Metabolic and fecal microbial changes in adult fetal growth restricted mice.

BACKGROUND: Fetal growth restriction (FGR) increases risk for development of obesity and type 2 diabetes. Using a mouse model of FGR, we tested whether metabolic outcomes were exacerbated by high-fat diet challenge or associated with fecal microbial taxa. METHODS: FGR was induced by maternal calorie restriction from gestation day 9 to 19. Control and FGR offspring were weaned to control (CON) or 45% fat diet (HFD). At age 16 weeks, offspring underwent intraperitoneal glucose tolerance testing, quantitative MRI body composition assessment, and energy balance studies. Total microbial DNA was used for amplification of the V4 variable region of the 16 S rRNA gene. Multivariable associations between groups and genera abundance were assessed using MaAsLin2. RESULTS: Adult male FGR mice fed HFD gained weight faster and had impaired glucose tolerance compared to control HFD males, without differences among females. Irrespective of weaning diet, adult FGR males had depletion of Akkermansia, a mucin-residing genus known to be associated with weight gain and glucose handling. FGR females had diminished Bifidobacterium. Metabolic changes in FGR offspring were associated with persistent gut microbial changes. CONCLUSION: FGR results in persistent gut microbial dysbiosis that may be a therapeutic target to improve metabolic outcomes. IMPACT: Fetal growth restriction increases risk for metabolic syndrome later in life, especially if followed by rapid postnatal weight gain. We report that a high fat diet impacts weight and glucose handling in a mouse model of fetal growth restriction in a sexually dimorphic manner. Adult growth-restricted offspring had persistent changes in fecal microbial taxa known to be associated with weight, glucose homeostasis, and bile acid metabolism, particularly Akkermansia, Bilophilia and Bifidobacteria. The gut microbiome may represent a therapeutic target to improve long-term metabolic outcomes related to fetal growth restriction.

Adults are just big kids: pediatric considerations for adult critical care nephrology.

PURPOSE OF REVIEW: In recent years, there has been growing attention to pediatric kidney health, especially pediatric acute kidney injury (AKI). However, there has been limited focus on the role of pediatric AKI on adult kidney health, specifically considerations for the critical care physician. RECENT FINDINGS: We summarize what is known in the field of pediatric AKI to inform adult medical care including factors throughout the early life course, including perinatal, neonatal, and pediatric exposures that impact survivor care later in adulthood. SUMMARY: The number of pediatric AKI survivors continues to increase, leading to a higher burden of chronic kidney disease and other long-term co-morbidities later in life. Adult medical providers should consider pediatric history and illnesses to inform the care they provide. Such knowledge may help internists, nephrologists, and intensivists alike to improve risk stratification, including a lower threshold for monitoring for AKI and kidney dysfunction in their patients.

What Do We C in Children With Scurvy? A Case Series Focused on Musculoskeletal Symptoms.

OBJECTIVES: Vitamin C deficiency in children commonly presents with musculoskeletal symptoms such as gait disturbance, refusal to bear weight, and bone or joint pain. We aimed to identify features that could facilitate early diagnosis of scurvy and estimate the cost of care for patients with musculoskeletal symptoms related to scurvy. METHODS: We conducted a retrospective chart review of patients at a single site with diagnostic codes for vitamin C deficiency, ascorbic acid deficiency, or scurvy. Medical records were reviewed to identify characteristics including presenting symptoms, medical history, and diagnostic workup. The Pediatric Health Information System was used to estimate diagnostic and hospitalization costs for each patient. RESULTS: We identified 47 patients with a diagnosis of scurvy, 49% of whom had a neurodevelopmental disorder. Sixteen of the 47 had musculoskeletal symptoms and were the focus of the cost analysis. Three of the 16 had moderate or severe malnutrition, and 3 had overweight or obesity. Six patients presented to an emergency department for care, 11 were managed inpatient, and 3 required critical care. Diagnostic workups included MRI, computed tomography, echocardiogram, endoscopy, lumbar puncture, and/or EEG. Across all patients evaluated, the cost of emergency department utilization, imaging studies, diagnostic procedures, and hospitalization totaled $470 144 (median $14 137 per patient). CONCLUSIONS: Children across the BMI spectrum, particularly those with neurodevelopmental disorders, can develop vitamin C deficiency. Increased awareness of scurvy and its signs and symptoms, particularly musculoskeletal manifestations, may reduce severe disease, limit adverse effects related to unnecessary tests/treatments, and facilitate high-value care.

Association of Maternal BMI and Rapid Infant Weight Gain With Childhood Body Size and Composition.

OBJECTIVES: Maternal prepregnancy BMI (ppBMI) and an infant's rapid weight gain (RWG) are each associated with increased risk for childhood obesity. We hypothesized that ppBMI and RWG interact to further raise childhood obesity risk. METHODS: Mother-infant dyads (n = 414) from the Healthy Start Study, an observational prebirth cohort, were included. RWG was defined as a weight-for-age z score increase of ≥0.67 from birth to 3 to 7 months. Body composition was measured by air displacement plethysmography at age 4 to 7 years. General linear regression models were fit to characterize associations between ppBMI, RWG, and their interaction with the outcomes of childhood BMI-for-age z score and percent fat mass (%FM). RESULTS: A total of 18.6% (n = 77) of offspring experienced RWG. Maternal ppBMI and RWG were both positively associated with offspring BMI z score and %FM. RWG amplified the association between ppBMI and BMI z score, especially among females. Females exposed to maternal obesity and RWG had an average BMI at the 94th percentile (1.50 increase in childhood BMI z score) compared with those exposed to normal ppBMI and no RWG (average childhood BMI at the 51st percentile). RWG had a weaker effect on the association between ppBMI and %FM. Adjustment for breastfeeding status or childhood daily caloric intake did not significantly alter findings. CONCLUSIONS: Rapid infant weight gain interacts with maternal ppBMI to jointly exacerbate risk of childhood obesity. Pediatric providers should monitor infants for RWG, especially in the context of maternal obesity, to reduce future risk of obesity.

Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition.

Rapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.

Case report: Pulmonary hypertensive crisis leading to cardiac arrest during endoscopic evaluation in a 6-year-old boy with autism, severe malnutrition, and undiagnosed scurvy.

Pediatric gastroenterologists are often responsible for the evaluation of malnutrition in the setting of selective eating. Endoscopic evaluation for conditions including eosinophilic esophagitis and celiac disease can help to identify and treat mucosal disease contributing to food selectivity. However, undiagnosed micronutrient deficiencies can cause cardiovascular derangements that significantly increase a patient's anesthetic risk. Vitamin C deficiency in particular, alone or in combination with severe malnutrition, is associated with a severe but reversible form of pulmonary arterial hypertension that, while life threatening in the acute phase, may significantly improve within days of starting ascorbic acid replacement therapy. Here we present a case of a 6-year-old boy with autism spectrum disorder (ASD), severe malnutrition, and undiagnosed chronic vitamin C deficiency who developed a pulmonary hypertensive crisis after induction of general anesthesia leading to cardiac arrest during endoscopic evaluation. While the association between food selectivity among youth with neurodevelopmental differences and vitamin C deficiency is well-described, and pulmonary hypertension is a recognized rare complication of scurvy, extant literature has not addressed next steps to improve patient outcomes. Using this case report as a foundation, we discuss specific patient populations to screen and treat for micronutrient deficiencies prior to anesthesia and propose a novel clinical algorithm for pre-anesthesia risk stratification and mitigation in patients specifically at risk for scurvy and associated pulmonary hypertension.

Case report: Cystic fibrosis with kwashiorkor: A rare presentation in the era of universal newborn screening.

Background: Universal newborn screening changed the way medical providers think about the presentation of cystic fibrosis (CF). Before implementation of universal screening, it was common for children with CF to present with failure to thrive, nutritional deficiencies, and recurrent infections. Now, nearly all cases of CF are diagnosed by newborn screening shortly after birth before significant symptoms develop. Therefore, providers often do not consider this illness in the setting of a normal newborn screen. Newborn screening significantly decreases the risk of complications in early childhood, yet definitive testing should be pursued if a patient with negative newborn screening presents with symptoms consistent with CF, including severe failure to thrive, metabolic alkalosis due to significant salt losses, or recurrent respiratory infections. Case presentation: We present a case of a 6-month-old infant male with kwashiorkor, severe edema, multiple vitamin deficiencies, hematemesis secondary to coagulopathy, and diffuse erythematous rash, all secondary to severe pancreatic insufficiency. His first newborn screen had an immunoreactive trypsinogen (IRT) value below the state cut-off value, so additional testing was not performed, and his growth trajectory appeared reassuring. He was ultimately diagnosed with CF by genetic testing and confirmatory sweat chloride testing, in the setting of his parents being known CF carriers and his severe presentation being clinically consistent with CF. Acutely, management with supplemental albumin, furosemide, potassium, and vitamin K was initiated to correct the presenting hypoalbuminemia, edema, and coagulopathy. Later, pancreatic enzyme supplementation and additional vitamins and minerals were added to manage ongoing deficiencies from pancreatic insufficiency. With appropriate treatment, his vitamin deficiencies and edema resolved, and his growth improved. Conclusion: Due to universal newborn screening, symptomatic presentation of CF is rare and presentation with kwashiorkor is extremely rare in resource-rich communities. The diagnosis of CF was delayed in our patient because of a normal newborn screen and falsely reassuring growth, which after diagnosis was determined to be secondary to severe edematous malnutrition. This case highlights that newborn screening is a useful but imperfect tool. Clinicians should continue to have suspicion for CF in the right clinical context, even in the setting of normal newborn screen results.

Associations between maternal obesity and offspring gut microbiome in the first year of life.

BACKGROUND: Maternal obesity is an important determinant of offspring obesity risk, which may be mediated via changes in the infant microbiome. OBJECTIVES: We examined infant faecal microbiome, short-chain fatty acids (SCFA), and maternal human milk oligosaccharides (HMO) in mothers with overweight/obese body mass index (BMI) (OW) compared with normal weight (NW) (Clinicaltrials.gov NCT01131117). METHODS: Infant stool samples at 1, 6, and 12 months were analysed by 16S rRNA sequencing. Maternal (BODPOD) and infant (quantitative nuclear magnetic resonance [QMR]) adiposity were measured. HMOs at 2 months postpartum and faecal SCFAs at 1 month were also assessed. Statistical analyses included multivariable and mixed linear models for assessment of microbiome diversity, composition, and associations of taxonomic abundance with metabolic and anthropometric variables. RESULTS: At 1 month, offspring of women with obesity had lower abundance of SCFA-producing bacteria (including Ruminococcus and Turicibacter) and lower faecal butyric acid levels. Lachnospiraceae abundance was lower in OW group at 6 months, and infant fat mass was negatively associated with the levels of Sutterella. Gradient boosting machine models indicated that higher α-diversity and specific microbial taxa at 1 month predicted elevated adiposity at 12 months with overall accuracy of 76.5%. Associations between maternal HMO concentrations and infant bacterial taxa differed between NW and OW groups. CONCLUSIONS: Elevated maternal BMI is associated with relative depletion of butyrate-producing microbes and faecal butyrate in the early infant faecal microbiome. Overall microbial richness may aid in prediction of elevated adiposity in later infancy.

Body composition trajectories from birth to 5 years and hepatic fat in early childhood.

BACKGROUND: Adiposity is an established risk factor for pediatric nonalcoholic fatty liver disease (NAFLD), but little is known about the influence of body composition patterns earlier in life on NAFLD risk. OBJECTIVES: We aimed to examine associations of body composition at birth and body composition trajectories from birth to early childhood with hepatic fat in early childhood. METHODS: Data were from the longitudinal Healthy Start Study in Colorado. Fat-free mass index (FFMI), fat mass index (FMI), percentage body fat (BF%), and BMI were assessed at birth and/or ∼5 y in >1200 children by air displacement plethysmography and anthropometrics. In a subset (n = 285), hepatic fat was also assessed at ∼5 y by MRI. We used a 2-stage modeling approach: first, we fit body composition trajectories from birth to early childhood using mixed models with participant-specific intercepts and linear slopes (i.e., individual deviations from the population average at birth and rate of change per year, respectively); second, associations of participant-specific trajectory deviations with hepatic fat were assessed by multivariable-adjusted linear regression. RESULTS: Participant-specific intercepts at birth for FFMI, FMI, BF%, and BMI were inversely associated with log-hepatic fat in early childhood in models adjusted for offspring demographics and maternal/prenatal variables [back-transformed ß (95% CI) per 1 SD: 0.93 (0.88, 0.99), 0.94 (0.88, 0.99), 0.94 (0.89, 0.99), and 0.90 (0.85, 0.96), respectively]. Whereas, faster velocities for BF% and BMI from birth to ∼5 y were positively associated with log-hepatic fat [back-transformed ß (95% CI) per 1 SD: 1.08 (1.01, 1.15) and 1.08 (1.02, 1.15), respectively]. These latter associations of BF% and BMI velocities with childhood hepatic fat were attenuated to the null when adjusted for participant-specific intercepts at birth. CONCLUSIONS: Our findings suggest that a smaller birth weight, combined with faster adiposity accretion in the first 5 y, predicts higher hepatic fat in early childhood. Strategies aiming to promote healthy body composition early in life may be critical for pediatric NAFLD prevention.This study was registered voluntarily at clinicaltrials.gov as NCT02273297.

Associations between Maternal Diet, Body Composition and Gut Microbial Ecology in Pregnancy.

Maternal body composition, gestational weight gain (GWG) and diet quality influence offspring obesity risk. While the gut microbiome is thought to play a crucial role, it is understudied in pregnancy. Using a longitudinal pregnancy cohort, maternal anthropometrics, body composition, fecal microbiome and dietary intake were assessed at 12, 24 and 36 weeks of gestation. Fecal samples (n = 101, 98 and 107, at each trimester, respectively) were utilized for microbiome analysis via 16S rRNA amplicon sequencing. Data analysis included alpha- and beta-diversity measures and assessment of compositional changes using MaAsLin2. Correlation analyses of serum metabolic and anthropometric markers were performed against bacterial abundance and predicted functional pathways. α-diversity was unaltered by pregnancy stage or maternal obesity status. Actinobacteria, Lachnospiraceae, Akkermansia, Bifidobacterium, Streptococcus and Anaerotuncus abundances were associated with gestation stage. Maternal obesity status was associated with increased abundance of Lachnospiraceae, Bilophila, Dialister and Roseburia. Maternal BMI, fat mass, triglyceride and insulin levels were positively associated with Bilophila. Correlations of bacterial abundance with diet intake showed that Ruminococcus and Paraprevotella were associated with total fat and unsaturated fatty acid intake, while Collinsella and Anaerostipes were associated with protein intake. While causal relationships remain unclear, collectively, these findings indicate pregnancy- and maternal obesity-dependent interactions between dietary factors and the maternal gut microbiome.

Longitudinal Changes of One-Carbon Metabolites and Amino Acid Concentrations during Pregnancy in the Women First Maternal Nutrition Trial.

BACKGROUND: Maternal dietary restriction and supplementation of one-carbon (1C) metabolites can impact offspring growth and DNA methylation. However, longitudinal research of 1C metabolite and amino acid (AA) concentrations over the reproductive cycle of human pregnancy is limited. OBJECTIVE: To investigate longitudinal 1C metabolite and AA concentrations prior to and during pregnancy and the effects of a small-quantity lipid-based nutrition supplement (LNS) containing >20 micronutrients and prepregnancy BMI (ppBMI). METHODS: This study was an ancillary study of the Women First Trial (NCT01883193, clinicaltrials.gov) focused on a subset of Guatemalan women (n = 134), 49% of whom entered pregnancy with a BMI ≥25 kg/m2. Ninety-five women received LNS during pregnancy (+LNS group), while the remainder did not (-LNS group). A subset of women from the Pakistan study site (n = 179) were used as a replication cohort, 124 of whom received LNS. Maternal blood was longitudinally collected on dried blood spot (DBS) cards at preconception, and at 12 and 34 wk gestation. A targeted metabolomics assay was performed on DBS samples at each time point using LC-MS/MS. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time, LNS, and ppBMI. RESULTS: Concentrations of 23 of 27 metabolites, including betaine, choline, and serine, changed from preconception across gestation after application of a Bonferroni multiple testing correction (P < 0.00185). Sixteen of those metabolites showed similar changes in the replication cohort. Asymmetric and symmetric dimethylarginine were decreased by LNS in the participants from Guatemala. Only tyrosine was statistically associated with ppBMI at both study sites. CONCLUSIONS: Time influenced most 1C metabolite and AA concentrations with a high degree of similarity between the 2 diverse study populations. These patterns were not significantly altered by LNS consumption or ppBMI. Future investigations will focus on 1C metabolite changes associated with infant outcomes, including DNA methylation. This trial was registered at clinicaltrials.gov as NCT01883193.