Background and Aims

Elevated plasma cholesterol plays a crucial role in the development of atherosclerotic cardiovascular disease. We recently showed that the gut microbiota-related short chain fatty acid propionate (PA) regulates cholesterol metabolism by modulating intestinal cholesterol absorption. Here, we examined the impact of PA on serum metabolome and how this may be related with its cholesterol lowering effect. 

Methods and Results

We performed a sub-analysis of a randomized placebo-controlled clinical trial analyzing the cholesterol lowering effect of PA. The enrolled patients were randomized to either receive a placebo (2x500mg, n=31) or PA (2x500mg, n=31) for 8 weeks and serum samples were collected at baseline (T1, 0 weeks) and at the end of the study (T2, 8 weeks). As previously reported, supplementation with PA resulted in a significant reduction in total cholesterol (TC) (PA vs. placebo -19.6 mg/dL (-7.3%) vs. -5.3mg/dL (-1,7%), p = 0.014) and low density lipoprotein-cholesterol (LDL-C) in serum (PA vs. placebo: -15.9mg/dL (-8.1%) vs. -1.6mg/dL (-0.5%), p = 0.016). Here, we performed a metabolomics analysis in serum samples collected at T1 and T2, using a targeted metabolomics kit (MxP® Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria) to investigate how oral PA supplementation may change serum metabolites. Volcano-plot demonstrated a significant increase in distinct bile acids (DCA (fold change = 0.393, p = 0.027); GUDCA (fold change = 0.51, p = 0.0023); TMCA (fold change = 0.931, p = 0.015) at T2 in the PA-group along with a significant reduction in serum cholesteryl-esters and distinct triglycerides. Since bile acids were reported to interfere with metabolic pathways important for cardiovascular health, we next examined whether changes of bile acids after PA supplementation correlated with changes in serum cholesterol levels. Interestingly, deoxycholic acid (DCA) exhibited a significant negative correlation with total cholesterol levels (Pearson r ∆-DCA vs. ∆-TC = -0.40, p = 0.042) and triglyceride levels in serum (Pearson r ∆-DCA vs. ∆-TG = -0.45, p = 0.021) in the PA group. Further, alteration of DCA levels tended to negatively correlate with changes in serum LDL levels (Pearson r ∆-DCA vs. ∆-LDL = -0.34, p = 0.089) in the PA group. 

Conclusion

Oral supplementation of PA reduces not only serum cholesterol levels but also significantly reshaped serum metabolome with a significant decrease in cholesteryl esters and triglycerides as well as a significant increase in distinct bile acids. Our findings show a regulatory role of the gut microbiota dependent metabolite PA on circulatory bile acid profile, which is linked to the cholesterol lowering properties of PA supplementation. Since bile acid and cholesterol metabolism are interdependent, modulation of bile acids could contribute to the cholesterol lowering effect of PA and thus, to its atheroprotective effect.