inheritance of two mutated alleles as the dominant, wildtype allele suppresses disease presentation leading to the expression of physiological normal phenotypes. However, there is existing evidence that challenges this school of thought. Here, we summarise existing literature evaluating metabolic and health impacts among carriers of autosomal recessive conditions, focusing on phenylketonuria (PKU), classical homocystinuria, galactosemia and Usher syndrome as examples. Our findings suggest that carriers, often described as 'unaffected', may actually display attenuated symptoms for the recessive disease they are carrying. For instance, PKU is an inborn error of metabolism characterised by the build-up of plasma phenylalanine attributed to the deficiency of the phenylalanine hydroxylase (PAH) enzyme. While less severe, PKU carriers also exhibit this impaired enzymatic activity, leading to elevated plasma phenylalanine levels, especially after phenylalanine consumption. Related to these metabolic alterations in the PAH pathway, there is early evidence to suggest that PKU carriers may have compromised cognitive and mental health outcomes. Overall, research on the health and metabolic impacts of PKU carriers is sparse, with most studies conducted several decades ago. However, early evidence suggests that intermediate phenotypes among carriers of autosomal recessive conditions are plausible. The illustrated possible intermediate phenotypes observed among carriers necessitates future research to determine possible clinical implications among this population.

The Impact of Nutrition, Physical Activity, Beneficial Microbes, and Fecal Microbiota Transplant for Improving Health.

The recognition that microbes are integral to human life has led to studies on how to manipulate them in favor of health outcomes. To date, there has been no conjoint recommendation for the intake of dietary compounds that can complement the ingested organisms in terms of promoting an improved health outcome. The aim of this review is to discuss how beneficial microbes in the form of probiotics, fermented foods, and donor feces are being used to manage health. In addition, we explore the rationale for selecting beneficial microbial strains and aligning diets to accommodate their propagation in the gut. A pilot clinical trial design is presented to examine the effects of probiotics and exercise in patients with phenylketonuria (PKU); it is the most common inborn error of amino acid metabolism, and it is a complication that requires lifelong dietary intervention. The example design is provided to illustrate the importance of using omics technology to see if the intervention elevates neuroactive biogenic amines in the plasma; increases the abundance of Eubacterium rectale, Coprococcus eutactus, Akkermansia muciniphila, or Butyricicoccus; and increases Escherichia/Shigella in the gut, all as markers of improved health. By emphasizing the combined importance of diet, microbial supplements, and the gut microbiome, we hope that future studies will better align these components, not only to improve outcomes, but also to enhance our understanding of the mechanisms.

Gene expression signatures and cardiometabolic outcomes following 8-week mango consumption in individuals with overweight/obesity.

Background: Little is known about the impact of mango consumption on metabolic pathways assessed by changes in gene expression. Methods: In this single-arm clinical trial, cardiometabolic outcomes and gene expression levels in whole blood samples from 26 men and women were examined at baseline and after 8 weeks of mango consumption and differential gene expression changes were determined. Based on changes in gene expression profiles, partial least squares discriminant analysis followed by hierarchical clustering were used to classify participants into subgroups of response and differences in gene expression changes and in cardiometabolic clinical outcomes following the intervention were tested. Results: Two subgroups of participants were separated based on the resemblance of gene expression profiles in response to the intervention and as responders (n = 8) and non-responders (n = 18). A total of 280 transcripts were significantly up-regulated and 603 transcripts down-regulated following the intervention in responders, as compared to non-responders. Several metabolic pathways, mainly related to oxygen and carbon dioxide transport as well as oxidative stress, were found to be significantly enriched with differentially expressed genes. In addition, significantly beneficial changes in hip and waist circumference, c-reactive protein, HOMA-IR and QUICKI indices were observed in responders vs. non-responders, following the intervention. Conclusion: The impact of mango consumption on cardiometabolic health appears to largely rely on interindividual variability. The novel transcriptomic-based clustering analysis used herein can provide insights for future research focused on unveiling the origins of heterogeneous responses to dietary interventions. Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT03825276].

Changes in systolic blood pressure, postprandial glucose, and gut microbial composition following mango consumption in individuals with overweight and obesity.

This study aimed to explore the impact of daily mango consumption (Mangifera indica) on cardiometabolic health and gut microbiota in individuals with overweight and obesity. Changes in cardiometabolic variables, gut microbiota diversity and composition, physical activity habits, and dietary intakes were assessed in 8 males and 19 females with overweight and obesity who consumed 280 g/day of mango pulp for 8 weeks. There were no significant changes in body weight, waist circumference, or plasma lipid levels. However, after consuming mangos for 8 weeks, participants showed a 3.5% reduction in systolic blood pressure (-4 ± 6 mm Hg, p = 0.011) as well as a 10.5% reduction in 2-hour plasma glucose concentration after a 75-g oral glucose tolerance test (-0.58 ± 1.03 mmol/L, p = 0.008). These beneficial cardiometabolic outcomes were accompanied with enhanced gut microbiota diversity and with changes in the abundance of specific gut bacterial species. Mango consumption may have beneficial effects on both blood pressure and glucose homeostasis in individuals with overweight and obesity. Further studies are warranted to determine the impact of long-term and regular mango intake on cardiometabolic risk factors of individuals with overweight and obesity, and the potential mechanisms linking gut microbial changes to those health benefits. This study was registered with clinicaltrials.gov as NCT03825276. Novelty: A 3.5% reduction in systolic blood pressure is noted after consuming mangos for 8 weeks. A 10.5% reduction in 2-hour plasma glucose concentration of an oral glucose tolerance test is observed after consuming mangos for 8 weeks. Mango consumption for 8 weeks may enhance gut microbial diversity and abundance of specific bacterial species.

Modified Delphi Process to Identify Research Priorities and Measures for Adult Lifestyle Programs to Address Type 2 Diabetes and Other Cardiometabolic Risk Conditions.

OBJECTIVES: Clinical and community guidelines recommend lifestyle (i.e. diet and physical activity) interventions for cardiometabolic conditions (including type 2 diabetes), yet current evidence suggests limited and variable services in primary care and public health settings. New implementation research studies are needed to ensure maximal effectiveness, equity and efficiency across all population subgroups and within the context of health systems. Such work will benefit from use of similar core measures and outcome indicators across studies. This Delphi process was undertaken by a new interdisciplinary volunteer researcher network to identify research priorities and core measures for such studies. METHODS: Interested network members completed 2 rounds of a modified Delphi process delivered through online questionnaire and teleconferences. Consensus was defined as the median and interquartile range within the top third of a 9-point scale. RESULTS: Twenty-five of 53 (47%) members and 18 (34%) participants completed the round 1 and round 2 surveys, respectively. Of 22 possible research priorities, 4 were rated high priority with consensus, including evaluating the efficacy and effectiveness of interventions in place, improving existing interventions for sustainability and clinical and public health research to advance existing knowledge to develop new capacities. Only 15 of the 93 measures and indicators proposed achieved similar consensus. CONCLUSIONS: This first effort confirms broad agreement on research priorities and limited agreement on core indicators/measures. The results provide a starting point for further development of common measures for implementation research in lifestyle studies addressing cardiometabolic conditions.

Nutrigenetics, omega-3 and plasma lipids/lipoproteins/apolipoproteins with evidence evaluation using the GRADE approach: a systematic review.

OBJECTIVES: Despite the uptake of nutrigenetic testing through direct-to-consumer services and healthcare professionals, systematic reviews determining scientific validity are limited in this field. The objective of this review was to: retrieve, synthesise and assess the quality of evidence (confidence) for nutrigenetic approaches related to the effect of genetic variation on plasma lipid, lipoprotein and apolipoprotein responsiveness to omega-3 fatty acid intake. DESIGN: A systematic review was conducted using three search engines (Embase, Web of Science and Medline) for articles published up until 1 August 2020. We aimed to systematically search, identify (select) and provide a narrative synthesis of all studies that assessed nutrigenetic associations/interactions for genetic variants (comparators) influencing the plasma lipid, lipoprotein and/or apolipoprotein response (outcomes) to omega-3 fatty acid intake (intervention/exposure) in humans-both paediatric and adult populations (population). We further aimed to assess the overall quality of evidence for specific priority nutrigenetic associations/interactions based on the following inclusion criteria: nutrigenetic associations/interactions reported for the same genetic variants (comparators) influencing the same plasma lipid, lipoprotein and/or apolipoprotein response (outcomes) to omega-3 fatty acid intake (intervention/exposure) in humans-both paediatric and adult populations (population) in at least two independent studies, irrespective of the findings. Risk of bias was assessed in individual studies. Evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach with a modification to further consider biological plausibility. RESULTS: Out of 1830 articles screened, 65 met the inclusion criteria for the narrative synthesis (n=23 observational, n=42 interventional); of these, 25 met the inclusion criteria for GRADE evidence evaluation. Overall, current evidence is insufficient for gene-diet associations related to omega-3 fatty acid intake on plasma apolipoproteins, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol and LDL particle size. However, there is strong (GRADE rating: moderate quality) evidence to suggest that male APOE-E4 carriers (rs429358, rs7412) exhibit significant triglyceride reductions in response to omega-3-rich fish oil with a dose-response effect. Moreover, strong (GRADE rating: high quality) evidence suggests that a 31-SNP nutrigenetic risk score can predict plasma triglyceride responsiveness to omega-3-rich fish oil in adults with overweight/obesity from various ethnicities. CONCLUSIONS: Most evidence in this area is weak, but two specific nutrigenetic interactions exhibited strong evidence, with generalisability limited to specific populations. PROSPERO REGISTRATION NUMBER: CRD42020185087.

Towards a Standardized Definition of Medical Nutrition Therapy and Regulatory Reform in Canada.

Various definitions have been proposed to describe Medical Nutrition Therapy (MNT). Broadly, MNT encompasses the provision of nutrition information and advice aimed to prevent, treat, and/or manage health conditions. In Canada, the provision of such information and advice is unregulated, thus allowing anyone to provide MNT services regardless of their education and training. This inevitably poses risks of harm such as the provision of unsafe and/or ineffective nutrition advice as well as delayed evidence-based treatment. Canadian research has further demonstrated that the general public is unable to properly differentiate between regulated, evidence-based nutrition providers (registered dietitians) and those who are unregulated. Therefore, the public is at risk. To reduce nutrition misinformation and ultimately improve the health and well-being of the public, the objective of this paper is, first, to propose a standardized definition of MNT for use across Canada and, second, to propose province- and territory-specific legislative amendments for the regulation of MNT throughout the country. We also present an opposing perspective to the proposed viewpoint. Ultimately, health care regulation across the country requires an overhaul before we expect that nutrition information and advice communicated to the public may be consistently evidence based.

Clinical Practice Guidelines Using GRADE and AGREE II for the Impact of Genetic Variants on Plasma Lipid/Lipoprotein/Apolipoprotein Responsiveness to Omega-3 Fatty Acids.

BACKGROUND: A recent systematic review, which used the GRADE methodology, concluded that there is strong evidence for two gene-diet associations related to omega-3 and plasma triglyceride (TG) responses. Systematic reviews can be used to inform the development of clinical practice guidelines (CPGs). OBJECTIVE: To provide guidance for clinical practice related to genetic testing for evaluating responsiveness to dietary/supplemental omega-3s and their impact on plasma lipids/lipoproteins/apolipoproteins. DESIGN: Using the results of the abovementioned systematic review, the first CPGs in nutrigenetics were developed using the established GRADE methodology and AGREE II approach. RESULTS: Three clinical practice recommendations were developed. Most gene-diet associations identified in the literature lack adequate scientific and clinical validity to warrant consideration for implementing in a practice setting. However, two gene-diet associations with strong evidence (GRADE quality: moderate and high) can be considered for implementation into clinical practice in certain cases: male APOE-E4 carriers (rs429358, rs7412) and TG changes in response to the omega-3 fatty acids eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) as well as a 31-SNP nutrigenetic risk score and TG changes in response to EPA+DHA among adults with overweight/obesity. Ethical and regulatory implications must be considered when providing APOE nutrigenetic tests given the well-established link between APOE genetic variation and Alzheimer's Disease. CONCLUSION: Most of the evidence in this area is not ready for implementation into clinical practice primarily due to low scientific validity (low quality of evidence). However, the first CPGs in nutrigenetics have been developed for two nutrigenetic associations with strong scientific validity, related to dietary/supplemental omega-3 and TG responses.

A Systematic Review and Recommendations Around Frameworks for Evaluating Scientific Validity in Nutritional Genomics.

Background: There is a significant lack of consistency used to determine the scientific validity of nutrigenetic research. The aims of this study were to examine existing frameworks used for determining scientific validity in nutrition and/or genetics and to determine which framework would be most appropriate to evaluate scientific validity in nutrigenetics in the future. Methods: A systematic review (PROSPERO registration: CRD42021261948) was conducted up until July 2021 using Medline, Embase, and Web of Science, with articles screened in duplicate. Gray literature searches were also conducted (June-July 2021), and reference lists of two relevant review articles were screened. Included articles provided the complete methods for a framework that has been used to evaluate scientific validity in nutrition and/or genetics. Articles were excluded if they provided a framework for evaluating health services/systems more broadly. Citing articles of the included articles were then screened in Google Scholar to determine if the framework had been used in nutrition or genetics, or both; frameworks that had not were excluded. Summary tables were piloted in duplicate and revised accordingly prior to synthesizing all included articles. Frameworks were critically appraised for their applicability to nutrigenetic scientific validity assessment using a predetermined categorization matrix, which included key factors deemed important by an expert panel for assessing scientific validity in nutrigenetics. Results: Upon screening 3,931 articles, a total of 49 articles representing 41 total frameworks, were included in the final analysis (19 used in genetics, 9 used in nutrition, and 13 used in both). Factors deemed important for evaluating nutrigenetic evidence related to study design and quality, generalizability, directness, consistency, precision, confounding, effect size, biological plausibility, publication/funding bias, allele and nutrient dose-response, and summary levels of evidence. Frameworks varied in the components of their scientific validity assessment, with most assessing study quality. Consideration of biological plausibility was more common in frameworks used in genetics. Dose-response effects were rarely considered. Two included frameworks incorporated all but one predetermined key factor important for nutrigenetic scientific validity assessment. Discussion/Conclusions: A single existing framework was highlighted as optimal for the rigorous evaluation of scientific validity in nutritional genomics, and minor modifications are proposed to strengthen it further. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=261948, PROSPERO [CRD42021261948].