Background and Aims

Elevated plasma cholesterol plays a key role in onset and progression of atherosclerotic cardiovascular disease. Recently, we demonstrated that the gut microbiota derived short chain fatty acid propionate (PA) impacts cholesterol metabolism by regulating intestinal cholesterol absorption in an immune dependent manner. Here, we investigated whether shifts in the serum metabolome following PA supplementation are linked 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. Patients included in the study were randomized to receive a placebo (n=31) or PA (2x500mg, n=31) for 8 weeks and serum samples were collected at baseline (0 weeks) and at the end of the study (8 weeks). As recently reported, supplementation with PA led to 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). We further examined potential shifts in the serum metabolome following PA supplementation using a targeted metabolomics kit (MxP® Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). Paired t-test indicated a significant increase particularly in 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) after 8 weeks in the PA-group combined with a significant reduction in serum cholesteryl-esters and triglycerides. Since bile acid and cholesterol metabolism are closely related, we further analyzed whether alterations in the serum bile acid pool were associated with changes in serum cholesterol levels after PA supplementation. Interestingly, the increase in the secondary bile acid deoxycholic acid (DCA) showed a negative correlation with total cholesterol levels (Pearson r ∆-DCA vs. ∆-TG = -0.45, p = 0.021) in the PA group. Moreover, variation in 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 the gut microbiota derived metabolite PA reduces serum cholesterol levels and concurrently mediates shifts in the serum metabolome with a significant increase in particular bile acids. Our results demonstrate a regulatory role for PA on the circulatory bile acid profile, which inversely correlates with its cholesterol lowering effect. Since bile acid and cholesterol metabolism are linked in a close interplay, alterations in the serum bile acid profile could contribute to the cholesterol lowering and, thus, to the atheroprotective effect of PA.