Although the prominent role of the microbiome in human health has been established, the early-life microbiome is now being recognized as a major influence on long-term human health and development. ...Variations in the composition and functional potential of the early-life microbiome are the result of lifestyle factors, such as mode of birth, breastfeeding, diet, and antibiotic usage. In addition, variations in the composition of the early-life microbiome have been associated with specific disease outcomes, such as asthma, obesity, and neurodevelopmental disorders. This points toward this bacterial consortium as a mediator between early lifestyle factors and health and disease. In addition, variations in the microbial intrauterine environment may predispose neonates to specific health outcomes later in life. A role of the microbiome in the Developmental Origins of Health and Disease is supported in this collective research. Highlighting the early-life critical window of susceptibility associated with microbiome development, we discuss infant microbial colonization, beginning with the maternal-to-fetal exchange of microbes in utero and up through the influence of breastfeeding in the first year of life. In addition, we review the available disease-specific evidence pointing toward the microbiome as a mechanistic mediator in the Developmental Origins of Health and Disease.
Low birthweight, premature birth, intrauterine growth retardation, and maternal malnutrition have been related to an increased risk of cardiovascular disease, type 2 diabetes mellitus, obesity, and ...neuropsychiatric disorders later in life. Conversely, high birthweight has been linked to future risk of cancer. Global DNA methylation estimated by the methylation of repetitive sequences in the genome is an indicator of susceptibility to chronic diseases. We used data and biospecimens from an epigenetic birth cohort to explore the association between trajectories of fetal and maternal weight and LINE-1 methylation in 319 mother-child dyads. Newborns with low or high birthweight had significantly lower LINE-1 methylation levels in their cord blood compared to normal weight infants after adjusting for gestational age, sex of the child, maternal age at delivery, and maternal smoking during pregnancy (p = 0.007 and p = 0.036, respectively), but the magnitude of the difference was small. Infants born prematurely also had lower LINE-1 methylation levels in cord blood compared to term infants, and this difference, though small, was statistically significant (p = 0.004). We did not find important associations between maternal prepregnancy BMI or gestational weight gain and global methylation of the cord blood or fetal placental tissue. In conclusion, we found significant differences in cord blood LINE-1 methylation among newborns with low and high birthweight as well as among prematurely born infants. Future studies may elucidate whether chromosomal instabilities or other functional consequences of these changes contribute to the increased risk of chronic diseases among individuals with these characteristics.
The human microbiota is a key contributor to many aspects of human health and its composition is largely influenced by diet. There is a growing body of scientific evidence to suggest that gut ...dysbiosis (microbial imbalance of the intestine) is associated with inflammatory and immune-mediated diseases (e.g., inflammatory bowel disease and asthma). Regular consumption of fermented foods (e.g., kimchi, kefir, etc.) may represent a potential avenue to counter the proinflammatory effects of gut dysbiosis. However, an assessment of the available literature in this research area is lacking. Here we provide a critical review of current human intervention studies that analyzed the effect of fermented foods on the composition and/or function of the human gut microbiota. A total of 19 human intervention studies were identified that met this search criteria. In this review, we discuss evidence that consumption of fermented foods may modify the gut microbiota in humans. Further, there is cursory evidence to suggest that gut microbiota compositional changes mediate associations between fermented food consumption and human health outcomes. Although promising, there remains considerable heterogeneity in the human populations targeted in the intervention studies we identified. Larger longitudinal feeding studies with longer follow-up are necessary to confirm and enhance the current data. Further, future studies should consider analyzing microbiota function as a means to elucidate the mechanism linking fermented food consumption with human health. This review highlights methodologic considerations for intervention trials, emphasizing an expanse of research opportunities related to fermented food consumption in humans.
Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence ...developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying this "developmental origins hypothesis" are poorly understood. This review focuses on the likely involvement of epigenetic mechanisms in the developmental origins of health and disease (DOHaD). We describe permanent effects of transient environmental influences on the developmental establishment of epigenetic gene regulation and evidence linking epigenetic dysregulation with human disease. We propose a definition of "epigenetic epidemiology" and delineate how this emerging field provides a basis from which to explore the role of epigenetic mechanisms in DOHaD. We suggest strategies for future human epidemiologic studies to identify causal associations between early exposures, long-term changes in epigenetic regulation, and disease, which may ultimately enable specific early-life interventions to improve human health.
Summary Background Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer. Potential underlying mechanisms include variation ...in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer. Methods We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer. We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors. Findings We identified 57 studies published between Oct 1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight (relative risk RR 1·15 95% CI 1·09–1·21), birth length (1·28 1·11–1·48), higher maternal age (1·13 1·02–1·25), and paternal age (1·12 1·05–1·19). Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0·48 0·30–0·78) and twin membership (0·93 0·87–1·00). No association was noted between risk of breast cancer and gestational age at birth (0·95 0·71–1·26) or maternal diethylstilbestrol treatment (1·40 0·86–2·28). Interpretation The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanisms responsible for such predisposition need to be elucidated.
The role of the gut microbiota in human health and disease has garnered heightened attention over the past decade. A thorough understanding of microbial variation over the life course and possible ...ways to influence and optimize the microbial pattern is essential to capitalize on the microbiota's potential to influence human health. Here, we review our current understanding of the concept of plasticity of the human gut microbiota throughout the life course. Characterization of the plasticity of the microbiota has emerged through recent research and suggests that the plasticity in the microbiota signature is largest at birth when the microbial colonization of the gut is initiated and mode of birth imprints its mark, then decreases postnatally continuously and becomes less malleable and largely stabilized with advancing age. This continuing loss of plasticity has important implication for the impact of the exposome on the microbiota and health throughout the life course and the identification of susceptible 'windows of opportunity' and methods for interventions.
Folate is an essential mediator in one-carbon metabolism, which provides methyl groups for DNA synthesis and methylation. The availability of active methyl groups can be influenced by the uptake of ...folic acid. We conducted a randomized intervention trial to test the influence of folic acid supplementation on DNA methylation in an unfortified population in Germany. A total of 16 healthy male volunteers (age range 23-61 y) were randomized to receive either 400 μg (
= 9) or 800 μg (
= 7) folic acid supplements daily for 8 weeks. Infinium Human Methylation 450K BeadChip Microarrays were used to assay site-specific DNA methylation across the genome. Microarray analyses were conducted on PBL DNA. We estimated several epigenetic clocks and mean DNA methylation across all autosomal probes on the array. AgeAccel was estimated as the residual variation in each metric. In virtually all participants, both serum and red blood cell (RBC) folate increased successively throughout the trial period. Participants with a larger increase in RBC folate had a larger increase in DNAmAge AgeAccel (Spearman Rho: 0.56,
-value = 0.03). No notable changes in the methylome resulting from the folic acid supplementation emerged. In this population with adequate folate levels derived from diet, an increase in RBC folate had a modest impact on the epigenetic clock predicting chronologic age.
ABSTRACT
Epigenetics plays an important role in orchestrating key biologic processes. Epigenetic marks, including DNA methylation, histones, chromatin structure, and noncoding RNAs, are modified ...throughout life in response to environmental and behavioral influences. With each new generation, DNA methylation patterns are erased in gametes and reset after fertilization, probably to prevent these epigenetic marks from being transferred from parents to their offspring. However, some recent animal studies suggest an apparent resistance to complete erasure of epigenetic marks during early development, enabling transgenerational epigenetic inheritance. Whether there are similar mechanisms in humans remains unclear, with the exception of epigenetic imprinting. Nevertheless, a distinctly different mechanism—namely, intrauterine exposure to environmental stressors that may affect establishment of the newly composing epigenetic patterns after fertilization—is often confused with transgenerational epigenetic inheritance. In this review, we delineate the definition of and requirement for transgenerational epigenetic inheritance, differentiate it from the consequences of intrauterine exposure, and discuss the available evidence in both animal models and humans.—Van Otterdijk, S. D., Michels, K. B. Transgenerational epigenetic inheritance in mammals: how good is the evidence? FASEB J. 30, 2457‐2465 (2016). www.fasebj.org
Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, ...hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.
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