Nutrients 2023 , 15 , 3466
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S-adenosylmethionine (SAMe), was found to reduce the total score of depression after 2 and 6 weeks of intake in another placebo-controlled study that included subjects with mild-to-moderate depression [5]. The cognitive and anxiety subdomains were also reduced significantly after 2 weeks of consumption. Another L. plantarum strain ( Lactiplantibacillus plantarum 299v, LP299V ® ) has shown positive effects on cognition and mood in subjects with major depression [6]. Intake of LP299V for 8 weeks led to an improvement in the “Attention and Perceptivity Test” and in the “California Verbal Learning Test”, compared with the placebo group (baseline vs. 8 weeks of intervention). The authors linked the effects to a reduction in kynurenine, a compound that is produced during the degradation of tryptophan, which can have a negative effect on cognition. LP299V has also been eval- uated in students during examination-induced stress, which showed a positive effect on cortisol levels [7]. Two earlier studies in the gut–brain axis area including LPHEAL9 focused on acute stress with measurements on one day [4] or on depressed subjects [5]. To further strengthen the understanding of the gut–brain axis impact of LPHEAL9, an explorative study was performed on healthy subjects with moderate stress who were followed for three months. The aim was to investigate if intake of LPHEAL9 could influence stress, cognition, mood, and quality of sleep. Subjects with moderate stress were included since earlier trials have indicated beneficial effects of probiotics on brain function when the system is challenged with stress [8–10]. To evaluate the mechanisms behind the effects, several blood biomarkers were followed, such as the levels of tryptophan, kynurenine, and different markers for inflammation.
2. Materials and Methods 2.1. Study Design
The study was a randomized, double-blinded, placebo-controlled, and parallel-designed study, carried out at a single site at Atlantia Clinical Trials, Cork, Ireland, between June 2021 and March 2022. It consisted of a screening visit, followed by a 2 week run-in phase and four assessment visits during a 12 week supplementation phase. Eligible subjects were randomized into the study at visit 2, baseline (week 0). Study assessments carried out during the visits included saliva awakening cortisol, analysis of biomarkers in blood samples, cognitive assessment, perceived stress, quality of sleep, and mood assessment. Subjects also answered questions regarding their lifestyle such as diet, exercise, and job on all occasions to determine if there had been some changes during the study time. Apart from the cognition tests that were conducted at baseline and at week 12, all other study assessments as well as safety assessments were carried out at baseline, visit 3 (week 4), visit 4 (week 8), and visit 5 (week 12). Before any study-related procedures, all subjects gave written informed consent, which specifically indicated that participation was voluntary and could be terminated at any time without giving any reason. The study was approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Cork (ECM 4 (ll) 9 March 2021) and registered at Clinical Trials (NCT04931082) before the first participant was included. The study was conducted in accordance with the ethical principles in the Declaration of Helsinki, the International Council for Harmonization, and E6 R2 Guideline for Good Clinical Practice (ICH GCP). 2.2. Study Population Healthy males and females aged 21 to 50 years with moderate stress were recruited via advertisements, and using a list of previously reported interested subjects. All subjects lived in the area of Cork, Ireland. Interested subjects were asked to fill in the Cohen’s Perceived Stress Scale (PSS) and the Hospital Anxiety and Depression Scale (HADS) questionnaires for the assessment of their stress levels. A PSS score between ≥ 14and ≤ 26, and a HADS score of ≤ 10 for anxiety and depression were required for enrollment. Subjects within these ranges, who fulfilled all inclusion and exclusion criteria, were asked to participate in the clinical study and were scheduled for their inclusion visit (visit 1). Exclusion criteria
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