4. Discussion
INFLAMMATION, INFLAMMATION OR INFECTION, INFLAMMATORY RESPONSE
Artificial high-intensity sweeteners are widely consumed due to their reduced energy content and low glycemic effect, which is relevant especially for bw control and under hyperglycemic conditions. While their use in food has been controversially discussed for decades concerning their potentially negative impact on metabolism [Beyond our canonical chemical sense of taste, the expression of the sweet-taste receptor on, e.g., intestinal cells [Beyond sweet and bitter taste receptors, sweeteners may activate further biological targets. For instance, it has been suggested that saccharin activates chemesthesis-related TRPV1 channels [In the present study, we show that plasma-typical concentrations of sweeteners upregulated transcript levels of their cognate taste receptors in vitro and ex vivo. Whereas mainly cytokines emerged as significant early discriminants in the present sweetener intervention study, at 24 h post-intervention, mainly taste and immune-related receptors appeared to have the highest discriminating power between pre-intervention and sweetener intervention. These observations were corroborated by our cluster analysis. The significant contributors that we identified to distinguish fasting state from sweetener intake ex vivo across all post-prandial time points overlapped with 60% of the transcripts that we found to be significantly regulated by saccharin 24 h in vitro. Comparing just the 24 h sweetener mixture intervention in vivo with the 24 h saccharin challenge in vitro, three significantly regulated transcripts emerged under both conditions, among them GPR17 and CCR1. Chemokine GPCR-related receptor GPR17 has been suggested to regulate inflammatory immune responses [The activation status of neutrophils shows high flexibility from resting state over primed to fully activated [Chemokines and their GPCRs, such as CCL21 and CCR7, are not only important mediators of innate and adaptive immune responses in acute inflammation or infection, but also are continuously fine-tuning an immunological homeostasis, balancing immunity and tolerance [Care must be taken, though, to not interpret the results from our sweetener intervention study solely towards inflammation-related processes. Indeed, the GO term inflammatory response was overrepresented in the functional network analysis of all 48 genes investigated, and at much higher significance levels as compared to the network analysis of the VIP gene sets, which were relevant for separating experimental groups at any sweetener post-intervention time from 0 h control. This, however, may reflect the lack of eminent inflammation- and neutrophil activation-related genes, such as IL-8 (CXCL8) and its receptors, CXCR1 and CXCR2, in all VIP gene sets, suggesting that a full-blown inflammatory immune response would hardly be triggered by the consumption of food-typical sweetener concentrations. Notably, a recent study reported that an 8-week intervention with diet soda sweetened with sucralose and acesulfame K altered the inflammatory transcriptome of adipose tissue from overweight females, but, however, did not alter circulating inflammatory markers [Importantly, though, inflammation-related cytokines, such as TNFα, may have modulatory functions on, e.g., taste receptor responses [Interestingly, in our hands the 30× sweetener mix induced a detectable Ca