Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal <i>Bifidobacterium breve</i> level responding to BBR alone or Prob+BBR treatment. Four <i>fadD</i> genes encoding long-chain acyl-CoA synthetase were identified in the genome of this <i>B. breve</i> strain, and transcriptionally activated by BBR. <i>In vitro</i> BBR treatment further decreased the concentration of FFA in the culture medium of <i>B. breve</i> compared to vehicle. Thus, the activation of <i>fadD</i> by BBR could enhance FFA import and mobilization in <i>B. breve</i> and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (<i>B. breve</i>) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.