Maternal obesity is associated with increased risk for development of metabolic disease in the next generation. Obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) affect over 1 billion people, including 10% of all children. Mechanisms by which early life exposure to poor maternal diet transmits disease risk to offspring in later life are poorly understood but involve early dysregulation of the offspring innate immune system. We fed pregnant dams a “Western-style” diet (WD) to investigate effects of maternal WD on early innate immunity. We found a significant increase in common myeloid progenitors in livers from fetuses at E15 exposed to maternal WD as compared with those exposed to normal chow diet. Despite weaning to a chow diet, adult offspring exposed to maternal WD showed elevated monocyte infiltration to the liver and increased Il1b expression. Glycolytic metabolites, markers of inflammatory metabolic reprogramming, were increased in liver macrophages (Mφ), while bone marrow-derived Mφ (BMDM) had decreased Il10 expression in offspring exposed to maternal WD. Notably, this phenotype was recapitulated in recipients of fecal transfer from 3-wk-old offspring of WD-fed dams. The aryl hydrocarbon receptor (AHR) is a sensor and modulator of the microbiome and immune cell homeostasis. We found decreased expression of the AHR target Cyp1a2 in livers of 3-wk-old offspring of WD-fed dams, concomitant with decreased abundance of circulating indole-3-acetate, a product of gut bacterial metabolism and an AHR ligand. Lastly, phagocytosis, a key Mφ function, was impaired in BMDM from offspring of WD-fed dams and improved by indoles in vitro. These data suggest a role for decreased microbiome-derived indoles in controlling innate immunity at multiple levels.


K.R. Jonscher: None. R. Janssen: None. S. Kovats: None. R. McMahan: None. J.E. Friedman: None.

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