Microbial Metabolite Indole-3-Propionic Acid Supplementation Does Not Protect Mice from the Cardiometabolic Consequences of a Western Diet.

: Emerging evidence suggests that intestinal microbes regulate host physiology and cardiometabolic health, although the mechanism(s) by which they do so are unclear. Indoles are a group of compounds produced from bacterial metabolism of the amino acid tryptophan. In light of recent data suggesting broad physiological effects of indoles on host physiology, we examined whether indole-3-propionic acid (IPA) would protect mice from the cardiometabolic consequences of a western diet. Male C57BL/6J mice were fed either a standard diet (SD) or western diet (WD) for 5mo and received normal autoclaved drinking water or water supplemented with IPA (0.1mg/ml) (SD+IPA and WD+IPA). WD-feeding led to increased liver triglycerides and makers of inflammation with no effect of IPA. At 5mo, arterial stiffness was significantly higher in WD and WD+IPA compared to SD (WD: 485.7±6.7 & WD+IPA: 492.8±8.6 vs SD: 436.9±7.0 cm/s, p 0.05). Supplementation with IPA in the SD+IPA group significantly increased glucose AUC compared to SD mice (SD+IPA: 1763.3±92.0 vs SD: 1397.6±64.0, p 0.05). Gut microbiota changes were driven by WD-feeding, whereas IPA supplementation drove differences in SD-fed mice. In conclusion, supplementation with IPA did not improve cardiometabolic outcomes in WD-fed mice and may have worsened some parameters in SD-fed mice, suggesting that IPA is not a critical signal mediating WD-induced cardiometabolic dysfunction downstream of the gut microbiota.