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Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring.

ABSTRACT: Maternal obesity and a high-fat diet (HFD) during the perinatal period have documented short- and long-term adverse outcomes for offspring. However, the mechanisms of maternal HFD effects on neonatal offspring are unclear. While the effects of maternal HFD exposure during pregnancy on the offspring are increasingly being appreciated, we do not know if maternal HFD alters the microbiota or affects neonatal susceptibility to inflammatory conditions, nor the mechanisms involved. In this study, we show that the offspring of mothers exposed to HFD develop a unique microbiota, marked by expansion of Firmicutes, and an increase in IL-17-producing type 3 innate lymphoid cells (ILC3s). The expansion of ILC3s was recapitulated through neocolonization with HFD microbiota alone. Further, the HFD offspring were susceptible to a neonatal model of inflammation that was reversible with IL-17 blockade. Collectively, these data suggest a previously unknown and unique role for ILC3s in the promotion of an early inflammatory susceptibility in the offspring of mothers exposed to HFD.

SUBMITTER: Babu ST

PROVIDER: S-EPMC6237468 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring.

Babu Sarah Thomas ST Niu Xinying X Raetz Megan M Savani Rashmin C RC Hooper Lora V LV Mirpuri Julie J

JCI insight 20181004 19

Maternal obesity and a high-fat diet (HFD) during the perinatal period have documented short- and long-term adverse outcomes for offspring. However, the mechanisms of maternal HFD effects on neonatal offspring are unclear. While the effects of maternal HFD exposure during pregnancy on the offspring are increasingly being appreciated, we do not know if maternal HFD alters the microbiota or affects neonatal susceptibility to inflammatory conditions, nor the mechanisms involved. In this study, we s ...[more]

PMID: 30282818

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Project description:Background: Accumulating evidence shows that high fat diet is closely associated with inflammatory bowel disease. However, the effects and underlying mechanisms of maternal high fat diet (MHFD) on the susceptibility of offspring to colitis in adulthood lacks confirmation. Methods: C57BL/6 pregnant mice were given either a high fat (60 E% fat, MHFD group) or control diet [10 E% fat, maternal control diet (MCD) group] during gestation and lactation. The intestinal development, mucosal barrier function, microbiota, and mucosal inflammation of 3-week old offspring were assessed. After weaning all mice were fed a control diet until 8 weeks of age when the microbiota was analyzed. Offspring were also treated with 2% DSS solution for 5 days and the severity of colitis was assessed. Results: The offspring in MHFD group were significantly heavier than those in MCD group only at 2-4 weeks of age, while no differences were found in the body weight between two groups at other measured time points. Compared with MCD group, MHFD significantly inhibited intestinal development and disrupted barrier function in 3-week old offspring. Although H&E staining showed no obvious microscopic inflammation in both groups of 3-week old offspring, increased production of inflammatory cytokines indicated low-grade inflammation was induced in MHFD group. Moreover, fecal analysis of the 3-week old offspring indicated that the microbiota compositions and diversity were significantly changed in MHFD group. Interestingly after 5 weeks consumption of control diet in both groups, the microbiota composition of offspring in MHFD group was still different from that in MCD group, although the bacterial diversity was partly recovered at 8 weeks of age. Finally, after DSS treatment in 8-week old offspring, MHFD significantly exacerbated the severity of colitis and increased the production of proinflammatory cytokine. Conclusions: Our data reveal that MHFD in early life can inhibit intestinal development, induce dysbiosis and low-grade inflammation and lead to the disruption of intestinal mucosal barrier in offspring, and enhance DSS-induced colitis in adulthood.

Project description:BackgroundCombined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated.MethodsFemale mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3 weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12 weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring.ResultsHFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. The mRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho β, and its downstream targets, proliferator-activated receptor-γ co-activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring.ConclusionsLeucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.

Project description:A maternal high-fat diet (HFD) has been shown to exert deleterious effects on fetal programming by impairing embryo growth, and exerts a long-term effect on the health of offspring. The present study aimed to evaluate the effect of a maternal HFD on the ovaries of offspring from the perspective of oxidative stress. Female C57BL/6J mice were randomly assigned to four groups fed various HFDs during the preconception (4 weeks) and gestation-lactation periods. Offspring were fed a normal diet after weaning, and serum and ovaries were collected at 10 weeks of age. The developmental status of follicles was observed using hematoxylin and eosin staining. The serum oxidative stress levels and insulin resistance were detected using ELISA test kits. The expression of phosphorylated form of H2AX histone variant (γH2AX), forkhead box protein O3a (FOXO3a), Bcl-2-like protein 11 (Bim)and insulin-like growth factor (IGF)-1 in ovarian tissue was analyzed using reverse transcription-quantitative PCR and western blot analyses to further explore the pathogenic mechanism. Prenatal exposure to a maternal HFD resulted in a reduced number of primordial and preantral follicles in the ovaries of offspring. Exposure to an HFD in the preconception period exerted a greater effect on the offspring compared with exposure to an HFD in the gestation-lactation period. A reduction in fat intake during the preconception, gestation and lactation periods significantly reduced the associated adverse outcomes. The expression of genes (FOXO3a, IGF-1, γH2AX and Bim) involved in oxidative stress showed a decreasing trend (high-fat/high-fat>high-fat/control>control/high-fat >control/control) in the ovaries of offspring. Overall, HFD exposure during the preconception period exerted a greater effect on offspring compared with HFD exposure during the gestation-lactation period. The long-term effect on follicular growth and development may be associated with increased oxidative stress and the activation of the insulin/PI3K/Akt pathway.

Dataset Information

Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring.

Publications

Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring.

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