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Epigenetic Dynamics of the Infant Immune System Reveals a Tumor Necrosis Factor Superfamily Signature in Early Human Life.

ABSTRACT: DNA methylation (DNAm) is an essential mechanism governing normal development in humans. Although most DNAm patterns in blood cells are established in utero, the genes associated with immune function undergo postnatal DNAm modifications, and the characterization of this subset of genes is incomplete. Accordingly, we used available longitudinal DNAm datasets from a large birth cohort in the U.S. to further identify postnatal DNAm variation in peripheral leukocytes from 105 children (n = 105) between birth and the first two years of life, as determined by postnatal changes in β values (with the percentage of methylation ranging from 0 to 1.0 at individual CpG sites). Our study is an extension of a previous analysis performed by our group and identified that: (1) as previously described, DNAm patterns at most CpG sites were established before birth and only a small group of genes underwent DNAm modifications postnatally, (2) this subset includes multiple immune genes critical for lymphocyte development, and (3) several members of the tumor necrosis factor receptor and cytokine superfamilies with essential roles in immune cell activation, survival, and lymphoid tissue development were among those with a larger postnatal variation. This study describes the precise epigenetic DNA methylation marks in important immune genes that change postnatally and raises relevant questions about the role of DNAm during postnatal immune development in early childhood.

SUBMITTER: Gutierrez MJ

PROVIDER: S-EPMC7486026 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Salmonella enterica serovar Typhimurium is an animal welfare and public health concern due to its ability to parasite livestock and potentially contaminate pork products. To reduce Salmonella shedding and the risk of pork contamination, antibiotic therapy is used and can contribute to antimicrobial resistance. Here we hypothesized that immune system education by the microbiota can play a role in intestinal resilience to infection. We used amoxicillin (15mg/Kg) to modulate the intestinal microbiome of 10 piglets, paired with same age pigs that received a placebo (n = 10) from 0 to 14 days of age. Animals were euthanized at 4-weeks old. Each pig donated colon sections for ex vivo culture (n = 20 explants/pig). Explants were inoculated with S. Typhimurium, PBS or LPS (n = 6 explants/pig/group, plus technical controls). The gut bacteriome was characterized by sequencing of the 16S rRNA at 7, 21 days of age, and upon in vitro culture. Explants response to infection was profiled through high-throughput mRNA sequencing. In vivo antibiotic treatment led to ?-diversity differences between groups at all times (P<0.05), while ?-diversity did not differ between amoxicillin and placebo groups on day 21 and at euthanasia (P<0.03 on day 7). Explant microbiomes were not different from in vivo. In vitro challenge with S. Typhimurium led to lower necrosis scores in explants from amoxicillin-treated pigs, when compared to explants placebo-treated pigs (P<0.05). This was coupled with the activation of immune-related pathways in explants from amoxicillin-treated pigs (IL-2 production, NO production, BCR activation), when compared to placebo-treated pigs. In addition, several DNA repair and intestinal wound healing pathways were also only activated in explants from amoxicillin-treated pigs. Taken together, these findings suggest that immune education by the amoxicillin-disturbed microbiota may have contributed to mitigate intestinal lesions following pathogen exposure.

Project description:OBJECTIVES:To examine the associations of antibiotic exposures during the first 2 years of life and the development of body mass over the first 7 years of life. DESIGN:Longitudinal birth cohort study. SUBJECTS:A total of 11?532 children born at ?2500?g in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based study of children born in Avon, UK in 1991-1992. MEASUREMENTS:Exposures to antibiotics during three different early-life time windows (<6 months, 6-14 months, 15-23 months), and indices of body mass at five time points (6 weeks, 10 months, 20 months, 38 months and 7 years). RESULTS:Antibiotic exposure during the earliest time window (<6 months) was consistently associated with increased body mass (+0.105 and +0.083 s.d. unit, increase in weight-for-length Z-scores at 10 and 20 months, P<0.001 and P=0.001, respectively; body mass index (BMI) Z-score at 38 months +0.067 s.d. units, P=0.009; overweight OR 1.22 at 38 months, P=0.029) in multivariable, mixed-effect models controlling for known social and behavioral obesity risk factors. Exposure from 6 to 14 months showed no association with body mass, while exposure from 15 to 23 months was significantly associated with increased BMI Z-score at 7 years (+0.049 s.d. units, P=0.050). Exposures to non-antibiotic medications were not associated with body mass. CONCLUSIONS:Exposure to antibiotics during the first 6 months of life is associated with consistent increases in body mass from 10 to 38 months. Exposures later in infancy (6-14 months, 15-23 months) are not consistently associated with increased body mass. Although effects of early exposures are modest at the individual level, they could have substantial consequences for population health. Given the prevalence of antibiotic exposures in infants, and in light of the growing concerns about childhood obesity, further studies are needed to isolate effects and define life-course implications for body mass and cardiovascular risks.

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Epigenetic Dynamics of the Infant Immune System Reveals a Tumor Necrosis Factor Superfamily Signature in Early Human Life.

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