My lab has been studying pathogenic bacteria and gastrointestinal biology since 1981 and the human microbiome since 2002. We conducted early 16S rRNA surveys of the esophagus, stomach, lung, and skin. Such studies helped establish the baseline present in health that then can be used to assess pathologic relationships. Nearly 20 years ago, we began to hypothesize that some of the diseases of modernization, including obesity, diabetes, malignancies, and immunologic disorders, were due to changes in the ancestral human microbiome. We have had especial emphasis on the role of the gastrointestinal tract microbiome in early life development, with consequences for how normal metabolism and immunity develop. Because of the widespread use of antibiotics, especially in young children, we have explored in animal models their role in perturbing the microbiome, and the downstream effects. More recently, we have been exploring microbiome changes that could be fueling the metabolic and inflammatory disease epidemics of obesity, IBD, asthma, allergies, type 1 diabetes, kidney stones, and particular cancers (including esophageal, gastric), respectively using mouse models to understand underlying mechanisms. We have used multi-“omic” approaches to address these questions. Specimens from mice of defined disease and control phenotypes permit linked analyses of tissue gene expression and gut metagenome with metabolic pathways to identify molecules that can be used for solutions to these problems.