Specialized immune cells protect against obesity by regulating the diverse communities of intestinal bacteria in mice, according to a new study, which shows how changes in gut microbiota can influence the development of metabolic disorders. The results suggest the potential for new microbiome-based therapies for obesity and other metabolic diseases. Obesity, a common metabolic syndrome affecting the health of nearly two billion people worldwide, has been linked to a variety of factors including genetics, diet, behavior and most recently, the host's microbiome. Studies in mice have revealed differences in the gut microbiota composition in lean and obese animals, which can predispose a mouse to obesity. Moreover, transplanted microbiota of obese humans can confer metabolic defects into otherwise healthy animals. Building on previous research, which identified the immune system as a key factor in regulating the composition of the microbiome, Charisse Petersen and colleagues discovered that specialized immune cells called T follicular helper (TFH) cells shield mice from obesity by promoting the production of immunoglobulin A (IgA) antibodies by B cells in the gut. Genetically altered mice with defective TFH cell development produced little IgA. This resulted in symptoms of metabolic syndrome, including fat accumulation and insulin resistance, which are characteristics of human metabolic disease. According to Petersen et al., dysfunctional IgA production impeded the colonization of Clostridia bacterial species, allowing the expansion of Desulfovibro bacteria. Clostridia and Desulfovibro, respectively, suppress and enhance the expression of genes that direct the absorption of dietary lipids. In a related perspective, Yuhao Wang and Lora Hopper write that "the Petersen et al.'s findings beautifully illuminate how immune system defects can lead to metabolic disease."