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Introducing Precision Nutrition for Vulnerable Children in Low-Resource Settings Introducing Precision Nutrition for Vulnerable Children in Low-Resource Settings Paraskevi Massara fell, albeit with striking subnational heterogeneity. However, in Department of Nutritional Sciences, Faculty of Medicine, 2020, globally 149 million children under 5 years of age were 1 Current programmatic University of Toronto, Toronto, Ontario, Canada stunted and 45 million were wasted. approaches are mostly generic, and not tailored to regional, James M Njunge communal, household or personal characteristics. For example, The Childhood Acute Illness & Nutrition (CHAIN) while vitamin A or zinc deficiency varies considerably in low- Network, Nairobi, Kenya; KEMRI-Wellcome Trust and middle-income countries,2 this is not usually considered in Research Programme, Kilifi, Kenya designing interventions such as the composition of ready-to-use therapeutic foods used to treat children with severe malnutrition. Deborah A van den Brink Such public health approaches have been effective at scale where Amsterdam UMC location University of Amsterdam, resources are limited; however, there is likely to be a ceiling for Amsterdam Centre for Global Child Health & Emma the gains attainable from a ‘one size fits all’ approach. Children’s Hospital, Amsterdam, the Netherlands “ Precision nutrition could help the Wieger Voskuijl target populations of interventions The Childhood Acute Illness & Nutrition (CHAIN) Network, where resources are limited” Nairobi, Kenya; Amsterdam UMC location University of Amsterdam, Amsterdam Centre for Global Child Health & Emma Children’s Hospital, Amsterdam, the Netherlands; Appropriate nutrition is essential for growth, development and Department of Paediatrics and Child Health, Kamuzu resilience, preventing diseases and their impacts. Ingested nutri- University of Health Sciences, Blantyre, Malawi ents transit through metabolic pathways influenced by genetics, James A Berkley epigenetics, the microbiome and environmental factors, contrib- Department of Nutritional Sciences, Faculty of Medicine, uting to heterogeneity in individual needs and responses. These University of Toronto, Toronto, Ontario, Canada; factors also underlie differences in disease susceptibility and the CHAIN Network, Nairobi, Kenya; the KEMRI/Wellcome response to therapy. Thus, they have the potential to inform rec- Trust Research Programme, Kilifi, Kenya; University of ommendations for different segments of populations (Figure 1) Oxford, UK in precision nutrition approaches. Precision nutrition combined with spatially resolved data could help the target populations of Robert H J Bandsma interventions where resources are limited.3 Integration of big data Department of Nutritional Sciences, Faculty of Medicine, related to genetic, epigenetic, microbiome, lifestyle and environ- University of Toronto, Toronto, Ontario, Canada; mental factors is required to expand our understanding of the di- the CHAIN Network, Nairobi, Kenya; the KEMRI/Wellcome versity of human metabolism in response to diet. Trust Research Programme, Kilifi, Kenya The emerging role of precision nutrition Precision nutrition encompasses utilizing a group or an individu- Current nutritional interventional approaches al’s characteristics to optimize interventions. It is rapidly gaining for vulnerable children traction, largely because of new ‘omics’ tools and consequent in- Considerable effort has been made to improve nutrition among sights into the roles of the intestinal microbiome in metabolic and vulnerable children, including those who are stunted and/or hormonal processes, and their association with diet. Differential wasted. Between 2000 and 2015, child growth deficits in Africa responses to diet due to genetic and epigenetic factors (‘nutrige- 29 Sight and Life Special Report / The Evidence Base Introducing Precision Nutrition for Vulnerable Children in Low-Resource Settings figure 1: The mu ltilevel role of precision nutrition to prevent and manage disease Social Clinical Metabolic Genetic Microbiome Global Region Community Household Individual netics’) are increasingly recognized. For example, malnutrition potentially require feeds with a different lipid composition.7 How- in all its forms (undernutrition, micronutrient deficiencies, over- ever, in general, local preferences have informed the composition 1 influences DNA methylation, affecting host weight or obesity) of therapeutic feeds in some countries including Bangladesh, metabolism.4 Metabolites of the microbiota, such as short-chain Vietnam and India to increase acceptability.8−10 fatty acids, can also alter DNA methylation and histone acetyla- tion, potentially affecting epigenetic regulation of metabolic pro- Intestinal microbiota cesses.5 Clinical status and social factors also offer the potential to The intestinal microbiota lives symbiotically within the host, har- target approaches. For example, integrating anthropometry, diet, boring ~100-fold more genes than the host. Its composition and physical activity and microbiome can accurately predict glycemic function are shaped by gestational age, birth mode, genetics, epi- response to a meal.6 genetics, feeding, antimicrobials and the environment. Diet is a key driver of variation in constituent organisms and their func- 11−16 The intestinal microbiota influences “ Identifying food components that tional gene content. improve beneficial functions of the human development and homeostasis by modulating immune 17,18 metabolism19,20 and energy ho- regulation, gut integrity, microbiota is a potential dietary meostasis, brain function and pathogen colonization resistance.21 approach to enhancing precision” Thus, the microbiota is an intermediary between nutrition and health, and an important target for precision nutrition-based in- terventions. Undernutrition has been associated with an ‘immature’ micro- Feeds for severe malnutrition biota phenotype that is largely refractory to current nutritional Two milk-based formulae – F-75 (lower protein, lower energy) interventions.22,23 Dysbiosis24,25 (altered microbiota composi- and F-100 (higher protein and higher energy) – are used to treat tion or function) likely interferes with processes essential for host children with severe malnutrition in the stabilization and reha- health and wellbeing. Identifying food components that improve bilitation phases of inpatient treatment, respectively. The World beneficial functions of the microbiota is a potential dietary ap- Health Organization recommends ready-to-use therapeutic foods proach to enhancing precision. Microbiota-directed feeds using that have a similar nutritional composition to F-100 for commu- readily available foods such as chickpea, soy, peanut and banana 26,27 Since both nity-based management of severe malnutrition in a single reha- can alter the microbiome, promoting weight gain. bilitation phase. While these feeds are critical, their composition, composition and targets may vary regionally, such precision nutri- amounts and duration have not been customized to meet the in- tion approaches have the potential to radically change strategies dividualized needs. Variability in energy requirements may need and may optimize benefits, given resource limitations. to be addressed, and proteomics and metabolomics studies have Functional readouts of the microbiome can assess the effects demonstrated that HIV-infected children with severe malnutrition of nutritional approaches. For example, short-chain fatty acids Sight and Life Special Report / The Evidence Base 30 Introducing Precision Nutrition for Vulnerable Children in Low-Resource Settings are bacterial fermentation compounds of dietary fibers that play markers and volatile organic compounds are associated with poor a role in immune regulation.28 Poorly digested fibers can lead 37−40 Both are a proxy for sys- outcomes in severe malnutrition. to the accumulation of pro-inflammatory metabolites.29 There- temic inflammation and altered microbiota, and could be devel- fore, assessing an individual’s fiber digestive capacity could lead oped as a near-bedside point-of-care tool. to differential nutritional recommendations for poor versus high fiber-digesters. Microbiome-dependent metabolism of pharma- Tools for precision nutrition ceutical compounds can also be assessed to optimize treatment Longitudinal growth analyses 30,31 For example, the relationship between metformin responses. Longitudinal growth monitoring is essential for the evaluation of and the microbiome is partially responsible for its beneficial ef- children’s nutritional and health status.41 Thus, growth pathways fects on lifespan.32 Thus, reshaping host–microbiota interactions constructed using longitudinal measurements are an important through precision nutrition is a new therapeutic avenue for both tool for assessing growth longitudinally at both individual child disease control and prevention, and could be harnessed to affect 42,43 The shapes of growth trajectories level and population level. functional/clinical outcomes including immune function, cogni- have been associated with health outcomes such as cardiometa- tion and growth. bolic health.44 Thus, it is possible to predict growth and therefore to design targeted interventions for individual children through Risk prediction for precision nutrition precision nutrition. Clinical parameters that are collected routinely in nutritionally and clinically vulnerable children can be harnessed to guide more Systems thinking precise nutritional management (Figure 2). Studies in intensive The role of nutrition in vulnerable children is multifaceted. care units in high-resource settings demonstrate that limiting ca- Systems thinking provides the framework to study the interre- 33 Ide- lationships between elements of the system and the function of loric intake during critical illness can improve outcomes. ally, nutritional intake should be based on individual basic energy the system as a whole.45 Potential advantages of system-based needs, but stratified approaches may be feasible with improved approaches include reducing inequities in health research and knowledge of energy requirements for malnourished children policymaking. This can be achieved by modeling complex social with different levels of clinical illness severity. Clinical warning interactions between different communities46,47 and bridging signs provide an opportunity to identify changes which occur the gap between research and practice by the potential impact of daily that can be used to stratify children to alternative nutritional implementing an intervention.48 Figure 3 shows an application and medical treatments (Figure 2).34−36 Specific metabolic bio- of systems thinking. figure 2: Biomar kers and clinical warning signs can be used to stratify patients and to monitor and evaluate a treatment plan, resulting in treatment more tailored to the individual’s needs CLINICAL WARNING SIGNS BIOMARKERS ∙ Triage scores ∙ Volatiles ∙ Continous monitoring ∙ Metabolomics ∙ Individual parameters Precision treatment based on current needs of the child 31 Sight and Life Special Report / The Evidence Base Introducing Precision Nutrition for Vulnerable Children in Low-Resource Settings figure 3: Precision nu trition for vulnerable children in low-resource settings from the systems thinking perspective Education Employment Media consumption Public health policies Food Sociodemographics Cost of production physical activity Cost of the Diet Diet Physical Domestic Physical activity ingredients quality activity physical activity infrastructures Supplement Individual Recreational availability physical activity Genetic makeup Digestion Gut and absorption microbiome Metabolic response References “ Tailoring interventions to actual 1 WHO . The UNICEF/WHO/World Bank Group Joint Child Malnutrition Estimates (JME) group released new data for 2021. Internet: needs may be cost-effective” https://www.who.int/news/item/06-05-2021-the-unicef-who-wb- joint-child-malnutrition-estimates-group-released-new-data-for-2021 In summary, new tools and approaches allow us to identify (accessed 24 September 2022). groups in whom interventions can be targeted to optimize benefit, 2 Zhao T , Liu S, Zhang R, Zhao Z, Yu H, Pu L, et al. Global Burden of thus introducing a precision nutrition approach to public health Vitamin A Deficiency in 204 Countries and Territories from 1990- nutrition. Resource limitations in low- and middle-income coun- 2019. Nutrients. 2022 Mar;14(5):950. tries are a major factor dictating programs and policy; however, 3 Osgo od-Zimmerman A, Millear AI, Stubbs RW, Shields C, Pickering BV, tailoring interventions to actual needs may be cost-effective, and Earl L, et al. Mapping child growth failure in Africa between 2000 this needs to be assessed in robust clinical trials. and 2015. Nature. 2018;555(7694):41–7. 4 Quilter CR, Harvey KM, Bauer J, Skinner BM, Gomez M, Shrivastava M, et al. Identification of methylation changes associated with Correspondence: Dr James A Berkley, positive and negative growth deviance in Gambian infants using a Kenya Medical Research Institute/Wellcome Trust Research targeted methyl sequencing approach of genomic DNA. FASEB Bioadv. Programme, Kilifi 80108, Kenya 2021;3(4):205–30. Email: jberkley@kemri-wellcome.org 5 Li D , Li Y, Yang S, Lu J, Jin X, Wu M. Diet-gut microbiota-epigenetics in metabolic diseases: From mechanisms to therapeutics. Biomed Dr Robert H J Bandsma, Pharmacother. 2022 Jun;153:113290. Departments of Paediatrics and Nutritional Sciences, 6 Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, University of Toronto, 555 University Avenue Toronto, et al. Personalized nutrition by prediction of glycemic responses. Cell. Ontario, Canada 2015;163(5):1079–94. Email: robert.bandsma@sickkids.ca 7 Gonzales GB, Njunge JM, Gichuki BM, Wen B, Potani I, Voskuijl, W et al. Plasma proteomics reveals markers of metabolic stress Sight and Life Special Report / The Evidence Base 32
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