A. Rehman et al.
The Journal of Nutrition xxx (xxxx) xxx
Introduction
to investigate the effect of 4 wk of supplementation of 2 150 mg Fruit fl ow on plasma TMAO (primary outcome), as well as fecal microbiota and concentrations of urine TMAO and other fecal and plasma metabolites, including lipopolysaccharides (LPS), bile acids (BA), SCFAs, and other organic acids (sec- ondary outcome). Given that fasting plasma TMAO may un- derestimate the TMAO-producing function of gut microbiota because of host ’ s ef fi cient renal clearance of plasma TMAO, we also performed an egg challenge to determine the acute effect of the intervention on postprandial plasma TMAO concentrations.
Targeted modulation of the gut microbiota has been suggested as a preventative and/or novel therapeutic approach for several diseases, including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular or intestinal in fl ammatory disease [1 – 3]. Several nutritional regimes are available today, including pre and pro- biotics; however, their full potential remains unexploited particu- larly in the case of prebiotics [4, 5]. To foster the appropriate use of theterm prebiotic , the International Scienti fi c Association of Probiotics and Prebiotics published a consensus paper in 2017, de fi ning a prebiotic as “ a substrate that is selectively utilized by host microor- ganisms conferring a health bene fi t [6]. ” Besides a few well-established prebiotics, including fructans [fructooligo- saccharides (FOS) and inulin] and galactans [gal- actooligosaccharides (GOS)] that fi t that category, several prebiotic candidates were listed to impact host microorganisms using invitro fermentation or clinical studies. However, the challenge remains to satisfy the criterion of conferring a host health bene fi t. Among the listed prebiotic candidates, plant polyphenols are also included with an estimated 90% to 95% that are not absorbed in the small intestine but reach the colon to undergo extensive biotransformation by the gut microbiota [7]. It has been hypothesized that the health bene fi ts associated with polyphenol consumption may depend on microbial utilization and metabolites produced rather than on the parent compound [8]. In addition, polyphenols may modulate the gut microbiota to confer a health bene fi t. One example is that polyphenols may attenuate trimethylamine-N-oxide (TMAO)-induced atheroscle- rosis by remodeling the gut microbiota and thus lowering TMAO synthesis [9 – 11]. TMAO is derived from trimethylamine (TMA), a microbial metabolite produced by various taxa of the gut microbiota primarily from dietary phosphatidylcholine and L-carnitine, commonly found in red meat, cheese, and eggs [12]. TMA is absorbed through the intestinal epithelium, transported to the liver, and converted into TMAO. TMAO is known for its proin fl ammatory and proatherogenic activities, and high base- line levels of TMAO have been linked to major adverse cardio- vascular events [13 – 16]. Fruit fl ow, a watery tomato extract, was the fi rst product in Europe to obtain an approved, proprietary health claim ( Water- soluble tomato concentrate helps maintain normal platelet aggrega- tion ) under Article 13 [5] of the European Health Claims Regu- lation 1924/2006 on nutrition and health claims [17,18]. It contains a range of tomato-derived secondary metabolites, including nucleosides, phenolic conjugates, and polyphenols, all showing different anti-platelet activity [17, 19 – 22]. The com- pounds present are all water-soluble and of low molecular weight; some (for example, nucleosides) are absorbed from the upper gastrointestinal tract very quickly on ingestion, whereas others (for example, fl avonoid glycosides) are absorbed much later in the digestive process, either from the lower small intes- tine or after microbial interaction in the proximal colon [17, 23]. It has been suggested that the different metabolic fates of the diverse compounds may contribute to the modulation of platelet function; however, the effect on TMAO through gut microbial changes remains unknown [24]. We hypothesized that Fruit fl ow would lower the TMAO levels by modulating gut microbiota and therefore performed a randomized, double-blind, placebo-controlled cross-over trial
Methods
Study population The study population comprised 40 overweight, and obese adults (BMI, 28 – 35 kg/m 2 ) aged 35 – 65 y. The main exclusion criteria were as follows: signi fi cant acute or chronic disease; smoking; a history of drug and/or alcohol abuse (more than 2 servings/d), pregnancy; antibiotic use within the previous 3 mo; major dietary changes in the past 3 mo; eating disorders; vege- tarians or vegans; enemas and dietary supplements including prebiotics, probiotics, or fi ber within 4 wk before the baseline visit and for the duration of the intervention; chronic medica- tions for active gastrointestinal disorders (unless the product was taken for at least 2 month before screening and the exact dosage was maintained throughout the study); and high habitual intake of tomatoes or tomato-based products as con fi rmed by a Food Frequency Questionnaire ( > 1000g per wk). Participants deemed eligible were randomly assigned to an intervention order on a 1:1 basis, where n ¼ 20 participants were assigned to the pla- cebo/Fruit fl ow arm (group 1), and n ¼ 20 participants to the Fruit fl ow/placebo arm (group 2). Study design The trial was designed as a randomized, double-blind, placebo- controlled, cross-over trial consisting of 5 visits: 1) the screening visit (visit 1); 2) after a 21-d run-in period, the start of intervention phase 1 (visit 2); 3) end of the 4-week intervention (visit 3); 4) 6- week wash-out, and the start of intervention phase 2 (visit 4); and 5) end of the 4-week intervention (visit 5) (Supplemental Figure 1). During the screening, vital signs were recorded, and a complete medical examination, including medical history and demographic or anthropometric assessment, was performed. In addition, weekly tomato consumption was queried, and a fasting venous blood sample was collected for safety pro fi ling. Partici- pants were provided with a stool collection kit including cooler bag and cooler block for transporting, instructions for collecting and storing the stool sample, and a Bristol Stool Chart [25] to be completed at the time of stool collection. At visit 2, participants arrived at the study site and fasted overnight for at least 10 hours. Participants returned the Bristol Stool Chart and stool sample collected and stored at 20 C in home freezers within 24 hours before the visit. A venous blood sample was collected for safety pro fi ling and analysis of plasma TMAO and lipopolysaccharides (LPS). In addition, a urine sample was collected for the analysis of urine TMAO, and participants completed a Gastrointestinal Symptom Rating Scale (GSRS) and Food Frequency Questionnaire before they were assigned into one of the 2 intervention groups.
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