Multi-species probiotic supplement enhances vagal nerve function - results of a randomized controlled trial in patients with depression and healthy controls

Abstract

Major depression (MD) significantly impacts individual well-being and society. The vagus nerve plays a pivotal role in the gut-brain axis, facilitating bidirectional communication between these systems. Recent meta-analyses suggest potential antidepressant effects of probiotics, although their mechanisms remain unclear. This study aimed to assess the impact of a multi-species probiotic (OMNi-BiOTiC® STRESS Repair) on vagus nerve function in 43 MD patients and 43 healthy controls (HC). Participants received either probiotics or placebo twice daily. Serum and stool samples were collected at baseline, 7 days, 28 days, and 3 months. Vagus nerve (VN) function was evaluated using 24-hour electrocardiography (ECG) for heart rate variability (HRV), alongside stool microbiome analysis via 16S rRNA sequencing. After 3 months, MD patients receiving probiotics demonstrated significantly improved morning VN function compared to HC. MD participants who were in the probiotic group showed a significant increase in Christensellales, particularly Akkermansia muciniphila along with improved sleep parameters (use of sleep medication, sleep latency) as measured by the Pittsburgh Sleep Quality Inventory (PSI). This study highlights potential physiological benefits of probiotics in MD, potentially mediated through VN stimulation. Understanding these mechanisms could lead to novel therapeutic approaches for MD management.

Keywords: Vagus nerve; depression; gut microbiome; heart rate variability; probiotic.

Graphical abstract

Figure 1.

Study schedule. Participants underwent blood and stool sampling, heart rate variability measurements and questionnaires at baseline, after 12 weeks and at 3 months. After one week stool sampling, questionnaires and heart rate variability measurement were performed.

Figure 2.

Consort flow diagram.

Figure 3.

24-hr heart rate (a) and morning heart rate (b) at 4 time points for healthy controls (HC) and patients with depression (MD), and morning heart rate for depressive patients (MD) at 3 months comparing the probiotic and placebo groups (c). Statistical comparisons were performed using a repeated-measures ANOVA for panels a and b, and an unpaired Student’s t-test for panel c. Sample sizes: (a, b baseline) n = 21 (HC placebo) n = 22 (HC probiotic) n = 17 (MD placebo) n = 20 (MD probiotic); (c, after 3 months) n = 35, n = 15 (placebo), n = 20 (probiotic). bpm = beats per minute.

Figure 4.

RMSSD morning values at 4 time points for healthy controls (HC) and patients with depression (MD), comparing the probiotic and placebo groups (a), for the MD group only (b), and RMSSD differences for patients with MD after 3 months of taking a probiotic (c). Statistical comparisons were performed using a repeated-measures ANOVA for panels a and b, and a Mann-Whitney U-test for panel c. Sample sizes: (a, b, baseline) n = 21 (HC placebo), n = 22 (HC probiotic), n = 17 (MD placebo), n = 20 (MD probiotic); (c) n = 35, n = 15 (placebo), n = 20 (probiotic). RMSSD = root mean square of successive differences.

Figure 5.

High-frequency (HF) power morning values at 4 time points for healthy controls (HC) and patients with depression (MD), comparing the probiotic and placebo groups (a), for the MD group only (b), and HF power differences for patients with MD after 3 months of taking a probiotic (c). Statistical comparisons were performed using a repeated-measures ANOVA for panels a and b, and an unpaired Student’s t-test for panel c. Sample sizes: (a, b, baseline) n = 21 (HC placebo), n = 22 (HC probiotic), n = 17 (MD placebo), n = 20 (MD probiotic); (c) n = 35, n = 15 (placebo), n = 20 (probiotic). HF = high frequency.

Figure 6.

Logarithm of respiratory sinus arrhythmia (LogRSA) morning values at 4 time points for healthy controls (HC) and patients with depression (MD), comparing the probiotic and placebo groups (a), for the MD group only (b), and LogRSA differences for patients with MD after 3 months of taking a probiotic (c). Statistical comparisons were performed using a repeated-measures ANOVA for panels a and b, and an unpaired Student’s t-test for panel c. Sample sizes: (a, b, baseline) n = 21 (HC placebo), n = 22 (HC probiotic), n = 17 (MD placebo), n = 20 (MD probiotic); (C) n = 35, n = 15 (placebo), n = 20 (probiotic). LogRSA = logarithm of respiratory sinus arrhythmia.

Figure 7.

Standard Deviation of the NN intervals (SDNN) morning values at 4 time points for healthy controls (HC) and patients with depression (MD), comparing the probiotic and placebo groups (a), for the MD group only (b), and SDNN differences for patients with MD after 3 months of taking a probiotic (c). Statistical comparisons were performed using a repeated-measures ANOVA for panels a and b, and an unpaired Student’s t-test for panel c. Sample sizes: (a, b, baseline) n = 21 (HC placebo), n = 22 (HC probiotic), n = 17 (MD placebo), n = 20 (MD probiotic); (c) n = 35, n = 15 (placebo), n = 20 (probiotic). SDNN =  Standard Deviation of the NN intervals.

Figure 8.

Difference in beta-diversity between patients with depression (MD, red dots) and healthy controls (HC, blue dots). Statistical comparisons were performed using redundancy analysis (RDA) with principal component (PC) scores for group differentiation. Sample sizes: n = 39 (MD), n = 44 (HC). RDA = redundancy analysis; PC = principal component.

Figure 9.

Differences in taxa between patients with depression taking a placebo and those taking a probiotic at time point 4 (12 weeks). Statistical comparisons were performed using differential abundance analysis. Sample sizes: n = 15 (placebo), n = 19 (probiotic).

Figure 10.

Pittsburgh Sleep Quality Inventory (PSQI) total scores at 4 time points for healthy controls (HC) and patients with depression (MD), comparing the probiotic and placebo groups (a), for the MD group only (b), and PSQI differences for patients with MD after 3 months of taking a probiotic (c). Statistical comparisons were performed using a repeated-measures ANOVA for panels a and b, and a Mann Whitney U-test for panel c. Sample sizes: (a, b, baseline) n = 23 (HC placebo), n = 21 (HC probiotic), n = 18 (MD placebo), n = 20 (MD probiotic) (c) n = 33, n = 16 (placebo), n = 17 (probiotic). PSQI = Pittsburgh Sleep Quality Inventory Score.