A. Rehman et al.
The Journal of Nutrition xxx (xxxx) xxx
employees of Atlantia Clinical Trials Ltd., which was contracted by DSM to carry out the clinical trial. AKDR is a member of the Scienti fi c Advisory Board of Provexis PLC, UK
LPS concentrations are high in the gut lumen where gut bacteria reside and low in plasma because the intestinal epithelial layer creates an effective barrier against LPS penetration. The observed reduction in plasma LPS after Fruit fl ow consumption, therefore, suggests improvements in intestinal barrier function, although we did not directly measure this. There are a few limitations of this study that require consid- eration. 1) The small sample size allows only limited interpreta- tion of data. Although we powered the study based on available effect size data, many participants had to be excluded from the analysis which resulted in only 22 participants for the per- protocol analysis. 2) Given the limited power and the explor- atory nature of the analysis of secondary outcomes, we did not control for multiplicity of testing. 3) Diet is a key modulator of the gut microbiota. Although this trial followed a cross-over design, there was no dietary monitoring during the intervention and therefore changes in habitual diet over time may have in fl uenced the outcome. In addition, we did not analyze dietary choline as a potential confounder, nor did we control for foods like marine fi sh which can contain variable levels of TMA and TMAO [43, 57, 58]. In fact, diets rich in long-chain omega 3 fatty acids of marine origin have been shown to increase plasma TMAO concentration suggesting TMAO levels as a biomarker of these healthy foods but not a universally valid biomarker of cardiometabolic risk [59]. In conclusion, 4 wk of supplementation with 2 150 mg Fruit fl ow per day, a watery tomato extract rich in secondary metabolites including polyphenols, signi fi cantly reduced fasting plasma and urine TMAO as well as plasma LPS from baseline to the end of intervention. However, these changes were signi fi cant only for urine TMAO when comparing the changes between groups. Given that both, plasma TMAO and LPS are suggested as biomarkers of cardiometabolic risk and intestinal permeability and low-grade in fl ammation, respectively, these effects can be considered host health bene fi ts. Changes in microbial beta, but not alpha, diversity paralleled these effects with a signi fi cant difference in Jaccard distance-based Principal Component be- tween groups as well as changes in microbial composition with Fruit fl ow, such as decreases in Bacteroides, Ruminococccus, and Hungatella and increases in Alistipes related OTUs which are all known for the involvement in TMA/TMAO metabolism [43 – 47]. There were no between-group differences in short-chain fatty acids and BA in both faces and plasma but several signi fi cant changes within groups such as an increase in CA in faces or plasma pyruvate with Fruit fl ow. In addition, an untargeted metabolomic analysis revealed TMAO as the most discriminant plasma metabolite between Fruit fl ow and placebo plasma sam- ples. Together, our results support earlier fi ndings that polyphenol-rich extracts can lower TMAO concentrations and that this may be related to a targeted modulation of the gut microbiota along the de fi nition of the prebiotic concept. Funding
Acknowledgments
We thank Julia Bird for assisting in clinical trial management, Estel Canet-Martinez and Stephane Etheve for coordinating an- alytics, Alex Karagiannis-Voules for statistical support, Niamh O ’ Kennedy at Provexis Plc, London, UK for coordinating the production of the material and the staff of Atlantia Clinical Trials Ltd. Atlantia for their work in the completion of this clinical trial. RES, SF, RD conceived and designed the experiments, GDG and SP completed the statistical analysis and RES, AR, SMT, and GDG wrote the manuscript. AKDR reviewed the manuscript. All au- thors helped interpreting the data, read and approved the fi nal manuscript. All data described in the manuscript, code book, and analytic code will be made available upon request. Appendix A. Supplementary data
Supplementary data to this article can be found online at http s://doi.org/10.1016/j.tjnut.2022.11.009.
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DSM Nutritional Products funded the study.
Author disclosures
RES, RD, AR, and SF are/were employees of DSM Nutritional Products Ltd., Kaiseraugst, Switzerland, which is involved in the commercialization of Fruit fl ow. SMT, GDG, and TGD are
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