Project Summary The incidence of obesity is rising globally and remains one of the biggest threats to adults and children. Obesity rates are rapidly increasing among the young. Approximately 12.7 million, or 17% children in the US, were reported to be either overweight or obese in 2015. Rising obesity rates have significant health consequences, contributing to increased rates of metabolic diseases such as diabetes, steatosis, hypertension, and heart disease. Obesity imposes a large economic burden on the individual, and on families and nations. In 2014 the global economic impact of obesity was estimated to be US $2.0 trillion or 2.8% of the global gross domestic product (GDP). In 2014, more than 2.1 billion people, nearly 30% of the global population, were overweight or obese and 5% of the deaths worldwide were attributable to obesity. If the incidence continues at this rate, almost half of the world's adult population will be overweight or obese by 2030. Reducing obesity is a public health priority that has substantial health and economic benefits. As obesity is accompanied by chronic low-grade inflammation in adipose tissues, mainly due to accumulated inflammatory cells (Th1/Th17 cells, macrophages, etc) (2), recent studies, including our own work, provided evidence to indicate that helminth-induced immunomodulation may prevent obesity onset and ameliorate the disease severity. Our preliminary experiments have determined the potential maternal impact on developmental programming affecting weight gain and adiposity in the offspring. We fed offspring of both normal control and helminth-infected mother mice with HFD, and observed that offspring from helminth-infected mothers gained significantly less body weight comparing with those from uninfected mothers. In addition to helminth-induced maternal Th2 immune status, recent 16S rRNA gene sequencing analysis revealed that H. polygyrus infection in mother mice significantly alters the composition of gut microbiome composition of offspring. Based on our preliminary results, we hypothesize that the maternal helminth-induced Th2 immune response and associated altered microbiota at critical periods of development may contribute to altered obesity in offspring through (a) Th2-dependent conditioning of the developing immune system in the offspring or (b) helminth-induced alterations of the maternal microbiota, which are then transmitted to the offspring to cause changes in response to dietary treatment. The experiments proposed in this application will explore the mechanisms by which maternal immune signals and microbiota modulate the development of obesity in offspring, and will provide new insights that will be applicable to our understanding of the pathogenesis of obesity in children. A clearer understanding of the immunoregulatory effects of maternal factors on the offspring may suggest new therapeutic approaches for the prevention and treatment of metabolic disorders and obesity in both children and a...