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ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers.
Oriá, RB, Freitas, RS, Roque, CR, Nascimento, JCR, Silva, AP, Malva, JO, Guerrant, RL, Vitek, MP
Pharmaceutics. 2023;(4)
Abstract
Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein's LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related to environmental-driven enteric dysfunction early in life, and such chronic inflammatory conditions may blunt the developmental trajectories of children with worrisome and often irreversible physical and cognitive faltering. This window of time for microbiota maturation and brain plasticity is key to protecting cognitive domains, brain health, and achieving optimal/full developmental potential. This review summarizes the potential role of promising apoE mimetic peptides to improve the function of the gut-brain axis, including targeting the blood-brain barrier in children afflicted with malnutrition and enteric infections.
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Immunoinflammatory role of apolipoprotein E4 in malnutrition and enteric infections and the increased risk for chronic diseases under adverse environments.
Freitas, RS, Roque, CR, Matos, GA, Belayev, L, de Azevedo, OGR, Alvarez-Leite, JI, Guerrant, RL, Oriá, RB
Nutrition reviews. 2022;(5):1001-1012
Abstract
Apolipoprotein E plays a crucial role in cholesterol metabolism. The immunomodulatory functions of the human polymorphic APOE gene have gained particular interest because APOE4, a well-recognized risk factor for late-onset Alzheimer's disease, has also been recently linked to increased risk of COVID-19 infection severity in a large UK biobank study. Although much is known about apoE functions in the nervous system, much less is known about APOE polymorphism effects on malnutrition and enteric infections and the consequences for later development in underprivileged environments. In this review, recent findings are summarized of apoE's effects on intestinal function in health and disease and the role of APOE4 in protecting against infection and malnutrition in children living in unfavorable settings, where poor sanitation and hygiene prevail, is highlighted. The potential impact of APOE4 on later development also is discussed and gaps in knowledge are identified that need to be addressed to protect children's development under adverse environments.
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Intervention and Mechanisms of Alanyl-glutamine for Inflammation, Nutrition, and Enteropathy: A Randomized Controlled Trial.
Moore, SR, Quinn, LA, Maier, EA, Guedes, MM, Quetz, JS, Perry, M, Ramprasad, C, Lanzarini Lopes, GML, Mayneris-Perxachs, J, Swann, J, et al
Journal of pediatric gastroenterology and nutrition. 2020;(3):393-400
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Abstract
OBJECTIVE Determine the minimum dosage of alanyl-glutamine (Ala-Gln) required to improve gut integrity and growth in children at risk of environmental enteropathy (EE). METHODS This was a double-blinded randomized placebo-controlled dose-response trial. We enrolled 140 children residing in a low-income community in Fortaleza, Brazil. Participants were 2 to 60 months old and had weight-for-age (WAZ), height-for-age (HAZ), or weight-for-height (WHZ) z-scores less than -1. We randomized children to 10 days of nutritional supplementation: Ala-Gln at 3 g/day, Ala-Gln at 6 g/day, Ala-Gln at 12 g/day, or an isonitrogenous dose of glycine (Gly) placebo at 12.5 g/day. Our primary outcome was urinary lactulose-mannitol excretion testing. Secondary outcomes were anthropometry, fecal markers of inflammation, urine metabolic profiles, and malabsorption (spot fecal energy). RESULTS Of 140 children, 103 completed 120 days of follow-up (24% dropout). In the group receiving the highest dose of Ala-Gln, we detected a modest improvement in urinary lactulose excretion from 0.19% on day 1 to 0.17% on day 10 (P = 0.05). We observed significant but transient improvements in WHZ at day 10 in 2 Ala-Gln groups, and in WHZ and WAZ in all Ala-Gln groups at day 30. We detected no effects on fecal inflammatory markers, diarrheal morbidity, or urine metabolic profiles; but did observe modest reductions in fecal energy and fecal lactoferrin in participants receiving Ala-Gln. CONCLUSIONS Intermediate dose Ala-Gln promotes short-term improvement in gut integrity and ponderal growth in children at risk of EE. Lower doses produced improvements in ponderal growth in the absence of enhanced gut integrity.
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Assessment of Neurodevelopment, Nutrition, and Inflammation From Fetal Life to Adolescence in Low-Resource Settings.
Suchdev, PS, Boivin, MJ, Forsyth, BW, Georgieff, MK, Guerrant, RL, Nelson, CA
Pediatrics. 2017;(Suppl 1):S23-S37
Abstract
Efforts to improve child neurodevelopment are critical to health, equity, and sustainable development, particularly in low-resource settings in the United States and globally. The colliding epidemics of food insecurity, infectious diseases, and noncommunicable diseases interact and impact neurodevelopment. Understanding the complex relationships between nutrition, inflammation, and neurodevelopment can inform clinical and public health interventions to improve outcomes. This article reviews key definitions, tools, and considerations for the assessment of nutrition, inflammation, and child neurodevelopment. The effectiveness of existing assessment tools to reflect status and biology, particularly in relation to each other, and to predict long-term changes in health is examined. The aim of this review is to present the extant evidence, identify critical research gaps, and suggest a research agenda for future longitudinal and intervention studies to address the assessment of nutrition, inflammation, and child neurodevelopment, particularly in low-resource settings. Despite research gaps, there is a strong relationship between nutrition, inflammation, environmental factors, and child neurodevelopment, which emphasizes the need to evaluate targeted, early interventions to improve long-term health and well-being.
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Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child Health Landscape.
Bhutta, ZA, Guerrant, RL, Nelson, CA
Pediatrics. 2017;(Suppl 1):S12-S22
Abstract
The last decade has witnessed major reductions in child mortality and a focus on saving lives with key interventions targeting major causes of child deaths, such as neonatal deaths and those due to childhood diarrhea and pneumonia. With the transition to Sustainable Development Goals, the global health community is expanding child health initiatives to address not only the ongoing need for reduced mortality, but also to decrease morbidity and adverse exposures toward improving health and developmental outcomes. The relationship between adverse environmental exposures frequently associated with factors operating in the prepregnancy period and during fetal development is well established. Also well appreciated are the developmental impacts (both short- and long-term) associated with postnatal factors, such as immunostimulation and environmental enteropathy, and the additional risks posed by the confluence of factors related to malnutrition, poor living conditions, and the high burden of infections. This article provides our current thinking on the pathogenesis and risk factors for adverse developmental outcomes among young children, setting the scene for potential interventions that can ameliorate these adversities among families and children at risk.
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Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children.
Mayneris-Perxachs, J, Lima, AA, Guerrant, RL, Leite, ÁM, Moura, AF, Lima, NL, Soares, AM, Havt, A, Moore, SR, Pinkerton, R, et al
Scientific reports. 2016;:19780
Abstract
Enteric infections, enteropathy and undernutrition in early childhood are preventable risk factors for child deaths, impaired neurodevelopment, and later life metabolic diseases. However, the mechanisms linking these exposures and outcomes remain to be elucidated, as do biomarkers for identifying children at risk. By examining the urinary metabolic phenotypes of nourished and undernourished children participating in a case-control study in Semi-Arid Brazil, we identified key differences with potential relevance to mechanisms, biomarkers and outcomes. Undernutrition was found to perturb several biochemical pathways, including choline and tryptophan metabolism, while also increasing the proteolytic activity of the gut microbiome. Furthermore, a metabolic adaptation was observed in the undernourished children to reduce energy expenditure, reflected by increased N-methylnicotinamide and reduced β-aminoisobutyric acid excretion. Interestingly, accelerated catch-up growth was observed in those undernourished children displaying a more robust metabolic adaptation several months earlier. Hence, urinary N-methylnicotinamide and β-aminoisobutyric acid represent promising biomarkers for predicting short-term growth outcomes in undernourished children and for identifying children destined for further growth shortfalls. These findings have important implications for understanding contributors to long-term sequelae of early undernutrition, including cognitive, growth, and metabolic functions.
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Effects of glutamine alone or in combination with zinc and vitamin A on growth, intestinal barrier function, stress and satiety-related hormones in Brazilian shantytown children.
Lima, AA, Anstead, GM, Zhang, Q, Figueiredo, ÍL, Soares, AM, Mota, RM, Lima, NL, Guerrant, RL, Oriá, RB
Clinics (Sao Paulo, Brazil). 2014;(4):225-33
Abstract
OBJECTIVE To determine the impact of supplemental zinc, vitamin A, and glutamine alone or in combination on growth, intestinal barrier function, stress and satiety-related hormones among Brazilian shantytown children with low median height-for-age z-scores. METHODS A randomized, double-blind, placebo-controlled trial was conducted in children aged two months to nine years from the urban shanty compound community of Fortaleza, Brazil. Demographic and anthropometric information was assessed. The random treatment groups available for testing (a total of 120 children) were as follows: (1) glutamine alone, n = 38; (2) glutamine plus vitamin A plus zinc, n = 37; and a placebo (zinc plus vitamin A vehicle) plus glycine (isonitrogenous to glutamine) control treatment, n = 38. Leptin, adiponectin, insulin-like growth factor (IGF-1), and plasma levels of cortisol were measured with immune-enzymatic assays; urinary lactulose/mannitol and serum amino acids were measured with high-performance liquid chromatography. ClinicalTrials.gov: NCT00133406. RESULTS Glutamine treatment significantly improved weight-for-height z-scores compared to the placebo-glycine control treatment. Either glutamine alone or all nutrients combined prevented disruption of the intestinal barrier function, as measured by the percentage of lactulose urinary excretion and the lactulose:mannitol absorption ratio. Plasma leptin was negatively correlated with plasma glutamine (p = 0.002) and arginine (p = 0.001) levels at baseline. After glutamine treatment, leptin was correlated with weight-for-age (WAZ) and weight-for-height z-scores (WHZ) (p≤0.002) at a 4-month follow-up. In addition, glutamine and all combined nutrients (glutamine, vitamin A, and zinc) improved the intestinal barrier function in these children. CONCLUSION Taken together, these findings reveal the benefits of glutamine alone or in combination with other gut-trophic nutrients in growing children via interactions with leptin.
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Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences.
Keusch, GT, Denno, DM, Black, RE, Duggan, C, Guerrant, RL, Lavery, JV, Nataro, JP, Rosenberg, IH, Ryan, ET, Tarr, PI, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014;(Suppl 4):S207-12
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Abstract
Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection.
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Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning.
Lima, AA, Kvalsund, MP, Souza, PP, Figueiredo, ÍL, Soares, AM, Mota, RM, Lima, NL, Pinkerton, RC, Patrick, PP, Guerrant, RL, et al
Clinics (Sao Paulo, Brazil). 2013;(3):351-8
Abstract
OBJECTIVE To identify the impact of supplemental zinc, vitamin A, and glutamine, alone or in combination, on long-term cognitive outcomes among Brazilian shantytown children with low median height-for-age z-scores. METHODS A randomized, double-blind, placebo-controlled trial was conducted in children aged three months to nine years old from the urban shanty compound community of Fortaleza, Brazil. Demographic and anthropometric information was assessed. The random treatment groups available for cognitive testing (total of 167 children) were: (1) placebo, n = 25; (2) glutamine, n = 23; (3) zinc, n = 18; (4) vitamin A, n = 19; (5) glutamine+zinc, n = 20; (6) glutamine+vitamin A, n = 21; (7) zinc+vitamin A, n = 23; and (8) glutamine+zinc+vitamin A, n = 18. Neuropsychological tests were administered for the cognitive domains of non-verbal intelligence and abstraction, psychomotor speed, verbal memory and recall ability, and semantic and phonetic verbal fluency. Statistical analyses were performed using SPSS, version 16.0. ClinicalTrials.gov: NCT00133406. RESULTS Girls receiving a combination of glutamine, zinc, and vitamin A had higher mean age-adjusted verbal learning scores than girls receiving only placebo (9.5 versus 6.4, p = 0.007) and girls receiving zinc+vitamin A (9.5 versus 6.5, p = 0.006). Similar group differences were not found between male study children. CONCLUSIONS The findings suggest that combination therapy offers a sex-specific advantage on tests of verbal learning, similar to that seen among female patients following traumatic brain injury.
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Improvement of intestinal permeability with alanyl-glutamine in HIV patients: a randomized, double blinded, placebo-controlled clinical trial.
Leite, RD, Lima, NL, Leite, CA, Farhat, CK, Guerrant, RL, Lima, AA
Arquivos de gastroenterologia. 2013;(1):56-63
Abstract
CONTEXT Glutamine is the main source of energy of the enterocyte and diarrhea and weight loss are frequent in HIV infected patients. OBJECTIVE To determine the effect of alanyl-glutamine supplementation on intestinal permeability and absorption in these patients. METHODS Randomized double-blinded, placebo-controlled study using isonitrogenous doses of alanyl-glutamine (24 g/day) and placebo (glycine, 25 g/day) during 10 days. Before and after this nutritional supplementation lactulose and mannitol urinary excretion were determined by high performance liquid chromatography. RESULTS Forty six patients with HIV/AIDS, 36 of whom were male, with 37.28 ± 3 (mean ± standard error) years were enrolled. Twenty two and 24 subjects were treated with alanyl-glutamine and with glycine respectively. In nine patients among all in the study protocol that reported diarrhea in the 14 days preceding the beginning of the study, mannitol urinary excretion was significantly lower than patients who did not report this symptom [median (range): 10.51 (3.01-19.75) vs. 15.37 (3.93-46.73); P = 0.0281] and lactulose/mannitol ratio was significantly higher [median (range): 0.04 (0.00-2.89) vs. 0.02 (0.00-0.19); P = 0.0317]. There was also a significant increase in mannitol urinary excretion in the group treated with alanyl-glutamine [median (range): 14.38 (8.25-23.98) before vs 21.24 (6.27-32.99) after treatment; n = 14, P = 0.0382]. CONCLUSION Our results suggest that the integrity and intestinal absorption are more intensely affected in patients with HIV/AIDS who recently have had diarrhea. Additionally, nutritional supplementation with alanyl-glutamine was associated with an improvement in intestinal absorption.