Probiotic treatment may influence core clock gene expression and metabolites in individuals with major depressive disorder (MDD), potentially linking gut microbiota to circadian rhythms and mood regulation.
Highlights:
- CLOCK Gene Expression: The expression level of the CLOCK gene significantly increased only in individuals receiving probiotic treatment, suggesting a direct impact of probiotics on circadian rhythms.
- ARNTL & TIMELESS Genes: Both ARNTL and TIMELESS gene expression levels changed significantly over the 4-week intervention period in both the probiotic and placebo groups.
- Metabolite Correlations: Various metabolites in serum and stool showed positive and negative correlations with core clock gene expression, indicating a complex interaction between gut microbiota and circadian gene regulation.
- Depression Scores: Both groups showed significant improvements in depression scores over the 28-day period, but no significant difference was observed between the probiotic and placebo groups.
- Gut Microbiome Influence: The study supports the idea that altering the gut microbiome with probiotics could favorably affect the molecular clock and mood through metabolites.
Source: Neuropsychobiology (2024)
Major Findings: Probiotics vs. Circadian Clock Gene Expression & Metabolites in Depression (2024)
Kathrin Kreuzer et al. conducted the PROVIT-CLOCK study to evaluate the effects of probiotic treatment on circadian clock gene expression and metabolites in individuals with major depressive disorder (MDD) – below are the major findings.
1. Significant Changes in CLOCK Gene Expression
The study found that the CLOCK gene, which plays a crucial role in regulating our internal biological clock, showed significant changes in its expression levels only in participants who received probiotic treatment.
This suggests that probiotics might directly influence how our body’s internal clock functions.
The CLOCK gene helps control our daily sleep-wake cycle and other bodily functions.
By taking probiotics, the levels of this gene changed, indicating that the gut bacteria might affect how well our internal clock works, potentially improving sleep and overall daily rhythms.
2. Alterations in ARNTL & TIMELESS Gene Expression
Both the ARNTL and TIMELESS genes, also essential for maintaining our internal clock, showed significant changes in their expression levels over the 4-week study period in both the probiotic and placebo groups.
These genes are part of a system that regulates our body’s daily cycles.
The changes in these genes’ activity in both groups suggest that other factors, such as regular meal times and sleep schedules during the study, might also influence our internal clock, regardless of probiotic intake.
3. Correlation Between Metabolites & Gene Expression
The study observed various correlations between metabolites (small molecules in the body) found in blood and stool samples and the expression levels of core clock genes.
Metabolites are produced by gut bacteria and can enter the bloodstream, influencing different bodily functions.
The study found that certain metabolites were linked to changes in the genes controlling our biological clock.
This indicates a complex interaction between what happens in our gut and how our internal clock operates, affecting our overall health and mood.
4. Improvement in Depression Scores
Both the probiotic and placebo groups showed significant improvements in depression scores over the 28-day period, but there was no significant difference between the two groups.
While both groups felt better over the course of the study, the improvement wasn’t significantly different between those taking probiotics and those taking a placebo.
This suggests that while probiotics might help, other factors like regular routines and care provided during the study also played a big role in improving depression symptoms.
5. Influence of Gut Microbiome on the Internal Clock
The study supports the idea that changing the gut microbiome with probiotics can favorably affect the molecular clock and mood through metabolites.
The gut microbiome, which consists of all the bacteria in our intestines, can influence various bodily functions, including our internal clock.
By altering the gut microbiome with probiotics, we can potentially improve the regulation of our sleep-wake cycles and overall mood, highlighting the importance of gut health in managing conditions like depression.
Study Overview: Probiotics on Clock Genes in Major Depression (2024)
The PROVIT-CLOCK study aimed to investigate the effects of a 4-week probiotic intervention on core clock gene expression and the metabolome in individuals with major depressive disorder (MDD).
Sample
- Participants: 53 individuals diagnosed with MDD.
- Criteria: Adults aged 18-75 years, diagnosed with a depressive episode per ICD-10 guidelines.
- Groups: Randomly assigned to either a probiotic group (24 participants) or a placebo group (29 participants).
Methods
- Design: Randomized, double-blind, placebo-controlled, multispecies probiotic intervention study.
- Intervention: Daily intake of a probiotic drink containing nine bacterial strains for 28 days.
- Assessments: Clinical assessments (depression severity using BDI-II and HAMD scales). Metabolomics analyses (1H nuclear magnetic resonance spectroscopy of stool and serum). Gene expression analysis (RT-qPCR) of core clock genes in peripheral blood mononuclear cells (PBMCs).
Limitations
- Sample Size: Relatively small, which may limit the generalizability of the findings.
- Duration: A 4-week study period may be insufficient to observe significant clinical differences between groups.
- Peripheral Measurements: Gene expression was measured in PBMCs, not brain tissue, which may not fully represent brain gene expression.
- Confounding Factors: Inclusion of vitamin B7 in both probiotic and placebo supplements could influence results. Variability in smoking habits and medication use among participants might also affect outcomes.
- Generalization: Findings may not be directly applicable to non-hospitalized or drug-free MDD patients.
How Probiotics Influence Clock Genes & Major Depression (Possible Mechanisms)
Influence on Clock Genes
Butyrate Production
- Mechanism: Probiotics, particularly those containing butyrate-producing bacteria (e.g., Coprococcus spp., Ruminococcus), enhance the production of butyrate, a short-chain fatty acid (SCFA).
- Effect: Butyrate can cross the blood-brain barrier and influence brain function by modulating gene expression. It acts as a histone deacetylase (HDAC) inhibitor, which can promote the expression of genes involved in circadian rhythms, including CLOCK, ARNTL, and TIMELESS.
Epigenetic Modulation
- Mechanism: SCFAs, such as butyrate, can modify the epigenetic landscape by inhibiting HDACs, leading to increased acetylation of histones.
- Effect: This results in a more open chromatin structure, facilitating the transcription of clock genes. Enhanced expression of CLOCK and ARNTL leads to improved regulation of circadian rhythms, impacting sleep-wake cycles and hormonal release.
Inflammation Reduction
- Mechanism: Probiotics can decrease systemic inflammation by modulating the gut microbiota, leading to reduced production of proinflammatory cytokines like IL-6.
- Effect: Lower inflammation levels can prevent the disruption of circadian rhythms. Inflammatory cytokines have been shown to interfere with the expression of clock genes, and their reduction can stabilize the molecular clock.
Metabolic Pathways
- Mechanism: Probiotics can alter the metabolome by increasing levels of specific metabolites, such as amino acids (lysine, valine, alanine) and betaine.
- Effect: These metabolites can act as cofactors or signaling molecules that influence the activity of clock genes. For instance, betaine is involved in methylation processes essential for gene regulation, impacting the expression of circadian genes.
Influence on Major Depression
Gut-Brain Axis
- Mechanism: Probiotics enhance gut barrier integrity and modulate gut-brain signaling through the production of neurotransmitters and metabolites.
- Effect: Improved gut health leads to better communication between the gut and brain. Neurotransmitters like serotonin, which are produced in the gut, can influence mood and cognitive functions, alleviating symptoms of depression.
Neurotransmitter Production
- Mechanism: Certain probiotics can increase the production of neurotransmitters such as serotonin and GABA by influencing the gut microbiota.
- Effect: Serotonin is crucial for mood regulation, and GABA has calming effects on the brain. Enhanced production of these neurotransmitters can directly reduce symptoms of depression and anxiety.
Reduction of Stress Hormones
- Mechanism: Probiotics can reduce the production of stress-related hormones like cortisol by modulating the hypothalamic-pituitary-adrenal (HPA) axis.
- Effect: Lower cortisol levels lead to reduced stress and improved mood. Chronic stress is a known factor in the development of depression, and managing stress hormones can help alleviate depressive symptoms.
Anti-inflammatory Effects
- Mechanism: Probiotics reduce systemic inflammation by decreasing the levels of proinflammatory cytokines (e.g., IL-6, TNF-alpha).
- Effect: Chronic inflammation is associated with depression. By reducing inflammation, probiotics can improve overall brain health and function, contributing to mood stabilization and reduction of depressive symptoms.
Enhanced Neuroplasticity
- Mechanism: Probiotics may enhance brain-derived neurotrophic factor (BDNF) levels, which are crucial for neuroplasticity.
- Effect: Increased BDNF levels promote the growth and differentiation of new neurons and synapses, which is essential for learning, memory, and overall brain resilience. Improved neuroplasticity can help in recovering from depressive states.
Potential Benefits of Probiotics for People with Depression
Likelihood of Benefit
Based on the findings of the PROVIT-CLOCK study, individuals with major depressive disorder (MDD) may benefit from probiotic supplementation.
The study demonstrated that probiotics could:
- Influence the expression of key circadian clock genes, potentially improving sleep-wake cycles and mood regulation.
- Reduce systemic inflammation, a known factor in depression.
- Enhance the production of beneficial metabolites and neurotransmitters, which can positively affect brain function and mood.
While the study showed promising results, it is important to note that the sample size was relatively small and the study duration was limited to 4 weeks.
Therefore, larger and longer-term studies are needed to confirm these findings and establish probiotics as a standard add-on therapy for depression.
Specific Probiotics Used in the Study
The specific probiotic formulation used in the PROVIT-CLOCK study was “OMNi-BiOTiC® Stress Repair,” which contains a blend of multiple bacterial strains.
Based on the study, the following strains are recommended for their potential benefits:
- Bifidobacteria: Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Bifidobacterium lactis W52.
- Lactobacilli: Lactobacillus acidophilus W22, Lactobacillus casei W56, Lactobacillus paracasei W20, Lactobacillus plantarum W62, Lactobacillus salivarius W24, Lactococcus lactis W19.
These strains were chosen for their ability to produce beneficial metabolites like butyrate and for their potential to reduce inflammation and improve gut health.
How to Take Probiotics Safely
- Consult a Healthcare Provider: Before starting any new supplement, it is important to consult with a healthcare provider, especially if you have any underlying health conditions or are taking other medications.
- Choose a Reputable Brand: Select a probiotic supplement from a reputable manufacturer that provides clear labeling of the strains and their concentrations.
- Follow Recommended Dosage: Adhere to the dosage instructions provided by the manufacturer. In the PROVIT-CLOCK study, participants took a daily dose containing at least 7.5 × 10^9 colony-forming units (CFUs).
- Consider Timing: Probiotics are often taken on an empty stomach to ensure maximum survival through the digestive tract. Follow the specific instructions on the product label.
- Monitor for Side Effects: Probiotics are generally safe, but some individuals may experience mild side effects such as bloating or gas. If severe side effects occur, discontinue use and consult a healthcare provider.
- Storage: Store probiotics as recommended by the manufacturer. Some probiotics require refrigeration to maintain their potency, while others are stable at room temperature.
Conclusion: Probiotic Supplements vs. Circadian Rhythm in Depression
The PROVIT-CLOCK study provides compelling evidence that probiotic supplementation can influence circadian clock gene expression and metabolites in individuals with major depressive disorder (MDD).
The probiotics used in the study, containing specific strains of bifidobacteria and lactobacilli, showed potential in improving sleep-wake cycles and reducing inflammation, which are critical factors in managing depression.
While the study’s results are promising, the relatively small sample size and short duration highlight the need for further research to confirm these findings.
Probiotics could emerge as a valuable add-on therapy for depression, offering a novel approach to improving mental health by targeting the gut-brain axis.
References
- Study: PROVIT-CLOCK: A Potential Influence of Probiotics and Vitamin B7 Add-On Treatment and Metabolites on Clock Gene Expression in Major Depression (2024)
- Authors: Kathrin Kreuzer et al.
