Despite the high prevalence of obesity and widespread public awareness of its associated health risks, broadly effective therapies for this disease have been elusive. Roux-en-Y gastric bypass (RYGB) is a complex gastrointestinal operation that leads to profoundly decreased body fat and improvement in glucose and lipid homeostasis. Recent studies have clearly demonstrated that this operation exerts its effects by influencing the physiological regulation of energy balance and metabolic homeostasis. Understanding the mechanisms of these effects will help elucidate the role of the GI tract in metabolic regulation and will facilitate the identification of novel molecular targets for agents to prevent and treat obesity, type 2 diabetes and related metabolic disorders. Recent studies of the mechanisms underlying the clinical and metabolic effects of RYGB have revealed important roles for both bile acid (BA) signaling and the intestinal microbiota. RYGB strongly influences the size and structure of the BA pool and both the composition and function of the microbiota. The biological activities of these two systems are highly interactive and mutually dependent, with enteric bacteria catalyzing modifications of BAs, and BAs influencing the luminal environment, in turn altering the ecological balance within the microbiota. The primary actors in this complex system remain largely unknown, and it is likely that subsets of the more than 100 different BAs and different populations within the several thousand strains of intestinal bacteria influence different aspects of metabolic regulation. The reciprocal influences of the BAs and microbiota suggest both an important role for host-microbiota communication and the potential for this interaction to be mediated via the enterohepatic cycling of regulatory metabolites, as well as directly across the intestinal epithelium. The overall goal of the proposed studies is to identify and characterize specific BAs and other metabolites whose behavior in response to RYGB suggests that they may play an important role in the physiological response to this operation.
For Aim 1, a targeted, metabolomic analysis of more than 70 BAs will be used to identify specific BAs whose concentration and/or anatomic distribution is selectively altered after RYGB.
For Aim 2, we will use a broad, well-characterized metabolomic platform to identify non-BA components of bile whose regulation in response to RYGB suggests that they may contribute to the metabolic outcomes of this intervention.
For Aim 3, we will assess the functional effects of the most promising BA and non-BA metabolites identified from Aims 1 and 2. The physiological effects of a limited number of these metabolites will be evaluated in vivo, where we will measure the metabolic response to their administration into the small intestine of diet-induced obese (DIO) mice. A larger subset of identified metabolites will be assessed in a more limited fashion in vitro, by directly applying them to cultured intestinal epithelial organoids prepared from DIO mice. We anticipate that these studies will identify metabolites that play a key role in metabolic regulation and exploit enterohepatic cycling to help mediate host-microbiota communication.
The human body and its resident microbiota exist in a complex symbiotic relationship. Although our understanding of microbiota:host interactions remains incomplete, evidence suggests that dysregulation of the microbiome may be an important contributor to many diseases prevalent in modern society, including obesity and its comorbidities. Building on the uniquely powerful metabolic benefits of bariatric surgery and the observation that changes in the gut microbiota contribute to these benefits, we will use cultured intestinal organoids to identify microbiota:mucosal interactions whose effects on mucosal gene expression most closely reflect the changes induced by gastric bypass surgery. Identification of these interactions and their molecular mechanisms could reveal important new targets for less invasive therapies that more effectively mimic the benefits of surgery itself.