A. Rehman et al.
The Journal of Nutrition xxx (xxxx) xxx
concentrations at the end of the intervention when compared with baseline in the Frui fl owgroup ( 5.3ng/mL, P 0.05) but not in the placebo group (Figure 5). Plasma BAs. There were no signi fi cant between-group differ- ences in plasma BA. Within groups, taurochenodeoxycholic acid (TCDCA) and taurodeoxycholic acid (TDCA) increased slightly with both Fruit fl ow and placebo, from baseline to the end of intervention, whereas chenodeoxycholic acid (CDCA), glyco- cholic acid (GCA), glycochenodeoxycholic acid (GCDCA), and glycodeoxycholic acid (GDCA) only increased in the Fruit fl ow group ( P 0.05, respectively, Supplemental Table 2). Plasma SCFA and other organic acids. There were no signi fi cant between-group differences (Supplemental Table 2). Within- groups, we observed a slight but signi fi cant increase in pyru- vate in the Fruit fl ow group, as well as increases in acetate in both the groups ( P 0.05, respectively). Fecal metabolites Fecal BAs. There were no signi fi cant between-group differences in fecal BA (Supplemental Table 3). We observed only one sig- ni fi cant within-group change; fecal cholic acid (CA) increased from baseline to the end of intervention in the Fruit fl ow group but not in the placebo group ( P 0.05, Supplemental Table 3). Fecal SCFA and other organic acids. There were no between- group differences in fecal SCFAs; only valerate increased from baseline to end of the intervention in the placebo group ( P 0.05, respectively, Supplemental Table 3). Stool consistency and gastrointestinal symptoms There were no signi fi cant between- or within-group differ- ences in stool consistency or gastrointestinal symptoms ( datanot shown ). Adverse events and blood safety pro fi les There were no serious adverse events (SAEs), or withdrawals due to adverse events (AEs) observed during the study. All AEs were of mild or moderate intensity, and none were deemed to be related to the investigational products by the assigned study clinician ( data not shown ). Standard hematology and biochemistry assessment showed no signi fi cant within and between-group ef- fects, including glucose, hsCRP, and bilirubin. Data not shown .
comparing both groups. In addition, there were several signi fi cant changes in relative abundance of microbial taxa with Fruit fl ow, such as decreases in Bacteroides, Ruminococccus, and Hungatella related OTUs, as well as increases in Alistipes which are all known for the involvement in TMA/TMAO metabolism. There were no between-group differences in SCFAs and BAs in both feces and plasma but several signi fi cant changes within groups such as an increase in CA in feces or plasma pyruvate with Fruit fl ow. TMAO has been established as an independent risk factor for promoting atherosclerosis by stimulating foam cell formation, deregulating enterohepatic cholesterol metabolism, and impairing macrophage reverse cholesterol transport [13, 15, 16, 38]. Given that the production of TMAO from dietary choline is dependent on metabolism by the intestinal microbiota [13, 15, 38], gut microbiota-based interventions have been suggested as a novel strategy for preventing and treating cardiovascular diseases (CVD). Several natural products rich in polyphenols have been shown recently in animals and humans to lower plasma TMAO levels [9 – 11]. For example, Chen et al. [10] fi rst demonstrated in mice that resveratrol attenuates TMAO-induced atherosclerosis by regulating TMAO synthesis via remodeling gut microbiota. This was con fi rmed in other studies with experimental rodents [11] as well as in a pilot study in 20 normal-weight subjects showing a signi fi cant decrease in serum TMAO (1.87 to 0.66 μ M) after 4 wk of supplementation with a 300 mg of polyphenol-rich grape pomace [9]. In contrast, a recent study in overweight and obese subjects revealed that raspberry consumption of 280 mg/d increased plasma TMAO levels, although the data revealed a large interin- dividual variability, with 6 subjects showing decreased plasma TMAO levels and 11 subjects with increased TMAO levels [39]. FIGURE2. Effects of 4-wk of supplementation of Fruit fl ow or placebo (maltodextrin) on gut microbiota beta diversity in overweight and obese adults. Principal component analysis (PCoA) is based on A) Bray – Curtis and B) Jaccard distance matrixes of Fruit fl ow and placebo groups at baseline and the end of the intervention. Ellipses represent an 80% con fi dence interval. Lines connect samples from the same participants. Density plots show the projection of PCoA points onto the PC1 and PC2 axis. N ¼ 22.
Discussion
We found that Fruit fl ow when administered over 4 wk at 2 150 mg Fruit fl ow per d, but not placebo, signi fi cantly reduced fasting plasma ( 1.5 μ M) and urine ( 19.1 μ M) TMAO as well as plasma LPS ( 5.3 ng/mL) from baseline to the end of interven- tion. However, these changes were signi fi cant only for urine TMAO when comparing the changes between groups. An untar- geted metabolomic analysis revealed a clear distinction between plasma samples collected after Fruit fl ow interventions and control samples, with TMAO being the top-ranking feature driving this distinction. When analyzing fecal microbiota, we found changes in microbial beta, but not alpha, diversity with a signi fi cant dif- ference in Jaccard distance-based principal component when
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