Gut microbiota dysbiosis is associated with malnutrition and reduced plasma amino acid levels: Lessons from genome-scale metabolic modeling.

Malnutrition is a severe non-communicable disease, which is prevalent in children from low-income countries. Recently, a number of metagenomics studies have illustrated associations between the altered gut microbiota and child malnutrition. However, these studies did not examine metabolic functions and interactions between individual species in the gut microbiota during health and malnutrition. Here, we applied genome-scale metabolic modeling to model the gut microbial species, which were selected from healthy and malnourished children from three countries. Our analysis showed reduced metabolite production capabilities in children from two low-income countries compared with a high-income country. Additionally, the models were also used to predict the community-level metabolic potentials of gut microbes and the patterns of pairwise interactions among species. Hereby we found that due to bacterial interactions there may be reduced production of certain amino acids in malnourished children compared with healthy children from the same communities. To gain insight into alterations in the metabolism of malnourished (stunted) children, we also performed targeted plasma metabolic profiling in the first 2 years of life of 25 healthy and 25 stunted children. Plasma metabolic profiling further revealed that stunted children had reduced plasma levels of essential amino acids compared to healthy controls. Our analyses provide a framework for future efforts towards further characterization of gut microbial metabolic capabilities and their contribution to malnutrition.

Does Malnutrition Have a Genetic Component?

Malnutrition is a complex disorder, defined by an imbalance, excess, or deficiency of nutrient intake. The visible signs of malnutrition are stunted growth and wasting, but malnourished children are also more likely to have delays in neurocognitive development, vaccine failure, and susceptibility to infection. Despite malnutrition being a major global health problem, we do not yet understand the pathogenesis of this complex disorder. Although lack of food is a major contributor to childhood malnutrition, it is not the sole cause. The mother's prenatal nutritional status, enteric infections, and intestinal inflammation also contribute to the risk of childhood malnutrition and recovery. Here, we discuss another potential risk factor, host and maternal genetics, that may play a role in the risk of malnutrition via several biological pathways. Understanding the genetic risks of malnutrition may help to identify ideal targets for intervention and treatment of malnutrition.

Nutritional rickets: vitamin D, calcium, and the genetic make-up.

BACKGROUND: The prevalence of vitamin D (vitD) deficiency presenting as rickets is increasing worldwide. Insufficient sun exposure, vitD administration, and/or calcium intake are the main causes. However, vitD system-related genes may also have a role. METHODS: Prospective study: 109 rachitic children completed a 6-mo study period or until rachitic manifestations disappeared. Thirty children were selected as controls. Clinical and biochemical data were evaluated at baseline in patients and controls and biochemistry re-evaluated at radiological healing. Therapy was stratified in three different protocols. Fifty-four single-nucleotide polymorphisms (SNPs) of five vitD system genes (VDR, CP2R1, CYP27B1, CYP24A1, and GC) were genotyped and their association with clinical and biochemcial data was analyzed. RESULTS: Therapy response was similar in terms of radiological healing although it was not so in terms of biochemical normalization. Only VDR gene (promoter, start-codon, and intronic genotypes) was rickets-associated in terms of serum 25-OH-D, calcium, radiological severity and time needed to heal. Eight patients with sufficient calcium intake and 25-OH-D levels carried a VDR genotype lacking minor allele homozygous genotypes at SNPs spread along the gene. CONCLUSION: Although patients presented epidemiologic factors strongly contributing to rickets, genetic modulation affecting predisposition, severity, and clinical course is exerted, at least in part, by VDR gene polymorphic variation.

Transgenerational effects of childhood conditions on third generation health and education outcomes.

This paper examines the extent to which pre-puberty nutritional conditions in one generation affect productivity-related outcomes in later generations. Recent findings from the biological literature suggest that the so-called slow growth period around age 9 is a sensitive period for male germ cell development. We build on this evidence and investigate whether undernutrition at those ages transmits to children and grandchildren. Our findings indicate that third generation males (females) tend to have higher mental health scores if their paternal grandfather (maternal grandmother) was exposed to a famine during the slow growth period. These effects appear to reflect biological responses to adaptive expectations about scarcity in the environment, and as such they can be seen as an economic correctional mechanism in evolution, with marked socio-economic implications for the offspring.

Epigenetics in Paediatric Gastroenterology, Hepatology, and Nutrition: Present Trends and Future Perspectives.

Epigenetics can be defined as stable, potentially heritable changes in the cellular phenotype caused by mechanisms other than alterations to the underlying DNA sequence. As such, any observed phenotypic changes including organ development, aging, and the occurrence of disease could be driven by epigenetic mechanisms in the presence of stable cellular DNA sequences. Indeed, with the exception of rare mutations, the human genome-sequence has remained remarkably stable over the past centuries. In contrast, substantial changes to our environment as part of our modern life style have not only led to a significant reduction of certain infectious diseases but also seen the exponential increase in complex traits including obesity and multifactorial diseases such as autoimmune disorders. It is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment, and a large body of existing evidence supports the importance of environmental factors such as diet and nutrition, infections, and exposure to toxins on human health. This seems to be particularly the case during vulnerable periods of human development such as pregnancy and early life. Importantly, as the first point of contact for many of such environmental factors including nutrition, the digestive system is being increasingly linked to a number of "modern" pathologies. In this review article, we aim to give a brief introduction to the basic molecular principals of epigenetics and provide a concise summary of the existing evidence for the role of epigenetic mechanisms in gastrointestinal health and disease, hepatology, and nutrition.

Neurological and Epigenetic Implications of Nutritional Deficiencies on Psychopathology: Conceptualization and Review of Evidence.

In recent years, a role for epigenetic modifications in the pathophysiology of disease has received significant attention. Many studies are now beginning to explore the gene-environment interactions, which may mediate early-life exposure to risk factors, such as nutritional deficiencies and later development of behavioral problems in children and adults. In this paper, we review the current literature on the role of epigenetics in the development of psychopathology, with a specific focus on the potential for epigenetic modifications to link nutrition and brain development. We propose a conceptual framework whereby epigenetic modifications (e.g., DNA methylation) mediate the link between micro- and macro-nutrient deficiency early in life and brain dysfunction (e.g., structural aberration, neurotransmitter perturbation), which has been linked to development of behavior problems later on in life.

The inheritance of obesity.

Syndromic adiposity appears to have a predisposition to run in families suggesting a hereditary element in its transmission. Purely genetic defects and DNA sequence variants have been directly associated with the development of adiposity; however, these account for a very small proportion of cases. A stronger association has been made between the intrauterine and early childhood nutritional environment of the foetus and young child and the predisposition of childhood and subsequent adulthood obesity. The nutritional environments include both a situation of nutritional deprivation or excess working through the interplay of epigenetic changes, and pancreatic and hypothalamic development. This is further compounded by the nutritional and lifestyle attitudes of the particular at-risk family. Adiposity prevention measures must include reenforced intervention strategies stating with lifestyle education schemes during pregnancy followed through until infancy and early childhood especially in those families/individuals identified as being at a risk of developing significant adiposity.

Angiotensin-converting enzyme gene insertion/deletion polymorphism in nutritional disorders in children.

PURPOSE: The aim of this study was to establish the role of angiotensin-converting enzyme gene insertion/deletion (ACE I/D) polymorphism in determining obesity or undernutrition in a child population in Romania. METHODS: We assessed 293 consecutively hospitalized patients in a tertiary emergency pediatric hospital. The patients were divided, according to body mass index (BMI), into three groups: group I, the control group consisting of 126 children, group II patients with undernutrition (85 patients) and group III patients with obesity (82 patients). ACE I/D polymorphisms were performed in all three patient groups, as well as the measuring of anthropometric parameters [middle upper arm circumference (MUAC), tricipital skinfold thickness (TST)]. All patients also underwent paraclinical evaluations (protein and albumin). The cutoffs criteria for moderate undernutrition were: BMI between -2.0 SD and -3.0 SD, severe undernutrition: BMI <-3.0 SD, moderate obesity: BMI between +2.0 SD and +3.0 SD and severe obesity: BMI >+3.0 SD. RESULTS: We observed that DD genotype (64.7%) was prevalent in the moderate undernutrition group, while ID (35.3%) and II genotypes were higher in the subgroup of severe undernutrition, with significant correlations in DD and ID genotype groups between BMI and MUAC, protein and albumin (p < 0.0001). In the obese group, we observed significant correlations in DD genotype, between BMI and MUAC (p = 0.0014) and TST, and for II genotype, between BMI and TST (p = 0.0071). II genotype was associated with severe obesity, while D allele carriers were associated with moderate undernutrition and moderate obesity. CONCLUSION: BMI, MUAC, TST and serum protein levels are correlated with D allele carriers of ACE genes in children with moderate undernutrition and moderate obesity, whereas II genotype is an unfavorable prognostic factor corresponding to severe obesity and severe undernutrition.

IL-6 572 C/G, 190 C/T, and 174 G/C gene polymorphisms in children's malnutrition.

OBJECTIVES: The aim of the present study was to establish the correlations between the polymorphisms of the genes interleukin-6 (IL-6) 572, 190, and 174 in children's malnutrition. METHODS: We assessed 283 hospitalized children and divided them into 2 groups: group I (control) included 110 patients with normal nutritional status, median (range) age 10.90 (1-18) years; and group II consisted of 173 malnourished patients, median (range) age 10.70 (1-18) years. RESULTS: The 2 groups underwent IL-6 572 cytosine allele (C)/guanine allele (G), 190 C/thymine allele (T), and 174 G/C polymorphism testing, measurement of anthropometric indicators (mid-upper arm circumference and tricipital skinfold thickness [TST]), and paraclinical evaluation (protein, albumin). We observed that the GG and CG genotypes were more frequent in malnourished children for the IL-6 174 gene (P = 0.0001), whereas the CT heterozygous genotype was more frequent in the malnourished group for the IL-6 190 gene (P = 0.003). Body mass index (BMI), middle upper arm circumference (MUAC), TST, and low serum albumin levels correlated with the GG and CG genotypes of the IL-6 572 and IL-6 174 genes, and with the CT genotype of the IL-6 190 gene, in children with malnutrition, whereas the IL-6 190 TT genotype was a protective factor for malnutrition (P = 0.0001). CONCLUSIONS: Malnutrition is more frequently associated in children with IL-6 174 G allele carriers (GG and CG genotypes), whereas IL-6 190 TT genotype has a protective function. In malnourished children, the IL-6 572/190/174 GG/CT/CG, GG/CT/GG, GG/CC/GG, and GG/CC/CG combined genotypes are more frequent.

Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome.

OBJECTIVE: We conducted a nationwide survey to determine the prevalence of common gastrointestinal and nutritional disorders in Rett syndrome (RTT) based on parental reporting and related the occurrence of these problems to age and methyl-CpG-binding protein 2 (MECP2) gene status. METHODS: We designed a questionnaire that probed symptoms, diagnoses, diagnostic tests, and treatment interventions related to gastrointestinal and nutritional problems in RTT. The International Rett Syndrome Foundation distributed the questionnaire to 1666 family-based members and forwarded their responses for our review. We interrogated the Rare Disease Clinical Research Network database to supplement findings related to medications used to treat gastrointestinal problems in RTT. RESULTS: Parents of 983 female patients with RTT (59%) responded and identified symptoms and diagnoses associated with gastrointestinal dysmotility (92%), chewing and swallowing difficulties (81%), weight deficits or excess (47%), growth deficits (45%), low bone mineral content or fractures (37%), and biliary tract disorders (3%). Height-for-age, weight-for-age, and body mass index z scores decreased significantly with age; height- and weight-, but not body mass index-for-age z scores were significantly lower in female subjects with MECP2 mutations than in those without. Vomiting, nighttime awakening, gastroesophageal reflux, chewing difficulty, and choking with feeding were significantly less likely to occur with increasing age. Short stature, low bone mineral content, fractures, and gastrostomy placement were significantly more likely to occur with increasing age. Chewing difficulty, choking with feeding, and nighttime awakening were significantly less likely to occur, whereas short stature was significantly more likely to occur, in female subjects with MECP2 mutations than in those without. Diagnostic evaluations and therapeutic interventions were used less frequently than the occurrence of symptoms or diagnoses in the RTT cohort. CONCLUSIONS: Gastrointestinal and nutritional problems perceived by parents are prevalent throughout life in girls and women with RTT and may pose a substantial medical burden for their caregivers. Physician awareness of these features of RTT may improve the health and quality of life of individuals affected with this disorder.

Bone development in children and adolescents with PKU.

INTRODUCTION: Individuals with phenylketonuria (PKU, OMIM 261600) have shown bone disease from childhood. Factors such as non-adherence to treatment, nutritional inadequacy, and high phenylalanine levels are associated with bone disease in several studies. This research aimed to describe the impact of dietary factors (consumption of energy, protein, calcium, phosphorus, and phenylalanine), and the control of plasma phenylalanine levels on bone age (BA) and bone mineral density (BMD). METHODOLOGY: Thirteen patients of both genders, from 8 to 16 years old participated in this study. Control data were collected of phenylalanine levels, food frequency and record, hand and fist X-rays, and spinal bone densitometry. RESULTS: In children group (CG), individuals non-adherent to diet (NAD) consumed lower amounts of calcium (472 ± 100 mg/day) and energy (1743 ± 486 Kcal); they had higher rates of phenylalanine (564 ± 94 µmol/L) in blood, intake phenylalanine (701 ± 334 mg/g), and higher protein intake from free foods (14 ± 6.67 g/day); bone age (BA) values higher than the chronological age (CA) and less BMD values (-0.7 ± 1.6 SD) also were verified. In adolescent group (AG, N = 8) of NAD, values were lower for energy intake (1379 ± 258 Kcal), calcium (801 ± 152 mg/day), phosphorus (657 ± 102 mg/day), food protein (25 ± 7.6 g/day), and intake phenylalanine (1067 ± 382 mg/day) than recommended. Higher levels of plasma phenylalanine (851 ± 244 µmol/L), bone age greater than chronological age and lower BMD values (-2.4 ± -2.5 SD) were observed. CONCLUSION: The results suggest effects on BA and on BMD, in both children and adolescent groups. The bone development is expressed differently in children and adolescents. The non-adherence to the diet verified in both groups and the consequent imbalance in the nutrients intake involved in bone metabolism suggest that these factors influence the failure to thrive in children and reduced bone mineralization in adolescents.

Malnutrition and infection influence the peripheral blood reticulocyte micronuclei frequency in children.

Malnutrition is a serious public health problem that affects approximately one third of all children. Developing countries have the highest incidence of malnourished children, and approximately 60% of deaths that occur in children under five are directly related to malnutrition and associated diseases. The relationship between malnutrition and genetic damage has been widely studied in humans and animal models. The micronucleus (MN) assay is useful in detecting chromosome damage induced by several factors. The aim of this study was to evaluate the effects of infection and malnutrition on the frequency of MN in erythrocytes from the peripheral blood of well-nourished, uninfected (WN) and well-nourished, infected (WNI) children, and moderately malnourished (UNM) and severely malnourished (UNS) children, both with infection, using a flow cytometric analysis technique. The percentage of reticulocytes (RETs) was significantly higher (1.5-fold) in WNI children than well-nourished controls. In addition, the UNS group had a 2.2-fold increase in the percentage of RETs compared to the WNI group. The frequency of micronucleated reticulocytes (MN-RETs) was 2.5 times greater, in WNI group compared to the WN group. These frequencies were significantly higher (1.7- and 2.1-fold) in UNM and UNS, respectively, compared to the WNI group. The results suggest that infection and malnutrition induce DNA damage in children.

A preliminary examination of the effects of genetic variants of redox enzymes on susceptibility to oedematous malnutrition and on percentage cytotoxicity in response to oxidative stress in vitro.

BACKGROUND: The causes of oedematous vs non-oedematous childhood malnutrition (OM vs NOM) remain elusive. It is possible that inherited differences in handling oxidant stressors are a contributing factor. AIMS: To test for associations between polymorphisms in five genes and (i) risk of OM, a case-control study, and (ii) percentage cytotoxicity in peripheral blood mononuclear cells (PBMCs) exposed to hydrogen peroxide (H(2)O(2)), an in vitro cell challenge study. METHODS: Participants had been admitted previously for treatment of OM (cases, n = 74) or NOM (controls, n = 50), or were an independent set of healthy pregnant women (n = 47) who donated peripheral blood mononuclear cells. We tested for associations between genetic variation and outcome using single markers or a bivariate score constructed by counting numbers of deleterious alleles for each of 15 possible pairs of markers. RESULTS: In the case-control study there were no significant single-marker associations with OM. We did find that higher bivariate scores were associated with OM for the pair of NAD(P)H:quinone oxidoreductase 1 and catalase (odds ratio 2·00, 95% CI 1·05-3·82). In the cell challenge experiments, there were no significant associations with percentage cytotoxicity. CONCLUSIONS: Variation in this small set of genes seems unlikely to have a large impact on either risk of OM or cytotoxicity after H(2)O(2) exposure. The use of larger sample sizes to test the effects of a much larger set of genetic variants will be required in order to determine whether genetic variation contributes to the risk of OM. Such studies have potential for improving our understanding of causal pathways in OM.

Fetal programming and cardiometabolic diseases: the role of angiotensin II and inflammation

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Correlación clínica- para-clínica en un escolar con hipertensión porta de etiología a esclarecer / Clinical-paraclinical in a school with portal hypertension to determine

La hipertensión porta (HTP) es el resultado del incremento de la presión dentro del sistema venoso porta. Se presenta con poca frecuencia en el paciente pediátrico pero es una de las mayores causas de morbilidad y mortalidad en el niño con enfermedad hepática. La mayoría de los pacientes con http presentan un estado hiperdinámico, lo cual aumenta el flujo venoso porta y mantiene la hipertensión. Puede ser secundaria a obstrucción a nivel prehepático, intrahepático o extrahehepático.

Portal hypertension (PH) is the result of increased pressure within the portal venous system. It occurs infrequently in the pediatric patient but it is a major cause of morbidity and mortality in children with liver disease. Most patients with PH have a hyperdynamic state, which increases venous flow and portal hypertension remains. May be secondary to obstruction at prehepatic, intrahepatic or extrahehepatic.

[Programming nutritional and metabolic disorders: the diabetic environment during gestation]. / Déterminisme des troubles nutritionnels et métaboliques : impact de l'environnement diabétique durant la gestation.

During the last years, obesity and subsequent metabolic disorders and cardiovascular diseases have tremendously increased. Recent studies have shown that risk factors of cardiovascular diseases appear as soon as in infancy. In many situations, these disorders are programmed in early life during fetal development. These observations have lead to the concept of programming. The first studies on this subject underlined the link between poor fetal growth and the risk of nutritional and metabolic disorders during adulthood. But, it is now evident that excess of fetal growth as it is observed during pregnancy with maternal diabetes leads to the same consequences. The metabolic syndrome or syndrome X is the name for a clustering of risk factors for cardiovascular diseases and type II diabetes that are of metabolic origin. This syndrome, first described in the adults, is more and more studied during childhood and adolescence. Metabolic syndrome is now described in youth, particularly in subjects with risk factors as obesity. Alterations of intra-uterine environment lead to modified early development and represent short-term adaptations transmitted from one generation to another. This intergeneration effect contributes to the burden of adult metabolic disorders and cardiovascular diseases, as seen in the last decades. There is considerable evidence for the contribution of epigenetic mechanisms for the lifelong and the intergenerational alteration of gene transcription by variation in the early life environment. One of the major challenges in the following years is to promote public health programs which are aimed at prevention of long-term consequences of fetal programming.

Use of metagenomics to understand the genetic basis of malnutrition.

Childhood malnutrition is not just due to lack of nutrients, it can also be caused by enteric infections leading to intestinal inflammation and malabsorption of nutrients. Human genetic polymorphisms can alter host genes that affect nutrient absorption and metabolism. Changes in intestinal microbial ecology and the microbiome (the collective genome of the intestinal microbiota) can also affect the harvest of nutrients from the diet. A substantial proportion of malnourished children fail to recover due to inappropriate treatment. However, there may be other causes for treatment failure, including changes in the microbiome and infection with an enteropathogen, and a genetic predisposition to malnutrition may exist. It is, therefore, logical to undertake the following: 1) investigate genetic predisposition to malnutrition, 2) determine the genetic markers and biomarkers that can help identify children at risk of malnutrition, and 3) look for new treatment modalities that can improve the clinical management of children with malnutrition.

Stress and body mass index each contributes independently to tumor necrosis factor-alpha production in prepubescent Latino children.

This investigation extended prior work by determining if stress and body mass index (BMI) contributed independently to tumor necrosis factor-alpha (TNF-alpha) levels among prepubescent Latino children and if sex and family history of type 2 diabetes mellitus (T2DM) modified these relationships. Data were collected in South Florida from 112 nondiabetic school-aged Hispanic children, of whom 43.8% were obese (BMI >/= 95th percentile) and 51.8% presented with a family history of T2DM. Stressful life events were assessed via parental report using a life events scale. Plasma TNF-alpha levels were determined with enzyme-linked immunosorbent assay. The relative contributions of stress and BMI with TNF-alpha levels and the potential interaction effects of sex and family history of T2DM were analyzed with multiple linear regression analyses. Stress and BMI each accounted for a significant proportion of the unique variance associated with TNF-alpha. The association between stress and TNF-alpha was not modified by sex or family history of T2DM. These findings implicate BMI and stress as independent determinants of TNF-alpha (an inflammatory cytokine and adipocytokine) among Latino children. Future investigations should examine the potential roles of exercise, nutritional status, age, and growth hormone in explicating the relationship between TNF-alpha production and psychosocial distress and risk for infection among obese children.

Malnutrition as an enteric infectious disease with long-term effects on child development.

Malnutrition is a major contributor to mortality and is increasingly recognized as a cause of potentially lifelong functional disability. Yet, a rate-limiting step in achieving normal nutrition may be impaired absorptive function due to multiple repeated enteric infections. This is especially problematic in children whose diets are marginal. In malnourished individuals, the infections are even more devastating. This review documents the evidence that intestinal infections lead to malnutrition and that malnutrition worsens intestinal infections. The clinical data presented here derive largely from long-term cohort studies that are supported by controlled animal studies. Also reviewed are the mechanisms by which enteric infections lead to undernutrition and by which malnutrition worsens enteric infections, with implications for potential novel interventions. Further intervention studies are needed to document the relevance of these mechanisms and, most importantly, to interrupt the vicious diarrhea-malnutrition cycle so children may develop their full potential.