Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring
Sarah Thomas Babu, Xinying Niu, Megan Raetz, Rashmin C. Savani, Lora V. Hooper, Julie Mirpuri
Sarah Thomas Babu, Xinying Niu, Megan Raetz, Rashmin C. Savani, Lora V. Hooper, Julie Mirpuri
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Research Article Immunology Inflammation

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.

Authors

Sarah Thomas Babu, Xinying Niu, Megan Raetz, Rashmin C. Savani, Lora V. Hooper, Julie Mirpuri

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Figure 2

Expansion of IL-17–producing ILC3s is seen in the lamina propria (LP) of HFD offspring.

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Expansion of IL-17–producing ILC3s is seen in the lamina propria (LP) of...
(A) Flow cytometric analysis of LP cells from 2-week-old RD/RD, HFD/HFD, and HFD/RD offspring was performed. Live cells were stained for CD45 (x axis) and IL-17 (y axis) and representative panels are shown here. Cells positive for CD45 and IL-17 are highlighted in the bold boxes. (B) Histograms showing CD45+ and IL-17+ cells as Rorγt+, CD4–, CD3–, NKp46+, CD127+, and CD117+ when compared with isotype controls. (C) Percentage of CD45+ cells and IL-17+ cells in 2-week-old RD/RD, HFD/HFD, and HFD/RD offspring. (D) IL-17+ cells and IL-17–producing ILC3s quantified as number of cells seen in 2-week-old RD/RD, HFD/HFD, and HFD/RD offspring. (E) Quantification of Firmicutes (log scale) in the small intestine of 2-week-old mice in RD/RD, HFD/HFD, and HFD/RD offspring by qRT-PCR. (F) Quantification of IL-17A (μg/μl) in the small intestine of 2-week-old mice by ELISA in RD/RD and HFD/HFD offspring. (G) qRT-PCR of IL-17F in RD/RD and HFD/HFD offspring showing no difference. RD/RD represent RD offspring cross-fostered to RD mothers at birth. HFD/HFD represents HFD offspring cross-fostered to HFD mothers at birth. HFD/RD represents HFD offspring cross-fostered to RD mothers at birth. These data are representative of at least 3 independent experiments, each involving 6–10 mice per group. Data are depicted as the mean ± SEM. *P < 0.05; **P < 0.01 by 1-way ANOVA with Tukey’s post hoc test (C–E) or 2-tailed Student’s t test (F and G). HFD, high-fat diet; RD, regular diet; ns, not significant.