PROJECT SUMMARY Sweet taste receptors (STRs) are expressed in a variety of tissues including the gastrointestinal tract. Intestinal STRs play a role regulating metabolic responses to the ingestion of sugars and non-caloric artificial sweeteners (NCASs). Paradoxically, consumption of NCASs is associated with metabolic dysregulation and obesity although the tissues do not metabolize these nutrients. The underlying pathophysiological mechanisms responsible for these observations are largely unknown, but it has been suggested that NCAS consumption alters gut microbiota to cause glucose intolerance. Considering that STR-mediated chemosensation in the gut is likely relevant to the metabolic effects of NCASs, we hypothesize that intestinal STRs provide a mechanistic link between NCAS- induced metabolic dysfunction and gut microbiota. Towards this end, we show that elimination of STR signaling in mice, through genetic ablation of the T1R2 protein (T1R2-knock out; KO), protects against metabolic derangements induced by the overconsumption of saccharin. Notably, basal (chow diet) T1R2-KO gut microbiota composition displays marked alterations compared to T1R2-wild type (WT), followed by elevated concentrations of fecal short-chain fatty acids (SCFAs). These changes are most notable in genera (Clostridium, Bacteroides and Blautia) that are known to influence host metabolism and are pertinent to human gut microbiota. Finally, to begin addressing the direct role of intestinal STRs in humans, we tested the effects of acute pharmacological inhibition (lactisole) of STRs in the gut and found that it alters the glycemic and insulin response to an oral glucose load. Taken together, these data emphasize the translational impact of our studies and suggest that chemosensory input involving STRs is likely relevant to nutrient metabolism and the development of metabolic diseases. Thus, we propose comprehensive studies that investigate the contribution of STRs in NCAS-induced glucose intolerance. We will explore potential causative mechanisms associated with gut microbiota and glucose transport/metabolism in enterocytes. We will perform a) qualitative phylogenetic (16S rDNA) and meta-genomic sequencing (RNA-Seq) analyses of gut microbiota, b) assessment of in vivo metabolic profiling and energy balance, c) assessment of targeted metabolites of intestinal epithelium and fecal SCFAs, and d) ex vivo assessment of intestinal glucose transport (Ussing Chamber). We expect that STR-mediated chemosensory signaling interacts with gut microbiota to alter the absorptive capacity of the gut and it is required for the development of glucose dysregulation induced by NCASs. Finally, to establish causality between host-microbiota pathways, we will conventionalize germ-free mice with microbiota from T1R2-KO mice subjected to NCAS feeding. The proposed studies will a) explore interactions of novel host chemosensory mechanisms with gut microbiota, b) define the role of STRs in the gut, and c) identify causative mechanisms that link NCAS consumption and the development of metabolic diseases. Understanding the nature of these regulatory mechanisms could lead to gut-restricted therapeutic interventions for the treatment of metabolic diseases.
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