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.

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.

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.

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.

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.

Breast milk (BM) is the only source of iodine and bioactive compounds that influence growth and development in infants. The content of BM may be influenced by maternal body mass index (BMI). The aim of this study was to investigate the effect of maternal weight on BM and cord blood iodine concentrations, growth-related hormones, infant anthropometric measurements. A total of 84 mother-infant pairs participated. Levels of leptin, adiponectin and insulin-like growth factor-I (IGF-I) in postnatal BM and cord blood were analysed by enzyme-linked immunosorbent assay (ELISA), iodine by Sandell-Kolthoff reaction. Dietary iodine intake of women was determined by food frequency questionnaire, and anthropometric measurements of infants at birth and 3 months were evaluated. Dietary iodine intake was found to be similar in normal weight (NW) and overweight/obese (OW/OB) women (p > 0.05). Breast milk iodine concentration (BMIC) was 17.4 μg in NW, 18.2 μg in OB/OW women. Adiponectin in cord blood and IGF-I in BM were higher OB/OW than NW women (p < 0.05). Positive correlations were found between the infant birth weight and adiponectin in BM, between the infant body weight at 3 months and leptin and adiponectin in BM, between the infant birth head circumference and IGF-I in BM (p < 0.05). In multiple linear regression model, leptin and adiponectin in BM had a positive effect on infant body weight (p < 0.05). Maternal BMI may influence infant body weight via leptin and adiponectin in BM and infant head circumference via IGF-I. No relationship was found between maternal BMI and iodine levels and anthropometric measurements of the infant. Longitudinal studies are recommended to understand the effect of BMIC on growth.

In 2024, we are celebrating the 280th anniversary of Jean-Baptiste Lamarck, whose early theories on inheritance and environmental adaptation have advanced the foundational concepts of Developmental Origins of Health and Disease (DOHaD). This proposal aims to explore how some Lamarckian ideas align with contemporary understandings of how environmental factors in early life can affect health throughout an individual’s lifetime and across generations. This text not only honors an important historical milestone but also reflects on how a DOHaD notion might have been present since the earliest years of biological science. It bridges historical scientific thought with present-day scientific research.

In utero exposure to income shocks has a lasting effect on child well-being. In an agricultural economy, fluctuations in rainfall directly affect household income. In this paper, we investigate the short- and long-run impact of pre-pregnancy, prenatal, and early-life exposure to fluctuations in rainfall on height for a sample of 2290 children in rural Pakistan. Given the widespread canal irrigation system prevalent in the country, we also investigate how fluctuations in river water flows affect child health. We find that fluctuations in rainfall during the pre-pregnancy period have the most lasting effects on the stature of children in the short and long run. Exposure of a mother to a 1 standard deviation reduction in rainfall during the pre-pregnancy period led her child to be 0.17 standard deviations (0.53 cm) shorter by age four. This negative impact of a pre-pregnancy rainfall shock on height persisted over time; the child continued to be 0.12 standard deviations (0.83 cm) shorter, on average, by 13 years of age. However, we find that the effect of pre-pregnancy rainfall fluctuations on children’s height is smaller in districts that have access to irrigation facilities.

Long-term birth cohorts are essential for studying health and disease over the life course. The retention of participants remains a challenge in study design. Previous research works on attrition are limited in length of follow-up time and lack of racial/ethnic diversity. Using data from the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study (WHEALS; United States cohort born between 2004 and 2007, n = 1258), we first performed longitudinal latent class analyses to identify patterns of participation spanning the prenatal period and six follow-up timepoints: 1, 6, 12, and 24 months; 3–6 years; and 10–12 years. Data collection included a combination of in-person visits, home visits, home specimen kits, and staff-administered questionnaires. We examined associations between baseline factors and participation class using multinomial logistic regression modeling, and with conditional inference modeling to identify variables most strongly associated with class. We identified four participation classes: high early participation with gradual loss-to-follow-up, sporadic participation, consistently high participation, and consistently low participation. Multiple baseline characteristics were associated with participation class. The “consistently high participation” class was disproportionately composed of participants who were older, were of higher education, had private insurance, had suburban residence, and were with higher income. Conditional inference trees identified maternal education, insurance, and income as most strongly associated with participation class. Through latent class modeling, we show that participants who were lost to follow-up fell into distinct groupings of participation. In the future, preparatory communications with those who are at the highest risk of study discontinuation may improve long-term retention.

This study aimed to investigate the mechanisms by which the association between maternal hyperglycemia and postnatal high-fat diet (HFD) exposure compromises metabolic parameters and hepatic autophagy in adult female pups. For this, Sprague Dawley rats, female pups from nondiabetic (control = FC) or diabetic (FD) mothers, were fed a standard diet (SD) or HFD from weaning until adulthood (n minimum = 5 rats/group): FC/SD, FC/HFD, FD/SD, and FD/HFD. In adulthood, these rats were tested with the oral glucose tolerance test, euthanized, and serum biochemistry parameters were analyzed. Liver samples were collected to evaluate cytokines, redox status, and protein expression autophagy and apoptosis markers. Histomorphometric analyses and an assessment of lipofuscin accumulation were also performed to reflect incomplete autolysosomal digestion. The FC/HFD, FD/SD, and FD/HFD groups showed glucose intolerance and an increased number of hepatocytes. Furthermore, FD/SD and FD/HFD rats showed hyperlipidemia and insulin resistance. Adaptations in hepatic redox pathways were observed in the FD/SD group with increased antioxidant defense marker activity. The FD/SD group also exhibited increased autophagy protein expression, such as p-AMPK, LC3-II/LC3-I, and p62/SQSTM1, lipofuscin accumulation, and caspase-3 activation. After exposure to HFD, the adult female pups of diabetic rats had a reduced p-AMPK and LC3-II/LC3-I ratio, the presence of steatosis, oxidative stress, and inflammation. The reduction of autophagy, stimulated by HFD, may be of vital importance for the susceptibility to metabolic dysfunction-associated fatty liver disease induced by maternal diabetes.