The infant gut microbiome and cognitive development in malnutrition.

Malnutrition affects 195 million children under the age of five worldwide with long term effects that include impaired cognitive development. Brain development occurs rapidly over the first 36 months of life. Whilst seemingly independent, changes to the brain and gut microbiome are linked by metabolites, hormones, and neurotransmitters as part of the gut-brain axis. In the context of severe malnutrition, the composition of the gut microbiome and the repertoire of biochemicals exchanged via the gut-brain axis vary when compared to healthy individuals. These effects are primarily due to the recognized interacting determinants, macro- and micronutrient deficiencies, infection, infestations and toxins related to poor sanitation, and a dearth of psycho-social stimulation. The standard of care for the treatment of severe acute malnutrition is focused on nutritional repletion and weight restoration through the provision of macro- and micronutrients, the latter usually in excess of recommended dietary allowances (RDA). However, existing formulations and supplements have not been designed to specifically address key recovery requirements for brain and gut microbiome development. Animal model studies indicate that treatments targeting the gut microbiome could improve brain development. Despite this, research on humans targeting the gut microbiome with the aim of restoring brain functionality are scarce. We conclude that there is a need for assessment of cognition and the use of various tools that permit visualization of the brain anatomy and function (e.g., Magnetic resonance imaging (MRI), functional near-infrared spectroscopy (fNIRS), electroencephalogram (EEG)) to understand how interventions targeting the gut microbiome impact brain development.

Multidimensional evaluation of the early emergence of executive function and development in Bangladeshi children using nutritional and psychosocial intervention: A randomized controlled trial protocol.

INTRODUCTION: Reversing malnutrition-induced impairment of cognition and emotional regulation is a critical global gap. We hypothesize that brain-targeted micronutrient supplemented nutritional rehabilitation in children with moderate acute malnutrition, followed by 2 years micronutrient supplementation will impact on the cognition and emotion regulation of these children. METHODS: The primary outcome of this prospective, randomized controlled trial is to study the development of executive functions (EFs) and emotion regulation (ER) in this cohort. Moderate acute malnourished (MAM; WLZ/WHZ <-2 and ≥-3 z-score, and/or 11.5 cm ≤ MUAC < 12.5cm; n = 140)children aged around one year (11m-13m) in Mirpur, Dhaka, Bangladesh will be randomized (1:1) to receive either locally produced Ready to Use Supplementary Food (RUSF) or Enhanced Ready to Use Supplementary Food (E-RUSF) until anthropometric recovery (WLZ/WHZ > -1SD), or for 3 months after enrollment (whichever is earlier). The randomized MAMs groups will be given either Small Quantity Lipid Based Nutrient Supplement (SQLNS) or Enhanced Small Quantity Lipid Based Nutrient Supplement (E-SQLNS), respectively until the end of the 2-year follow up period. Standard psychosocial stimulation will be provided to the MAMs intervention groups. Biological samples will be collected, anthropometric and neurocognitive assessments will be performed at 2 (22m-26m) and 3 (34m-38m) years of age. Two control groups will be recruited: 1), non-malnourished one-year (11m-13m) old children (WLZ/WHZ score>-1SD; n = 70); and 2) three-year (34m-38m) old children (n = 70) with untreated MAM (WHZ <-2 and ≥-3 z-score, and/or 11.5≤MUAC<12.5 cm). The 3-year-old MAM reference group will be assessed once and provided with 2 months of nutritional rehabilitation support (RUSF Nutriset's Plumpy'Sup™).

Consumption of Monounsaturated Fatty Acids Is Associated with Improved Cardiometabolic Outcomes in Four African-Origin Populations Spanning the Epidemiologic Transition.

Long-chain omega-3 PUFAs, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are of increasing interest because of their favorable effect on cardiometabolic risk. This study explores the association between omega 6 and 3 fatty acids intake and cardiometabolic risk in four African-origin populations spanning the epidemiological transition. Data are obtained from a cohort of 2500 adults aged 25-45 enrolled in the Modeling the Epidemiologic Transition Study (METS), from the US, Ghana, Jamaica, and the Seychelles. Dietary intake was measured using two 24 h recalls from the Nutrient Data System for Research (NDSR). The prevalence of cardiometabolic risk was analyzed by comparing the lowest and highest quartile of omega-3 (EPA+ DHA) consumption and by comparing participants who consumed a ratio of arachidonic acid (AA)/EPA + DHA ≤4:1 and >4:1. Data were analyzed using multiple variable logistic regression adjusted for age, gender, activity, calorie intake, alcohol intake, and smoking status. The lowest quartile of EPA + DHA intake is associated with cardiometabolic risk 2.16 (1.45, 3.2), inflammation 1.59 (1.17, 2.16), and obesity 2.06 (1.50, 2.82). Additionally, consuming an AA/EPA + DHA ratio of >4:1 is also associated with cardiometabolic risk 1.80 (1.24, 2.60), inflammation 1.47 (1.06, 2.03), and obesity 1.72 (1.25, 2.39). Our findings corroborate previous research supporting a beneficial role for monounsaturated fatty acids in reducing cardiometabolic risk.

Effects of randomized supplementation of methionine or alanine on cysteine and glutathione production during the early phase of treatment of children with edematous malnutrition.

BACKGROUND: We have shown that a low glutathione concentration and synthesis rate in erythrocytes are associated with a shortage of protein-derived cysteine in children with edematous severe acute malnutrition (SAM). OBJECTIVE: We tested the hypothesis that methionine supplementation may increase protein-derived cysteine and upregulate cysteine synthesis, thereby improving glutathione synthesis during the early treatment of edematous SAM. DESIGN: The cysteine flux, its de novo synthesis and release from protein breakdown, and erythrocyte glutathione synthesis rate were measured in 12 children with edematous SAM in the fed state by using stable isotope tracers at 3 clinical phases as follows: 3 ± 1 d (±SE) [clinical phase 1 (CP1)], 8 ± 1 d [clinical phase 2 (CP2)], and 14 ± 2 d (clinical phase 3) after admission. Subjects were randomly assigned to receive equimolar supplements (0.5 mmol ⋅ kg(-1) ⋅ d(-1)) of methionine or alanine (control) immediately after CP1. RESULTS: In the methionine compared with the alanine group, cysteine flux derived from protein breakdown was faster at CP2 than CP1 (P < 0.05), and the change in plasma cysteine concentration from CP1 to CP2 was greater (P < 0.05). However, there was no evidence of a difference in cysteine de novo synthesis and its total flux or erythrocyte glutathione synthesis rate and concentration between groups. CONCLUSIONS: Methionine supplementation increased cysteine flux from body protein but had no significant effect on glutathione synthesis rates. Although cysteine is made from methionine, increased dietary cysteine may be necessary to partially fulfill its demand in edematous SAM because glutathione synthesis rates and concentrations were less than previous values shown at full recovery. This study was registered at clinicaltrials.gov as NCT00473031.

Dietary supplementation with aromatic amino acids increases protein synthesis in children with severe acute malnutrition.

Although 2 earlier studies reported that aromatic amino acid (AAA) supplementation of children with severe acute malnutrition (SAM) improved whole-body protein anabolism during the early postadmission (maintenance) phase of rehabilitation, it is not known whether this positive effect was maintained during the catch-up growth and recovery phases of treatment. This study aimed to determine whether supplementation with an AAA cocktail (330 mg · kg(-1) · d(-1)) vs. isonitrogenous Ala would improve measures of protein kinetics in 22 children, aged 4-31 mo, during the catch-up growth and recovery phases of treatment for SAM. Protein kinetics were assessed by measuring leucine, phenylalanine, and urea kinetics with the use of standard stable isotope tracer methods in the fed state. Supplementation started at the end of the maintenance period when the children were clinically/metabolically stable and continued up to full nutritional recovery. Three experiments were performed: at the end of maintenance (at ∼13 d postadmission), at mid-catch-up growth (at ∼23 d post- admission when the children had replenished 50% of their weight deficit), and at recovery (at ∼48 d postadmission when they had achieved at least 90% weight for length). Children in the AAA group had significantly faster protein synthesis compared with those in the Ala group at mid-catch-up growth (101 ± 10 vs. 72 ± 7 µmol phenylalanine · kg(-1) · h(-1); P < 0.05) and better protein balance at mid-catch-up growth (49 ± 5 vs. 30 ± 2 µmol phenylalanine · kg(-1) · h(-1); P < 0.05) and at recovery (37 ± 8 vs. 11 ± 3 µmol phenylalanine · kg(-1) · h(-1); P < 0.05). We conclude that dietary supplementation with AAA accelerates net protein synthesis in children during nutritional rehabilitation for SAM.

Supplementation with aromatic amino acids improves leucine kinetics but not aromatic amino acid kinetics in infants with infection, severe malnutrition, and edema.

We investigated whether supplementation with an aromatic amino acid (AAA) cocktail consisting of 0.5 mmol each of phenylalanine, tryptophan, and tyrosine compared with isonitrogenous amounts of alanine (Ala) would improve measures of protein kinetics in 14 (8 with AAA, 6 Ala) children with edematous malnutrition (aged 6-24 mo) during the infected acute malnourished state. Supplementation started immediately after the baseline experiment, 2 d postadmission and continued to the end of the acute phase of treatment. The second (postsupplementation) experiment was done approximately 12 d postadmission. We measured leucine kinetics, phenylalanine and tyrosine fluxes, using an i.g. 8-h prime continuous infusion of (2)H(3)-leucine, and an i.v. 6-h prime continuous infusion of (13)C-leucine, (2)H(2)-tyrosine, and (2)H(5)-phenylalanine in the fed state. Leucine flux tended to be faster (P = 0.06) in the AAA group compared with Ala group after supplementation (mean difference +/- SEM): 22.6 +/- 10.9 micromol/(kg . h). The rate of leucine appearance from protein breakdown [28.1 +/- 9.4 micromol/(kg . h)] and the nonoxidative disposal of leucine [i.e., leucine to protein synthesis; 35.4 +/- 12.9 micromol/(kg . h)] were faster (P < 0.02) in the AAA group than in the Ala group. There was no significant effect of supplementation on leucine splanchnic metabolism, phenylalanine, and tyrosine fluxes. These findings are consistent with the hypothesis that the blunting of the protein catabolic response to infection in children with edematous malnutrition syndrome is due to limited availability of aromatic amino acids.

Cysteine supplementation improves the erythrocyte glutathione synthesis rate in children with severe edematous malnutrition.

BACKGROUND: Children with severe edematous malnutrition have higher than normal oxidant damage and lower concentrations of the antioxidant reduced glutathione (GSH), which are associated with slower synthesis of GSH and with low extra- and intracellular concentrations of the precursor amino acid cysteine. OBJECTIVE: We tested whether early dietary supplementation with cysteine could restore a normal GSH concentration and synthesis rate in these children. DESIGN: Erythrocyte cysteine and GSH concentrations and the fractional and absolute synthesis rates of GSH were measured in 2 groups of 16 edematous malnourished children, 10 boys and 6 girls aged 6-18 mo, at 3 times after hospital admission: at approximately 2 d (period 1), when they were malnourished and infected; at approximately 11 d (period 2), when they were malnourished but cleared of infection; and at approximately 50 d (period 3), when they had recovered. Supplementation with either 0.5 mmol. kg(-1). d(-1) N-acetylcysteine (NAC group) or alanine (control group) started immediately after period 1 and continued until recovery. RESULTS: From period 1 to period 2 the concentration and the absolute synthesis rate of GSH increased significantly (P < 0.05) in the NAC group but not in the control group. The increases in the GSH concentration and synthesis rate were approximately 150% and 510% greater, respectively, in the NAC group than in the control group. The increases in the NAC group were associated with a significant effect of supplement (P < 0.03) on erythrocyte cysteine concentration. CONCLUSION: These results suggest that the GSH synthesis rate and concentration can be restored during the early phase of treatment if patients are supplemented with cysteine.

The appropriateness of the current antibiotic empiric therapy based on the bacteria isolated from severely malnourished Jamaican children

We performed a retrospective audit of antimicrobial sensitivities of bacteria isolated from children admitted with a diagnosis of malnutrition to the Tropical Metabolism Research Unit (TMRU), University of the West Indies, between January 1995 and December 1999. There were 150 admissions for severe malnutrition to the TMRU during this period, which was approximately 50 percent fewer than in a previous TMRU study done ten years ago, between 1984 and 1989. In the present study, bacteraemia was documented in 10 percent of 150 severely malnourished children between 1 and 31 months of age. The most common organism isolated were coagulase-negative Staphylococci, which represented 40 percent of the total isolates. The micro-organism grown were most likely to be sensitive to amoxycillin/clavulanic acid. The current TMRU treatment protocol for severe malnutrition recommends use of crystalline penicillin plus gentamicin as empirical antibiotic therapy. This study has provided valuable information suggesting that the current empiric antibiotic therapy may be inappropriate. (AU)

Management of diabetes mellitus in three settings in Jamaica

Fewer than 10 percent of the patients were controlled with diet alone. Insulin was the most commonly prescribed agent at SPMC (46 percent). compared to 7 percent each at the two other clinics. Sulfonylurea drugs alone or in combination with metformin were the most common agents at PUBMC and PRMC. Overall, 40 percent of the patients had satisfactory blood glucose control (<8 mmol/L fasting or <10 mmol/L post prandial). There was no significant difference among the clinics in the proportion of patients with satisfactory blood glucose control (P=0.26). A blood glucose measurement had been recorded in the preceding year in 84 percent of the patients at SPMC, 79 percent at PRMC, and 67 percent at PUBMC. Glycosylated hemoglobin was infrequently measured: 16 percent at SPMC, 10 percent at PRMC, and 0 percent at PUBMC. Overall, 96 percent of patients had surveillance for hypertension, and 81 percent had surveillance for proteinuria. Surveillance for foot and retinal complications was generally infrequent and had been noted in patients' clinic records most commonly at APMC (14 percent for foot complications, and 13 percent for retinal complications). The staff at the three clinics seldom advised the diabetic patients on diet, exercise, and other nonpharmacological measures, according to the clinics records. THe management of diabetes in Jamaica fell short of international guidelines. Our results also indicate the need to better sensitize health care professionals to these standards in order to reduce the burden of diabetes (AU)

Management of diabetes mellitus in three settings in Jamaica

Objetivos. Evaluar la calidad de la atención a los pacientes diabéticos en tres consultorios (uno privado y dos públicos) de Jamaica, un país con ingresos medios y una alta prevalencia de diabetes (13 por ciento). Métodos. Durante un censo de 6 semanas realizado en 1995 se recogieron retrospectivamente datos sobre 437 pacientes diabéticos en estos tres consultorios: un ambulatorio de especialidades de un hospital público (AEP), una clinica privada (CP) y una policlínica pública (PP). Resultados. La mediana de edad de los pacientes osciló entre 56 años en el AEP y la CP y 63 años en la PP. La duración mediana del período de observación fue de 6,0 años en el AEP, 9,2 en la CP y 6,3 en la PP. menos de 10 por ciento de los pacientes fueron controlados únicamente con dieta. El tratamiento prescrito con más frecuencia en el AEP fue la insulina (46 por ciento, frente a 7 por ciento en cada uno de los otros dos consultorios). Las sulfonilureas, solas o combinadas con metformina, fueron los agentes más utilizados en la CP y la PP. en total 40 por ciento de los pacientes tuvieron un control satisfactorio de la glucemia (8 mmol/L en ayunas o 10 mmol/L tras las comidas) y no hubo diferencias significativas entre los consultorios con respecto al porcentaje de pacientes con control satisfactorio de la glucemia (P=0,26). La glucemia había sido registrada en el año anterior en 84 por ciento de los pacientes del AEP, 79 por ciento de la CP y 67 por ciento de la PP. Las determinaciones de la hemoglobina glucosilada fueron raras: 16 por ciento en el AEP, 10 por ciento en la CP y 0 por ciento en la PP. En total, en 96 por ciento de los pacientes se había vigilado la hipertensión y en 81 por ciento la proteinuria. La vigilancia de las complicaciones retinianas y podiátricas fue generalmente infrecuente y había sido registrada en las historias clínicas principalmente en los pacientes atendidos en el AEP (14 por ciento para las complicaciones podiátricas y 13 por ciento para las retinarias). Según las histórias clínicas, el personal de los tres consultorios raramente aconsejó a los pacientes sobre la dieta, el ejercicio y otras medidas no farmacológicas. La conducta clínica ante la diabetes en Jamaica no cumple las directrices internacionales y es necesario sensibilizar mejor a los profesionales sanitarios acerca de estas normas con el fin de reducir las consecuencias de la enfermedad

Changes in red cell sodium content and blood pressure levels with potassium supplementation in black hypertensive patients

Red cell sodium and potassium content were measured in 24 black hypertensive patients while they were hypokalaemic on thiazide diuretic therapy and again after potassium supplements (48 meq elemental K+/day). Mean and diastolic blood pressure levels fell by 4.1-4.4 and 4.5-5.2 mm Hg respectively with potassium supplementation, while both urinary excretion of potassium and serum potassium rose. Urinary sodium excretion was unchanged. Red cell potasssium remained within the normal range but red cell sodium, initially high, fell with potassium therapy. This study confirms the importance of potassium supplementation where hypokalaemic results from diuretic therapy (AU)

Effect of glycine supplementation on the pyroglutamic aciduria during recovery from severe malnutrition - abstract

We have previously demonstrated that as benzoic acid conjugates with endogenous glycine to form hippuric acid, the resulting glycine debt is associated with an increased pyroglutamic acid (PGA) excretion. We concluded that PGA could be used as an index of glycine insufficiency. Glycine is a substrate for glutathione (GSH) synthesis and PGA is an intermediate of the gamma-glutamyl cycle in which GSH is formed. As demand for glycine is enormous during periods of rapid growth, we supplemented glycine (127 mg/kg/d) to five rapid growing children (weight gain > 10g/kg/d) during recovery from severe malnutrition. Urinary PGA and blood GSH were measured before and after supplementation. SUBJECT 1: Diagnosis - kwashiorkor, Age - 18, Wt - 7.34, Change PGA - -73, Change GSH - +6.6; SUBJECT 2: Diagnosis - Mar/kwash, Age - 23, Wt - 6.55, Change PGA - -233, Change GSH - +7.6; SUBJECT 3: Diagnosis - mar/kwash, Age - 10, Wt 7.89, Change PGA - -55, Change GSH - +10.4; SUBJECT 4: Diagnosis - undernourished, Age - 14, Wt - 7.93, Change PGA - -53, Change GSH - +8.2; SUBJECT 5: Diagnosis - marasmus, Age - 12, Wt - 6.39, Change PGA - 0, Change GSH - + 4.9; SUBJECT 6: Diagnosis - kwashiorkor, Age - 14, Wt - 7.89, Change PGA - +245, Change GSH - -8.7. In four of the subjects, PGA decreased after supplementation while there was a concomitant increase in GSH. One showed no change in PGA excretion and had stopped growing. The other child showed the opposite result. PGA is usually associated with a deficiency of the enzyme GSH synthetase which is reponsible for the synthesis of GSH from glycine and glutamylcysteine. Our results support the hypothesis that if the availability of glycine were low then the reaction catalysed by GSH synthetase would be reduced because of limited substrated, and that the mechanism is effectively the same as with an absence of the enzyme - that is an increased PGA excretion. In this case, glycine corrects the defect. Furthermore, the data provide evidence that rapidly growing children may have an increased requirement for glycine (AU)

Effect of potassium supplementation in hypertensive patients with diuretic-induced hypokalaemia: changes in bloodpressure and red cell sodium content - abstract

Hypokalaemia is a frequent accompaniment of chronic diuretic therapy of hypertension. It is associated with an increased risk of cardiac arrhythmias as well as several biochemical abnormalities. Potassium supplementation produces a rise in serum potassium level and a fall in the mean blood pressure. The mechanisms underlying the changes in blood pressure with changes in body potassium status are ill understood but might involve changes in cell electrolytes. We therefore measured red cell sodium and potassium content in hypertensive patients during diuretic-induced hypokalaemia and after potassium supplementation. Eleven patients were treated with bendrofluazide (10 mg daily) for a monthe before measurements of serum and urine potassium, blood glucose level, uric acid and red cell sodium and potassium concentrations were made. Potassium chloride (60 mmol/day) was added for another month and the same measurements repeated. Red cell electrolyte content was measured by flame photometry after isolating the cells by density centrifugation. Mean blood pressure fell (103 ñ 3 to 95 ñ 3mm hg, p<0.005) with the change in serum potassium level from 3.1 ñ 0.1 to 4.1 ñ 0.3 meq/l(p<0.05). Red cell sodium content fell from 13.8 ñ 1.4 to 10.8 ñ 1.3 mmol Na/l RBC while potassium content was unchanged 90.7 ñ 8.6 vs 81.1 ñ 7.2 (p>0.10). Insignificant reductions in blood glucose and uric acid levels occurred. The fall in cell sodium concentration could contribute to the fall in blood pressure if similar changes occurred in vascular smooth muscle cells. Potassium supplementation enhance blood pressure control in hypokalaemic hypertensives (AU)

Glycine metabolism: the effect of benzoic acid on pyroglutamic acid excretion - abstract

Pyroglutamic acid is an intermediate of the r-glutamyl cycle for glutathione synthesis. Inhibition of the pathway, due to deficiency of the enzyme glutathiione synthetase, has been shown to result in accumulation and increased excretion of pyroglutamic acid. Glutathione synthetase requires glycine as a substrate, and we reasoned that limited availability of glycine may also cause increased urinary excretion of pyroglutamic acid. We therefore investigated whether pyroglutamic acid excretion rate might provide an index of glycine insufficiency. Benzoic acid readily combines with glycine to form hippuric acid, which is ultimately excreted. Therefore, benzoic acid, administration should drain the endogenous glycine pool, thus providing inadequate substrate for glutathione synthesis, and causing increased pyroglutamic acid excretion. We gave benzoic acid, and the benzoic acid for all subjects ranged between 20 and 26 æmol/mmol creatinine. Two hours after oral benzoic acid, the urinary pyroglutamic acid had increased to 42 æmol/mmol creatinine and remained elevated for the next 4 hrs., at 38 æmol/mm creatinine. When glycine was given with the benoic acid, the pyroglutamic acid reached a maximum of 37 æmol/mmol creatinine in 2 hours, and fell rapidly over the next 4 hours to 25 æmol/mmol creatinine. The levels had returned to initial values by eight hours. Levels of hippuric acid were increased with benzoic acid administration and there was a further increase when the glycine supplement was given. These data show that benzoic acid conjugates with endogenous glycine to form hippuric acid, and that the presumed glycine deficit is associated with increased pyroglutamic acid excretion. We suggest that pyroglutamic acid excretion rate could therefore be used as an index of glycine insufficiency (AU)