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Probiotics-induced changes in gut microbial composition and its effects on cognitive performance after stress: exploratory analyses.
Bloemendaal, M, Szopinska-Tokov, J, Belzer, C, Boverhoff, D, Papalini, S, Michels, F, van Hemert, S, Arias Vasquez, A, Aarts, E
Translational psychiatry. 2021;(1):300
Abstract
Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, in exploratory analyses, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci, and Bifidobacteria in healthy, female subjects (probiotics group n = 27, placebo group n = 29). In an identical pre-session and post-session, subjects performed a working memory task before and after an acute stress intervention. Global gut microbial beta diversity changed over time, but we were not able to detect differences between intervention groups. At the taxonomic level, Time by Intervention interactions were not significant after multiple comparison correction; the relative abundance of eight genera in the probiotics group was higher (uncorrected) relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-010. In a second analysis step, association analyses were done only within this selection of microbial genera, revealing the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics' effect on stress-induced working memory changes (rspearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fiber intake). That is subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fiber degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g., maintaining intestinal-barrier and blood-brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.
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Gut feelings: A randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms.
Chahwan, B, Kwan, S, Isik, A, van Hemert, S, Burke, C, Roberts, L
Journal of affective disorders. 2019;253:317-326
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Depression is a debilitating psychiatric disorder that is the leading cause of disability world-wide. Multiple causes of depression have been identified, including genetic, neurological, inflammatory, personality, cognitive, and environmental factors. The aim of this study was to investigate the effectiveness of the multispecies probiotic Ecologic® Barrier for reducing symptoms in adults with mild to severe levels of depression. The study was a triple-blinded parallel, placebo-controlled randomised clinical trial. Participants were randomly allocated into two groups; probiotic and placebo. 71 participants with depressive symptoms were recruited and allocated sequentially over 12 months. Results indicate that all participants across both probiotic and placebo groups exhibited a reduction in depressive symptoms over the time-period of the trial. Thus, the routine involved with daily preparation and consumption of the probiotic and scheduled appointments, as well as involvement in these behaviours with the aim of seeking improvement in depressive symptoms had positive impacts on mood, irrespective of whether the probiotic or placebo was consumed. Authors conclude that their findings offer evidence to indicate that probiotic consumption can exert change on cognitive patterns associated with depression.
Expert Review
Conflicts of interest:
None
Take Home Message:
- This study offers evidence to indicate that probiotic consumption can exert change on cognitive patterns associated with depression.
- The study suggests that probiotics, rather than having a direct effect on depressive symptoms, potentially act on immune system activity, inflammation and gut barrier integrity which contribute to the expression of depression.
- Probiotics may be a useful adjunct to potentiate the effects of other therapies, such as CBT.
- This study points to the validity of managing physical health as part of mental health treatment.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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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:
With evidence suggesting that decreased gut barrier function and inflammation are correlated with depression, this study set out to determine the effect of consumption of probiotic supplements on depressive symptoms from a sample of 71 participants with depression. The study was a triple-blinded parallel, placebo-controlled randomised clinical trial conducted over 8 weeks in Australia. Pre and post intervention measures of symptoms and vulnerability markers of depression as well as gut microbiota were compared alongside psychological variables and gut microbiota composition to non-depressed, placebo and probiotic groups. All the clinical trial participants demonstrated an improvement in symptoms – participants in the probiotic group demonstrated a significantly greater reduction in cognitive reactivity compared with the placebo group. Probiotics did not significantly alter the microbiota of depressed individuals, however a significant correlation was found between Ruminococcus gnavus and one of the metrics for depression.
Clinical practice applications:
This study was small and carried out over a short period of time. While significant results were found, which signify potential considerations for clinical practice, the results from this study do not offer evidence that the probiotics used had a direct effect on depressive symptoms – they suggest that probiotics potentially act on cognitive processes contributing to depression which may include immune system activity, inflammation, and gut barrier integrity. Overall, this study offers evidence to indicate that probiotic consumption can exert change on cognitive patterns associated with depression. In clinical practice, probiotics may be a useful adjunct to potentiate the effects of therapies, such as CBT. Finally, the use of probiotics promotes the concept of managing physical health as part of mental health treatment.
Considerations for future research:
These preliminary results are promising and offer a number of future research and clinical avenues to build upon. The results do however, indicate that a longer trial may be needed to fully assess the effects of probiotics on mood and the mechanisms by which probiotics may be influencing this. The study also suggests that further research using a range of concentrations in a dose response study may be warranted to determine the optimal dose; a greater dose over a longer period may produce detectable changes in microbiota as well as further differences in psychological data.
Abstract
BACKGROUND Depression is the leading cause of disability worldwide; with evidence suggesting that decreased gut barrier function and inflammation are correlated with depressive symptoms. We conducted a clinical trial to determine the effect of consumption of probiotic supplements (Winclove's Ecologic® Barrier) on depressive symptoms in a sample of participants with mild to severe depression. METHOD 71 participants were randomly allocated to either probiotic or placebo, which was, consumed daily over eight weeks. Pre- and post-intervention measures of symptoms and vulnerability markers of depression as well as gut microbiota composition were compared. Clinical trial participants were also compared on psychological variables and gut microbiota composition to a non-depressed group (n = 20). RESULTS All clinical trial participants demonstrated improvement in symptoms, suggesting non-specific therapeutic effects associated with weekly monitoring visits. Participants in the probiotic group demonstrated a significantly greater reduction in cognitive reactivity compared with the placebo group, particularly in the mild/moderate subgroup. Probiotics did not significantly alter the microbiota of depressed individuals, however, a significant correlation was found between Ruminococcus gnavus and one depression metric. LIMITATIONS There was a high attrition rate, which may be attributed to weekly monitoring visits. Additionally, modulation of the gut microbiota may need more specific testing to distinguish subtle changes. CONCLUSIONS While microbiota composition was similar between all groups, probiotics did affect a psychological variable associated with susceptibility to depression. Further research is needed to investigate how probiotics can be utilised to modify mental wellbeing, and whether they can act as an adjunct to existing treatments.
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Stress matters: Randomized controlled trial on the effect of probiotics on neurocognition.
Papalini, S, Michels, F, Kohn, N, Wegman, J, van Hemert, S, Roelofs, K, Arias-Vasquez, A, Aarts, E
Neurobiology of stress. 2019;10:100141
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Increasing animal studies indicate the role of probiotics in regulating mood and cognition through the gut-brain axis, however in human studies evidence of this causal association is lacking. The aim of this double-blind, randomised, placebo-controlled intervention was to investigate the effects of probiotics on neurocognitive measures in 58 healthy participants. Participants were randomly assigned to either probiotic or placebo group and were tested once before and after the 28-day intervention. The neurocognitive outcomes measured included emotion reactivity, emotion regulation, cognitive control and the effects of acute stress on working memory. These were assessed through functional MRI (fMRI) and questionnaires. This study found when stress was induced, probiotic supplementation led to a significant improvement in working memory performance. Without stress, there was no causal association between neurocognitive outcomes and probiotic intake. Based on these results, the authors conclude that during challenging situations, probiotics can aid in buffering the detrimental effects of stress on cognition.
Abstract
Probiotics are microorganisms that provide health benefits when consumed. In animals, probiotics reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal stress response. However, in humans, a causal understanding of the gut-brain link in emotion and cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in presence of stress, remains unclear. We investigated the effects of a multispecies probiotic (Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-controlled, between-subjects intervention study, 58 healthy participants were tested once before and once after a 28-day intervention. Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures. However, relative to placebo, the probiotics group did show a significant stress-related increase in working memory performance after supplementation. This change was associated with intervention-related neural changes in frontal cortex during cognitive control exclusively in the probiotics group. Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under challenging situations, buffering against the detrimental effects of stress on cognition.
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Intestinal Permeability Measured by Urinary Sucrose Excretion Correlates with Serum Zonulin and Faecal Calprotectin Concentrations in UC Patients in Remission.
Wegh, CAM, de Roos, NM, Hovenier, R, Meijerink, J, Besseling-van der Vaart, I, van Hemert, S, Witteman, BJM
Journal of nutrition and metabolism. 2019;:2472754
Abstract
BACKGROUND AND AIMS Ulcerative colitis (UC) is associated with an increased intestinal permeability, possibly through a dysbiosis of intestinal bacteria. We investigated which markers are most relevant to assess intestinal permeability in UC patients and whether probiotics had an effect on these markers. METHODS In this twelve-week placebo-controlled randomized double-blind study, twenty-five subjects with UC in remission received either placebo or a multispecies probiotics. Samples of blood, urine, and faeces were taken at baseline, week 6, and week 12 to assess intestinal permeability and inflammation. Diaries and Bristol stool scale were kept to record stool frequency and consistency. Quality of life was scored from 32-224 with the inflammatory bowel disease questionnaire (IBD-Q). RESULTS This group of UC patients, in clinical remission, did not show increased intestinal permeability at baseline of this study. During the study, no significant group or time effects were found for intestinal permeability measured by the 5-sugar absorption test, serum zonulin, and faecal zonulin. Likewise, the inflammatory markers C-reactive protein (CRP), calprotectin, and the cytokines IFNγ, TNFα, IL-6, and IL-10 were not significantly affected. Stool frequency and consistency were not significantly affected either. The IBD-Q score, 194 for the probiotics group and 195 for the placebo group, remained unaffected. Correlations were tested between all outcomes; urinary sucrose excretion was significantly correlated with serum zonulin (r = 0.62) and faecal calprotectin (r = 0.55). Faecal zonulin was not significantly correlated with any of the other markers. CONCLUSION Serum zonulin may be a more relevant biomarker of intestinal permeability than faecal zonulin, due to its correlation with other biomarkers of intestinal permeability. UC patients in remission did not show an effect of the probiotic treatment or a change in gut permeability. This should not discourage further studies because effects might be present during active disease or shortly after a flare up.
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Dose-Dependent Effects of Multispecies Probiotic Supplementation on the Lipopolysaccharide (LPS) Level and Cardiometabolic Profile in Obese Postmenopausal Women: A 12-Week Randomized Clinical Trial.
Szulińska, M, Łoniewski, I, van Hemert, S, Sobieska, M, Bogdański, P
Nutrients. 2018;(6)
Abstract
During the postmenopausal period, the risk of cardiovascular diseases is increased in many obese women and is associated with a worse cardiometabolic profile and a sub-chronic low-grade systemic inflammation caused by a gut barrier permeability dysfunction. Here, we tested whether administration of two different dosages of the multispecies probiotic Ecologic® Barrier influenced the cardiometabolic biochemical parameters and lipopolysaccharide levels, the latter used as a marker of increased gut permeability in obese postmenopausal women. A total of 81 obese Caucasian postmenopausal women participated in the trial. The subjects were randomly assigned to three groups that received a placebo, a low dose (LD) (2.5 × 10⁸ colony forming units (CFU) per day), or a high dose (HD) (1 × 1010 CFU per day) of lyophilisate powder containing live multispecies probiotic bacteria. The probiotic supplement was administered each day in two equal portions for 12 weeks. We found significant (p < 0.05) favorable changes (mostly large or medium effects) in the evaluated parameters in both the HD and LD groups but not in the placebo group. In the HD group, lipopolysaccharide, waist, fat mass, subcutaneous fat, uric acid, total cholesterol, triglycerides, low-density lipoprotein cholesterol, glucose, insulin, and insulin-resistant index (HOMA-IR) were improved. Similar changes were observed in the LD group, except for lipopolysaccharide, uric acid, triglycerides, and glucose levels. Additionally, significant differences were observed in both groups in terms of fat percentage and visceral fat. When the mean changes were compared between the three groups, statistically significant differences in lipopolysaccharide levels, uric acid, glucose, insulin, and HOMA-IR were found. Post hoc tests revealed significant differences in the mean changes (mostly medium effects) between the HD and LD groups for uric acid, glucose, insulin, and HOMA-IR. In the 12-week randomized, placebo-controlled, double-blind intervention, we observed that supplementation with the multispecies probiotic Ecologic® Barrier favorably affected the risk factors in a dose-dependent manner, showing beneficial effects on the cardiometabolic parameters and gut permeability of the patients. Our results suggest that this product can be effective in the prevention and treatment of cardiovascular diseases in obese postmenopausal women.
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Microscopic colitis-microbiome, barrier function and associated diseases.
van Hemert, S, Skonieczna-Żydecka, K, Loniewski, I, Szredzki, P, Marlicz, W
Annals of translational medicine. 2018;(3):39
Abstract
Microscopic colitis (MC) is a chronic inflammatory bowel disease (IBD) with little in terms of endoscopic abnormalities and is frequently associated with other autoimmune diseases. The peak incidence of the disease is in middle aged or older populations, mostly females. The pathogenesis of MC is complex, multifactorial and poorly understood. Current concepts revolve around innate immunity or microbiome alterations as well as gut barrier dysfunction, all of which lead to the development of subtle inflammatory lesions in gut mucosa. The results of numerous basic and clinical studies involving molecular techniques as well as advanced endoscopic imaging revealed the important role of both intrinsic (e.g., hormonal) as well as extrinsic (e.g., NSAIDs and PPIs) factors in the modulation of gastrointestinal microbiome and MC pathogenesis. Capsule endoscopy as well confocal endomicroscopy imaging, alongside standard endoscopic techniques offer new tools in the evaluation of MC patients and allow their better stratification for novel treatment protocols based on modulation of gut microbiome and barrier function.
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From clinical uncertainties to precision medicine: the emerging role of the gut barrier and microbiome in small bowel functional diseases.
Marlicz, W, Yung, DE, Skonieczna-Żydecka, K, Loniewski, I, van Hemert, S, Loniewska, B, Koulaouzidis, A
Expert review of gastroenterology & hepatology. 2017;(10):961-978
Abstract
Over the last decade, remarkable progress has been made in the understanding of disease pathophysiology. Many new theories expound on the importance of emerging factors such as microbiome influences, genomics/omics, stem cells, innate intestinal immunity or mucosal barrier complexities. This has introduced a further dimension of uncertainty into clinical decision-making, but equally, may shed some light on less well-understood and difficult to manage conditions. Areas covered: Comprehensive review of the literature on gut barrier and microbiome relevant to small bowel pathology. A PubMed/Medline search from 1990 to April 2017 was undertaken and papers from this range were included. Expert commentary: The scenario of clinical uncertainty is well-illustrated by functional gastrointestinal disorders (FGIDs). The movement towards achieving a better understanding of FGIDs is expressed in the Rome IV guidelines. Novel diagnostic and therapeutic protocols focused on the GB and SB microbiome can facilitate diagnosis, management and improve our understanding of the underlying pathological mechanisms in FGIDs.
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The effects of a multispecies probiotic on migraine and markers of intestinal permeability-results of a randomized placebo-controlled study.
de Roos, NM, van Hemert, S, Rovers, JMP, Smits, MG, Witteman, BJM
European journal of clinical nutrition. 2017;(12):1455-1462
Abstract
BACKGROUND/OBJECTIVES Migraine, associated with several gastrointestinal disorders, may result from increased intestinal permeability, allowing endotoxins to enter the bloodstream. We tested whether probiotics could reduce migraine through an effect on intestinal permeability and inflammation. SUBJECTS/METHODS In total, 63 patients were randomly allocated to the probiotic (n=31) or the placebo group (n=32). Participants ingested a multispecies probiotic (5x109 colony-forming units) or placebo daily for 12 weeks. Migraine was assessed with the Migraine Disability Assessment Scale (MIDAS), the Headache Disability Inventory (HDI) and headache diaries. At baseline and 12 weeks, intestinal permeability was measured with the urinary lactulose/mannitol test and fecal and serum zonulin; inflammation was measured from interleukin (IL) -6, IL-10, tumor necrosis factor-α and C-reactive protein in serum. RESULTS The MIDAS migraine intensity score significantly decreased in both groups (P<0.001) and the HDI score significantly decreased in the probiotic group (P=0.032) and borderline in the placebo group (P=0.053). In the probiotics group, patients had a median of 6 migraine days in the first month, 4 in the second month (P=0.002) and 5 in the last month, which was not significantly different from the 5, 4, and 4 days in the placebo group. A ⩾2day reduction in migraine days was seen in 12/31 patients in the probiotics group versus 7/29 in the placebo group (ns). Probiotic use did not significantly affect medication use, intestinal permeability or inflammation compared to placebo. CONCLUSIONS In this study, we could not confirm significant benefit from a multispecies probiotic compared to a placebo on the outcome parameters of migraine and intestinal integrity.
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Microbes central to human reproduction.
Reid, G, Brigidi, P, Burton, JP, Contractor, N, Duncan, S, Fargier, E, Hill, C, Lebeer, S, Martín, R, McBain, AJ, et al
American journal of reproductive immunology (New York, N.Y. : 1989). 2015;(1):1-11
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Abstract
As studies uncover the breadth of microbes associated with human life, opportunities will emerge to manipulate and augment their functions in ways that improve health and longevity. From involvement in the complexities of reproduction and fetal/infant development, to delaying the onset of disease, and indeed countering many maladies, microbes offer hope for human well-being. Evidence is emerging to suggest that microbes may play a beneficial role in body sites traditionally viewed as being sterile. Although further evidence is required, we propose that much of medical dogma is about to change significantly through recognition and understanding of these hitherto unrecognized microbe-host interactions. A meeting of the International Scientific Association for Probiotics and Prebiotics held in Aberdeen, Scotland (June 2014), presented new views and challenged established concepts on the role of microbes in reproduction and health of the mother and infant. This article summarizes some of the main aspects of these discussions.
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The effects of the multispecies probiotic mixture Ecologic®Barrier on migraine: results of an open-label pilot study.
de Roos, NM, Giezenaar, CG, Rovers, JM, Witteman, BJ, Smits, MG, van Hemert, S
Beneficial microbes. 2015;(5):641-6
Abstract
Migraine prevalence is associated with gastrointestinal disorders. Possible underlying mechanisms could be increased gut permeability and inflammation. Probiotics may decrease intestinal permeability as well as inflammation, and therefore may reduce the frequency and/or intensity of migraine attacks. Therefore we assessed feasibility, possible clinical efficacy, and adverse reactions of probiotic treatment in migraine patients. 29 migraine patients took 2 g/d of a probiotic food supplement (Ecologic(®)Barrier, 2.5×10(9) cfu/g) during 12 weeks. Participants recorded frequency and intensity of migraine in a headache diary and completed the Migraine Disability Assessment Scale (MIDAS) and Henry Ford Hospital Headache Disability Inventory (HDI) at baseline and after 12 weeks of treatment. Compliance was measured every 4 weeks by counting the remaining sachets with probiotics. The study was completed by 27/29 (93%) patients who took 95% of the supplements. Obstipation was reported by 4 patients during the first 2 weeks of treatment only. The mean±standard deviation (SD) number of migraine days/month decreased significantly from 6.7±2.4 at baseline to 5.1±2.2 (P=0.008) in week 5-8 and 5.2±2.4 in week 9-12 (P=0.001). The mean±SD intensity of migraine decreased significantly from 6.3±1.5 at baseline to 5.5±1.9 after treatment (P=0.005). The MIDAS score improved from 24.8±25.5 to 16.6±13.5 (P=0.031). However, the mean HDI did not change significantly. In conclusion, probiotics may decrease migraine supporting a possible role for the intestine in migraine management. Feasibility and lack of adverse reactions justify further placebo-controlled studies.