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 is 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 5 mo and received normal autoclaved drinking water or water supplemented with IPA (0.1 mg/mL; SD + IPA and WD + IPA). WD feeding led to increased liver triglycerides and makers of inflammation, with no effect of IPA. At 5 mo, arterial stiffness was significantly higher in WD and WD + IPA compared with SD (WD: 485.7 +/- 6.7 and WD + IPA: 492.8 +/- 8.6 vs. SD: 436.9 +/- 7.0 cm/s, P < 0.05) but not SD + IPA (SD + IPA: 468.1 +/- 6.6 vs. WD groups, P > 0.05). Supplementation with IPA in the SD + IPA group significantly increased glucose AUC compared with SD mice (SD + IPA: 1,763.3 +/- 92.0 vs. SD: 1,397.6 +/- 64.0, P < 0.05), and no significant differences were observed among either the WD or WD + IPA groups (WD: 1,623.5 +/- 77.3 and WD + IPA: 1,658.4 +/- 88.4, 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. NEW & NOTEWORTHY The gut microbiota has been shown to mediate host health. Emerging data implicate gut microbial metabolites of tryptophan metabolism as potential important mediators. We examined the effects of indole-3-propionic acid in Western diet-fed mice and found no beneficial cardiometabolic effects. Our data do not support the supposition that indole-3-propionic acid (IPA) mediates beneficial metabolic effects downstream of the gut microbiota and may be potentially deleterious in higher circulating levels.