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Bifidobacterium longum subsp. longum Reduces Perceived Psychological Stress in Healthy Adults: An Exploratory Clinical Trial.
Boehme, M, Rémond-Derbez, N, Lerond, C, Lavalle, L, Keddani, S, Steinmann, M, Rytz, A, Dalile, B, Verbeke, K, Van Oudenhove, L, et al
Nutrients. 2023;15(14)
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Psychosocial stress is a common issue and one way in which nutrition may modulate the stress response is via the microbiota-gut-brain axis. This 6-week randomised, double-blind, placebo-controlled trial of 45 healthy adults with mild-to-moderate stress evaluated the effects of Bifidobacterium longum (BL) NCC3001 on psychological and physiological markers of stress and the response to an acute stress test. Outcome measures included cortisol awakening response, heart rate, heart rate variability and various questionnaires assessing stress, anxiety, depression, sleep and gastrointestinal symptoms. Compared to placebo, probiotic intake led to a significant decrease in perceived stress and an improvement in subjective sleep after 6 weeks. There was no difference in cortisol awakening response. The subjects in both groups did not experience significant gastrointestinal symptoms and scored low on anxiety and depression at baseline. In response to the acute stress test, cortisol levels were higher in the probiotic than the placebo group, whilst no clear differences were seen in heart rate and heart rate variability. Subjects in the probiotic group had a lower pain experience during the stress test whilst subjects in the placebo group had an increase in positive mood following the test. The authors conclude that these results support their hypothesis that BL NCC3001 may alleviate stress and improve sleep in adults with moderate stress levels.
Expert Review
Conflicts of interest:
None
Take Home Message:
- There is mounting evidence to suggest that nutritional interventions can influence our stress responses. One of the routes by which nutrition can influence physiological and psychological stress responses involves the microbiota– gut–brain-axis.
- This exploratory trial suggests that supplementation with Bifidobacterium longum (BL) strain NCC3001 leads to a beneficial effect on stress relief and improves subjective sleep quality in a healthy adult population reporting moderate levels of psychological stress.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
A randomised, placebo-controlled, two-arm, parallel, double-blind exploratory clinical trial was conducted to investigate the effect Bifidobacterium longum (BL) strain NCC3001 on stress-related psychological and physiological parameters and acute stress in healthy adults who typically experience mild-to-moderate-levels of stress.
Method
47 Participants between the ages of 25-65 years old with mild-to-moderate psychological stress received 1x1010 CFU of Bifidobacterium longum (BL) strain NCC3001 daily or a placebo for 6 weeks.
Participants completed the Perceived Stress Scale (PSS), the Hospital Anxiety and Depression Scales (HAD-A and HADS-D), the Gastrointestinal Symptom Rating Scale (GSRA), the Pittsburgh Sleep Quality Index (PSQI) questionnaire, the Positive and Negative Affect Schedule (PANAS), the State Trait Anxiety Inventory (STAI-6), the Maastricht Acute Stress Test (MAST) and the Visual Analog Scales (VAS, which measures pain intensity) during the clinical study. The Depression, Anxiety and Stress Scale (DASS-42) questionnaire was also used to depict the progression of the participants through the study.
Faecal samples were taken at baseline and 6 weeks and awakening saliva samples were taken at baseline, 2, 4, 6 and 8 weeks. At the endpoint, 45/49 (91%) of the subjects completed the study. One participant reported an adverse event and the other withdrew without an explanation. Two participants were excluded from the full analysis.
Results
The primary outcomes were:
- After 6-week of the probiotic intervention, there was a significant decrease in perceived stress in the probiotic group (21.4%) compared to the placebo group (-10.2%), p = 0.017.
- There was a significant improvement in subjective sleep in the probiotic group compared to the placebo group (p = 0.037).
- There was a significant decrease in the positive PANAS change score from the pre-stressor stage in the probiotic group compared to the placebo group (p = 0.01).
- There were lower pain values (VAS) scores from pre-stressor to post-stressor in the probiotic group compared to the placebo group (p = 0.05).
- There was no significant difference between groups in anxiety (HADS-A) and Depression (HADS_D) scores.
Conclusion
Oral supplementation with BL NCC3001 may have beneficial effects on stress relief and improves subjective sleep quality in a healthy adult population reporting moderate levels of psychological stress.
Clinical practice applications:
- While the mechanism underlying the correlation between the microbiota and the gut-brain-axis is not fully understood, it is thought to play a critical role in the links between the microbiota, mood, stress, and brain health.
- This exploratory trial additionally supports the potential of specific probiotics being used to reduce perceived stress and improve subjective sleep quality in healthy adults.
Considerations for future research:
- Larger, powered clinical trials are needed to provide further insights into the mechanisms underlying the stress-relieving and sleep-improving effect of Bifidobacterium longum.
- Furthermore, the dosage and duration of the probiotics need further investigation in a larger healthy population.
- Comparative research is needed to help investigate the effect of different probiotic strains on stress relief and sleep quality.
Abstract
Emerging science shows that probiotic intake may impact stress and mental health. We investigated the effect of a 6-week intervention with Bifidobacterium longum (BL) NCC3001 (1 × 1010 CFU/daily) on stress-related psychological and physiological parameters in 45 healthy adults with mild-to-moderate stress using a randomized, placebo-controlled, two-arm, parallel, double-blind design. The main results showed that supplementation with the probiotic significantly reduced the perceived stress and improved the subjective sleep quality score compared to placebo. Comparing the two groups, momentary subjective assessments concomitant to the Maastricht Acute Stress Test revealed a lower amount of pain experience in the probiotic group and a higher amount of relief at the end of the procedure in the placebo group, reflected by higher scores in the positive affect state. The awakening of the salivary cortisol response was not affected by the intervention, yet the reduction observed in the salivary cortisol stress response post-intervention was higher in the placebo group than the probiotic group. Multivariate analysis further indicated that a reduction in perceived stress correlated with a reduction in anxiety, in depression, and in the cortisol awakening response after the 6-week intervention. This exploratory trial provides promising insights into BL NCC3001 to reduce perceived stress in a healthy population and supports the potential of nutritional solutions including probiotics to improve mental health.
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Serotonin Reuptake Inhibitors and the Gut Microbiome: Significance of the Gut Microbiome in Relation to Mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis.
Sjöstedt, P, Enander, J, Isung, J
Frontiers in psychiatry. 2021;12:682868
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In preceding centuries common thought was that psychiatric disorders originated from the gut. In later years this concept was replaced by the idea of it being a disorder of the brain and that an imbalance of neurotransmitters is the cause of depression and other psychiatric conditions (monoamine hypothesis). This theory has been dominating psychiatric research for the past decades, and selective serotonin reuptake inhibitors (SSRIs) have become a widespread treatment option for psychological disorders. Despite their benefits, their use also presents clinical challenges such as treatment resistance, side effects or loss of effect. Consequently, the monoamine hypothesis has become disputed with other pathophysiological mechanisms having been proposed in recent years. With an appreciation of the pathophysiological complexities, this opinion-based article sought to present alternate views and to suggest areas for future research regarding psychiatric disorders, SSRIs and the gut-brain axis. The gut-brain axis has complex communication and signalling pathways in essence, the gut microbiome can exert significant effects on emotions, behaviours, metabolic risks, and the metabolism of drugs. Nerve cells of the gut also generate substantial amounts of serotonin for use within the gut. Equally, the gut microbiome produces and uses serotonin. It appears that some of the side effects associated with SSRIs, such as weight gain, are mediated via the gut microbiome. Further evidence suggests that SSRIs and several other psychotropic drugs exert antimicrobial action, which can alter the balance and integrity of the gut microbiome. Therefore, it would be valuable to further investigate the impact of long-term SSRI use on the microbial constellation in the gut and whether certain microbiome patterns could help predict treatment responsiveness or side effects, that may be manageable via microbiome manipulation. The authors believe that an advanced understanding of the dynamics of the gut microbiome could provide better and personalized treatment options for mental health conditions. This article provides a brief insight into current thoughts and theories of psychiatric disorders, SSRIs and the gut.
Abstract
The monoamine hypothesis of psychopharmacology has been dominating the biological psychiatric research field for decades. Currently psychiatric research has increasingly appreciated psychiatric disorders and suicidal behavior as being highly complex and multi-etiological. In this pathway the gut microbiome and its interrelationship with the brain is gaining traction. The usage of selective serotonin reuptake inhibitors (SSRIs) is increasing in the general population. This is due to their effect on a broad range of psychiatric disorders, and their favorable side effect profile. Still, there are enigmatic aspects about SSRIs, such as the difficulty to predict effect in individual patients, inter-individual differences in side effect, tachyphylaxis (a sudden loss of response to a certain drug), and to date, uncertainties on how they exert their clinical effect. A majority of the serotonin in the human body is produced within the gut, and SSRIs affect enteric neurons. They also exhibit antimicrobial properties that comes with the potential of disrupting microbial hemostasis. We propose that the role of the gut-brain axis and the gut microbiome in relation to psychopharmacology should be more highlighted. With this article, together with similar articles, we would like to provide a hypothetical framework for future studies within this field. We believe that this would have the potential to provide a paradigm shift within the field of psychopharmacology, and result in findings that potentially could contribute to the development of a more personalized and tailored treatment.
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Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging.
Biragyn, A, Ferrucci, L
The Lancet. Oncology. 2018;19(6):e295-e304
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This study looks at the important role our gut bacterial and commensal microbes play in supporting immunity and potentially reducing the risk of cancer from aging. Cancer risk increases as we age and is one of the main causes of reduced life expectancy. Our gut microbiome changes continually in response to diet, lifestyle, infection, and activation of immune responses. Gut dysbiosis is characterised by a shift towards proinflammatory commensals and a reduction of beneficial microbes, which can cause impairment and leakiness of the intestinal barrier. This is thought to trigger inflammaging or rather aging in a state of continual inflammation, where the immune system is in a heightened state of activation, and the body essentially creates an environment conducive to cancer. The gut is populated by trillions of species of bacteria which work together with our immune cells. As we age the diversity and density of these beneficial bacteria reduce. Therapies which support the balance of our commensal bacteria may prove effective at reducing rates of cancer in the elderly.
Abstract
Cancer incidence substantially increases with ageing in both men and women, although the reason for this increase is unknown. In this Series paper, we propose that age-associated changes in gut commensal microbes, otherwise known as the microbiota, facilitate cancer development and growth by compromising immune fitness. Ageing is associated with a reduction in the beneficial commensal microbes, which control the expansion of pathogenic commensals and maintain the integrity of the intestinal barrier through the production of mucus and lipid metabolites, such as short-chain fatty acids. Expansion of gut dysbiosis and leakage of microbial products contributes to the chronic proinflammatory state (inflammaging), which negatively affects the immune system and impairs the removal of mutant and senescent cells, thereby enabling tumour outgrowth. Studies in animal models and the importance of commensals in cancer immunotherapy suggest that this status can be reversible. Thus, interventions that alter the composition of the gut microbiota might reduce inflammaging and rejuvenate immune functions to provide anticancer benefits in frail elderly people.
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Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Nagy-Szakal, D, Williams, BL, Mishra, N, Che, X, Lee, B, Bateman, L, Klimas, NG, Komaroff, AL, Levine, S, Montoya, JG, et al
Microbiome. 2017;5(1):44
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, swollen lymph glands and irritable bowel syndrome (IBS). It is associated with gut bacterial dysbiosis, systemic inflammation and both gastro intestinal (GI) and neurological disturbances. The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. This experiment looked at fecal bacterial samples and metabolic pathway markers in 50 ME/CFS patients and 50 healthy controls. In ME/CFS subgroups, measures of symptom severity including pain, fatigue, and reduced motivation were correlated with the amounts and types of gut bacteria and certain metabolic pathways. Future prospective studies should consider more detailed exploration of IBS subtypes, associated GI symptoms, and their relationship to ME/CFS dysbiosis. This may enable more accurate diagnosis and the development of specific therapeutic strategies.
Abstract
BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. RESULTS Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. CONCLUSIONS Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.