Journal of Developmental Origins of Health and Disease最新文献

To clarify the effects of kefir in critical periods of development in adult diseases, we study the effects of kefir intake during early life on gut microbiota and prevention of colorectal carcinogenesis in adulthood. Lactating Wistar rats were divided into three groups: control (C), kefir lactation (KL), and kefir puberty (KP) groups. The C and KP groups received 1 mL of water/day; KL dams received kefir milk daily (10⁸ CFU/mL) during lactation. After weaning (postnatal day 21), KP pups received kefir treatment until 60 days. At 67 days old, colorectal carcinogenesis was induced through intraperitoneal injection of 1, 2-dimethylhydrazine. The gut microbiota composition were analyzed by 16S rRNA gene sequencing and DESeq2 (differential abundance method), revealing significant differences in bacterial abundances between the kefir consumption periods. Maternal kefir intake strong anticancer power, suppressed tumors in adult offspring and reduced the relative risk of offspring tumor development. The gut microbiota in cecal samples of the KL group was enriched with Lactobacillus, Romboutsia, and Blautia. In contrast, control animals were enriched with Acinetobacter. The administration of kefir during critical periods of development, with emphasis on lactation, affected the gut microbial community structure to promote host benefits. Pearson analysis indicated positive correlation between tumor number with IL-1 levels. Therefore, the probiotic fermented food intake in early life may be effective as chemopreventive potential against colon tumor development, especially in lactation period.

Nutritional status during the developmental periods leads to predisposition to several diseases and comorbidities, highlighting metabolic and reproductive changes throughout adult life, and in the next generations. One of the experimental models used to induce undernutrition is litter size expansion, which decreases the availability of breast milk to pups and delays development. This work evaluated the effects of maternal undernutrition induced by litter size expansion, a maternal undernutrition preconception model, on the metabolic and reproductive alterations of the offspring. For this, metabolic and reproductive parameters were evaluated in male and female offspring of female rats reared in normal (NL - 10 pups: 5 males and 5 females) and large (LL - 16 pups: 8 males and 8 females) litters. Male and female offspring of LL mothers presented higher food intake than the offspring of NL mothers. Male offspring from undernourished females showed reduced body weight from lactation to adulthood, nasoanal distance in childhood, increased nasoanal distance, and decreased Lee index in adult life, while female offspring showed decreased nasoanal distance in childhood. The male offspring from LL mothers showed increased insulin plasma levels and glucose tolerance, and reduced triglycerides plasma levels, without changes in the female offspring. These results indicate that neonatal undernutrition in females predisposes their male and female offspring to develop metabolic alterations, without reproductive repercussions, and male offspring seems to be more susceptible to present these metabolic changes than females. Thus, there are sexual differences in the metabolic responses of the offspring elicited by maternal preconceptional undernutrition.

Early gut microbiome development may impact brain and behavioral development. Using a nonhuman primate model (Macaca mulatta), we investigated the association between social environments and the gut microbiome on infant neurodevelopment and cognitive function. Infant rhesus monkeys (n = 33) were either mother-peer-reared (MPR) or nursery-reared (NR). Neurodevelopmental outcomes, namely emotional responsivity, visual orientation, and motor maturity, were assessed with the Primate Neonatal Neurobehavioral Assessment (PNNA) at 14-30 days. Cognitive development was assessed through tasks evaluating infant reward association, cognitive flexibility, and impulsivity at 6-8 months. The fecal microbiome was quantified from rectal swabs via 16S rRNA sequencing. Factor analysis was used to identify "co-abundance factors" describing patterns of microbial composition. We used multiple linear regressions with AIC Model Selection and differential abundance analysis (MaAsLin2) to evaluate relationships between co-abundance factors, microbiome diversity, and neuro-/cognitive development outcomes. At 30 days of age, a gut microbiome co-abundance factor, or pattern, with high Prevotella and Lactobacillus (β = -0.88, p = 0.04, AIC Weight = 68%) and gut microbiome alpha diversity as measured by Shannon diversity (β = -1.33, p = 0.02, AIC Weight = 80%) were both negatively associated with infant emotional responsivity. At 30 days of age, being NR was also associated with lower emotional responsivity (Factor 1 model: β = -3.13, p < 0.01; Shannon diversity model: β = -3.77, p < 0.01). The infant gut microbiome, along with early-rearing environments, may shape domains of neuro-/cognitive development related to temperament.

The nutritional environment during fetal and early postnatal life has a long-term impact on growth, development, and metabolic health of the offspring, a process termed "nutritional programming." Rodent models studying programming effects of nutritional interventions use either purified or grain-based rodent diets as background diets. However, the impact of these diets on phenotypic outcomes in these models has not been comprehensively investigated. We used a previously validated (C57BL/6J) mouse model to investigate the effects of infant milk formula (IMF) interventions on nutritional programming. Specifically, we investigated the effects of maternal diet type (i.e., grain-based vs purified) during early lactation and prior to the intervention on offspring growth, metabolic phenotype, and gut microbiota profile. Maternal exposure to purified diet led to an increased post-weaning growth velocity in the offspring and reduced adult diet-induced obesity. Further, maternal exposure to purified diet reduced the offspring gut microbiota diversity and modified its composition post-weaning. These data not only reinforce the notion that maternal nutrition significantly influences the programming of offspring vulnerability to an obesogenic diet in adulthood but emphasizes the importance of careful selection of standard background diet type when designing any preclinical study with (early life) nutritional interventions.

Preterm birth exposes the neonate to hypoxic-ischaemic and excitotoxic insults that impair neurodevelopment and are magnified by the premature loss of placentally supplied, inhibitory neurosteroids. The cerebellum is a neuronally dense brain region, which undergoes critical periods of development during late gestation, when preterm births frequently occur. We propose that neurosteroid replacement therapy using tiagabine and zuranolone will protect the cerebellum against preterm-associated insults. Guinea pig dams received c-section surgery preterm (gestational age (GA) 64) or at term (GA70) with preterm pups administered tiagabine (2.5 mg/kg/day), zuranolone (1 mg/kg/day) or vehicle (15% β-cyclodextrin) until term equivalent age (GA70). Behavioural testing was performed at corrected postnatal day 8 (PND8) and PND41 with tissue collection occurring at PND42. Neurodevelopmental markers (MBP, OLIG2 and NeuN) were assessed within the cerebellum by immunohistochemistry, whilst GABAergic and glutamatergic pathway expression was quantified using high throughput RT-PCR. Zuranolone and, to a lesser extent, tiagabine were able to protect against hyperactive behaviour at PND8 in males, whilst in females, a less marked hyperactive phenotype was present with neither treatment impacting behaviour further. Both treatments improved MBP staining, whilst tiagabine was found to restore oligodendrocyte maturation in females only. GABAergic and glutamatergic pathway expression was found to be restored by both treatments in females. Overall, this study demonstrates the neuroprotective attributes of neurosteroid replacement therapy using tiagabine and zuranolone, thereby demonstrating their potential to mitigate long-term neurodevelopmental impairments. Furthermore, the sexually dimorphic effects observed suggest future investigations may show increased benefit by using sex-specific treatment regimes.

Children born growth-restricted are well recognized to be at an increased risk of poor neurodevelopmental outcomes. This prospective study examined the influence of chest-to-head circumference ratio at birth on neurodevelopment in the first three years among children enrolled in the Japan Environment and Children's Study. We analyzed information of 84,311 children (43,217 boys, 41,094 girls). Children were divided into low, normal, and high chest-to-head circumference ratio groups. Neurodevelopment was assessed every six months (from 6 months to 3 years) using the Ages and Stages Questionnaire (Japanese translation), with delays defined as scores below 2 standard deviations from the mean. Additionally, we evaluated the contributions of chest and head circumference to the observed association. Linear mixed-effect regression revealed increased risk of delays in communication, gross motor, fine motor, problem-solving, and personal-social skills in the low-ratio group compared to the normal-ratio group. Adjusted risk ratios were in the range of 1.14 - 1.39 in boys and 1.16 - 1.37 in girls, with no such increase observed in the high-ratio group. The heightened risk in the low-ratio group was likely associated with a relatively narrow chest rather than a large head. The area under the ROC curves in predicting any developmental delay at three years for newborn measurements ranged from 0.513 to 0.526 in boys and 0.509 to 0.531 in girls. These findings suggest that a low chest-to-head circumference ratio may indicate children who are at risk for neurodevelopmental deficits. However, the ability to predict poor neurodevelopmental outcomes at three years of age is limited.

It is known that adverse stimuli, such as altered diets during pregnancy and lactation, can result in deleterious effects on the progeny. The aim of this study was to evaluate the possible gastrointestinal repercussions in the offspring of Wistar rats exposed to high-fat diets. Pregnant rats were divided into three groups: normolipidic diet (3.5% lipids), a diet containing 28% lipids, and a diet with 40% lipids. Body weight and food, water, daily caloric, and macronutrient intake were evaluated in the pregnant rats. Structural and functional gastrointestinal parameters were assessed in 30-day-old male pups. Depending on the lipid content of the maternal diet, the pups may exhibit gastric mucosal thickening, an increase in the relative weight of the small intestine, a reduction in the jejunal and ileal mucosa, and a decrease in the total thickness of the ileum. Additionally, there may be a reduction in the number of villi per area in these organs and a thinning of the muscular layer in the large intestine. The structural changes induced by the maternal high-fat diet seem to reduce the stomach's sensitivity to ethanol-induced ulcers, which is the only functional alteration observed. Therefore, the offspring of dams exposed to high-fat diets during pregnancy and lactation exhibits impaired gastrointestinal development, with alterations depending on dietary fat content and specific gastrointestinal regions. Structural changes did not always result in functional abnormalities and, in some cases, appeared protective. The long-term consequences of the observed morphological alterations require further investigation.

Household income and caregiver mental health are important drivers of children's health and development. The COVID-19 pandemic created huge economic and mental health disruptions. This study examines financial hardship and its relationship with caregiver and child mental health using Australia's only representative data spanning three years of the pandemic. Analysis of the repeated, cross-sectional National Child Health Poll included 12,408 caregivers and 20,339 children over six waves (June 2020-April 2023). Caregivers reported their income (dichotomised into low versus not) and deprivation (missing one or more of eight essential items, versus not) and mental health for themselves (Kessler-6, poor versus not) and each child (Self-Rated Mental Health, poor/fair versus good/very good/excellent). Binary logistic models were fitted to predict marginal probabilities of mental health measures by low income and deprivation, over time. Results show that while low income decreased from 41% to 34% over the study period, deprivation increased from 30% to 35%. Poor mental health peaked with stay-at-home orders in 2021 before recovering. Caregivers experiencing low income or deprivation had higher rates of poor mental health throughout the study and slower recovery compared to those without financial hardship. Children in families experiencing financial hardship had slightly higher proportions of poor/fair mental health in 2021-2022, but they were mostly equivalent in June 2020 and April 2023 (range 6-8%). Addressing financial hardship may offer an avenue for improving caregiver mental health. This has implications for post-pandemic recovery and addressing contemporary issues of increasing cost of living and limited mental health supports and services.

Prenatal alcohol exposure (PAE) is associated with cognitive, behavioural, and developmental impairments throughout the lifespan of affected individuals, but there is limited evidence on how early this impact can be identified through routinely collected childhood data. This paper explores the relationship between PAE and the Early Years Foundation Stage Profile (EYFSP), a statutory teacher-based summative assessment of early development in relation to learning goals. This analysis uses the Born in Bradford dataset, a UK based cohort (n = 13,959; full dataset), which collected self-reported PAE from 11,905 mothers, with 19.8% reporting drinking alcohol at some point during pregnancy. Coarsened exact matching was conducted to examine relationships between patterns of PAE and children achieving a 'Good Level of Development' on the EYFSP, a binary variable assessed at 4-5 years of age, controlling for known confounders, including deprivation, mother's education, exposure to other teratogenic substances, and child's age at assessment. Additionally, we examined EYFSP sub-scores to identify specific developmental deficits associated with PAE.The key finding is a statistically significant association between PAE at a level of consuming 5 or more units of alcohol (equivalent to 50 ml or 40 g of pure alcohol) at least once per week from the 4^th month of pregnancy onwards and lower EYFSP scores when accounting for established confounding variables. These findings highlight that the detrimental impact of alcohol during pregnancy can be identified using statutory educational assessments. This has implications internationally for prevention work, policy, and commissioning of support services for people impacted by PAE.

Nutrition is the critical nongenetic factor that has a major influence on the health status of an organism. The nutritional status of the mother during gestation and lactation plays a vital role in defining the offspring's health. Undernutrition during these critical periods may induce chronic metabolic disorders like obesity and cardiovascular diseases in mothers as well as in offspring. The present study aims to evaluate the impact of undernutrition during gestational and lactational periods on the plasma metabolic profile of dams. Additionally, we investigated the potential synergistic mitigating effects of astaxanthin and docosahexaenoic acid (DHA) on dysregulated plasma metabolic profiles. Evaluation of plasma lipid profile revealed that undernourishment resulted in elevated levels of total cholesterol, triglycerides, low density and very low-density lipoproteins in dams. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based untargeted metabolomics illustrated that pathways related to lipid metabolism, such as cholesterol metabolism, steroid biosynthesis and metabolism of amine-derived hormones, were dysregulated by undernourishment. Additionally, pathway enrichment analysis predicted that there is a high incidence of development of desmosterolosis, hypercholesterolaemia, lysosomal acid lipase deficiency and Smith-Lemli-Opitz syndrome in the offspring, reflecting predisposition in mothers. However, synergistic supplementation of astaxanthin and DHA ameliorated these adverse effects by regulating a separate set of metabolic pathways associated with lipid metabolism. They included branched chain amino acid degradation such as valine, leucine and isoleucine, metabolism of alpha-linolenic acid, lipoic acid, lysine degradation, biosynthesis, elongation and degradation of fatty acids.