Members of the Proteobacteria phylum, including Enterobacteriaceae, produce gases and SCFA that have been previously associated with inflammation and insulin resistance. Likewise, APM consumption in conjunction with HF also decreased Clostridium Cluster XI, from which pathogenic bacteria can arise. This cluster may also have contributed to the significant decreased in butyrate, as it contains many butyrate-producing bacteria. It is well established that microbiota communicate and mediate many of their benefits to the host organism through a variety of secreted metabolites. Given this, serum metabolomics analysis was performed. Results demonstrated numerous serum metabolites changing in response to both diet and APM consumption, with the most predominant changes noted in the SCFA. These metabolites are important as they represent the end products of bacterial fermentation and are key signaling intermediates between the microbiota and host. APM associated with changes in acetate and butyrate in CH fed, but not HF animals. In both CH and HF, APM, resulted in a particularly large elevations in propionate, greater than any other SCFA examined. This is likely attributable to increases in Clostridium that produces the metabolite during the fermentation of oligosaccharides. Propionate is rapidly gaining recognition for its communicative role between gut bacteria and the host and has been implicated in altering gene expression, insulin Remdesivir AbMole resistance, behaviour, overall metabolic health, taste aversion, irritable bowel syndrome as well as mitochondrial dysfunction and autism. Hence, there are multiple mechanisms and interactions that could explain the involvement of propionate with APM in the present study. In particular, the observed changes in insulin tolerance may be attributable to alterations in mitochondrial function, perhaps by impairing fatty acid metabolism. Alternatively, propionate is known to impact on immune system colonic motility and permeability, functions that likely influence host gut microbiota. Applicable to the results of the present study, propionate has also been identified as a highly efficient gluconeogenic substrate for both the intestine and the liver. Given the above-mentioned results showing changes in both gut microbiota and SCFA, it is hypothesized that APM alters gut microbiota to favor propionate production in the colon. The end result may be an elevation in hepatic gluconeogenesis and therefore an increase in net hepatic glucose output. This mechanism may explain the higher fasting glucose levels as well as the reduction in insulin-stimulated suppression of gluconeogenesis during the ITT observed in this study.