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Colonic butyrate administration modulates fear memory but not the acute stress response in men: A randomized, triple-blind, placebo-controlled trial.
Dalile, B, Fuchs, A, La Torre, D, Vervliet, B, Van Oudenhove, L, Verbeke, K
Progress in neuro-psychopharmacology & biological psychiatry. 2024;:110939
Abstract
Short-chain fatty acids (SCFAs) are produced in the colon following bacterial fermentation of dietary fiber and are important microbiota-gut-brain messengers. However, their mechanistic role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is scarcely studied in humans. We have previously shown that colonic administration of a SCFA mixture (acetate, propionate, butyrate) lowers the cortisol response to stress in healthy participants, but does not impact fear conditioning and extinction. To disentangle the effects of the three main SCFAs, we examined whether butyrate alone would similarly modulate these psychobiological responses in a randomized, triple-blind, placebo-controlled intervention study in 71 healthy male participants (Mage = 25.2, MBMI = 22.7 [n = 35 butyrate group, n = 36 placebo group]). Colon-delivery capsules with pH-dependent coating were used to administer 5.28 g of butyrate or placebo daily for one week. Butyrate administration significantly increased serum butyrate concentrations without modulating serum acetate or propionate, nor fecal SCFAs. Butyrate administration also significantly modulated fear memory at the subjective but not physiological levels. Contrary to expectations, no changes in subjective nor neuroendocrine responses to acute stress were evident between the treatment groups from pre- to post-intervention. We conclude that colonic butyrate administration alone is not sufficient to modulate psychobiological stress responses, unlike administration of a SCFA mixture. The influence of colonic and systemic butyrate on fear memory and the persistence of fear extinction should be further systematically investigated in future studies.
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The role of short-chain fatty acids (SCFAs) in regulating stress responses, eating behavior, and nutritional state in anorexia nervosa: protocol for a randomized controlled trial.
Quagebeur, R, Dalile, B, Raes, J, Van Oudenhove, L, Verbeke, K, Vrieze, E
Journal of eating disorders. 2023;(1):191
Abstract
OBJECTIVE This protocol proposes investigating the effects of short-chain fatty acids (SCFAs)-namely acetate, propionate, and butyrate-as mediators of microbiota-gut-brain interactions on the acute stress response, eating behavior, and nutritional state in malnourished patients with anorexia nervosa (AN). SCFAs are produced by bacterial fermentation of dietary fiber in the gut and have recently been proposed as crucial mediators of the gut microbiota's effects on the host. Emerging evidence suggests that SCFAs impact human psychobiology through endocrine, neural, and immune pathways and may regulate stress responses and eating behavior. METHOD We will conduct a randomized, triple-blind, placebo-controlled trial in 92 patients with AN. Patients will receive either a placebo or a mixture of SCFAs (acetate propionate, butyrate) using pH-dependent colon-delivery capsules for six weeks. This clinical trial is an add-on to the standard inpatient psychotherapeutic program focusing on nutritional rehabilitation. HYPOTHESES We hypothesize that colonic SCFAs delivery will modulate neuroendocrine, cardiovascular, and subjective responses to an acute laboratory psychosocial stress task. As secondary outcome measures, we will assess alterations in restrictive eating behavior and nutritional status, as reflected by changes in body mass index. Additionally, we will explore changes in microbiota composition, gastrointestinal symptoms, eating disorder psychopathology, and related comorbidities. DISCUSSION The findings of this study would enhance our understanding of how gut microbiota-affiliated metabolites, particularly SCFAs, impact the stress response and eating behavior of individuals with AN. It has the potential to provide essential insights into the complex interplay between the gut, stress system, and eating behavior and facilitate new therapeutic targets for stress-related psychiatric disorders. This protocol is prospectively registered with ClinicalTrials.gov, with trial registration number NCT06064201.
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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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Plain language summary
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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Promotion of starch retrogradation by enzymatic elongation of amylopectin chains does not reduce glycemic responses: a randomized cross-over clinical trial.
Korompokis, K, Delcour, JA, Verbeke, K
Food & function. 2023;(9):4280-4287
Abstract
The molecular structure of amylopectin (AP) governs the propensity of its chains to re-associate into crystalline arrangements after starch gelatinization. Amylose (AM) crystallization and AP re-crystallization (i.e. retrogradation) decrease starch digestibility. The aim of this work was to enzymatically elongate AP chains using an amylomaltase (AMM, i.e. 4-α-glucanotransferase) from Thermus thermophilus to promote AP retrogradation and to investigate the impact thereof on in vivo glycemic responses in healthy subjects. Participants (n = 32) consumed two oatmeal porridges (containing 22.5 g available carbohydrates) prepared with or without the enzymatic modification and stored at 4 °C for 24 h. Finger-prick blood samples were taken fasting and at intervals during 3 h following test-meal consumption. The incremental area under the curve (iAUC0-180) was determined. The AMM was very effective at elongating the AP chains at the expense of AM, resulting in increased retrogradation capacity upon storage at low temperature. Nevertheless, postprandial glycemic responses were not different after consumption of either the AMM modified oatmeal porridge or its unmodified counterpart (iAUC0-180 = 73 ± 30 vs. 82 ± 43 mmol min L-1, respectively; p = 0.17). Unexpectedly, promoting starch retrogradation by selectively modifying its molecular structure did not result in reduced glycemic responses, challenging the notion that starch retrogradation negatively impacts glycemic responses in vivo.
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Combining dietary fibres to reduce intestinal gas production in patients with IBS.
Verbeke, K
Gut. 2022;(5):848-849
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Extruded Wheat Bran Consumption Increases Serum Short-Chain Fatty Acids but Does Not Modulate Psychobiological Functions in Healthy Men: A Randomized, Placebo-Controlled Trial.
Dalile, B, La Torre, D, Kalc, P, Zoppas, F, Roye, C, Loret, C, Lamothe, L, Bergonzelli, G, Courtin, CM, Vervliet, B, et al
Frontiers in nutrition. 2022;:896154
Abstract
BACKGROUND Incorporation of wheat bran (WB) into food products increases intake of dietary fiber, which has been associated with improved mood and cognition and a lower risk for psychiatric disorders such as depression, with short-chain fatty acids (SCFAs) as candidate mediators of these effects. Modifying WB using extrusion cooking increases SCFA production in vitro relative to unmodified WB. OBJECTIVE The aim of this study was to evaluate the effects of extruded WB on psychobiological functioning and the mediating role of SCFAs. METHODS In a randomized, triple-blind, placebo-controlled trial, 69 healthy male participants consumed 55 g of breakfast cereal containing either extruded WB or placebo daily for 28 days. At pre- and post-intervention visits, the cortisol response to experimentally induced stress was measured as a primary outcome. In addition, serum SCFAs and brain-derived neurotrophic factors were quantified as potential mediators. Secondary psychobiological outcomes included subjective stress responses, responses to experimentally induced fear, cortisol awakening response, heart rate variability, and retrospective subjective mood ratings. Intestinal permeability, fecal SCFAs, and stool consistency were measured as secondary biological outcomes. RESULTS Extruded WB increased serum acetate and butyrate (p < 0.05). None of the primary or secondary outcomes were affected by the intervention. Participants who consumed a placebo exhibited an increase in the percentage of fecal dry weight but did not report increased constipation. Despite these statistically significant effects, these changes were small in magnitude. CONCLUSIONS Extruded WB consumption increased serum short-chain fatty acids but did not modulate psychobiological functions in healthy men. Effective modulation of psychobiological functions may require greater increases in SCFAs than those achieved following extruded WB consumption. Rather than attempting to induce health benefits with a single fiber-rich food, combinations of different fibers, particularly highly fermentable ones, might be needed to further increase SCFA production and uptake in the systemic circulation to observe an effect on psychobiological processes.
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Lactobacillus rhamnosus CNCM I-3690 decreases subjective academic stress in healthy adults: a randomized placebo-controlled trial.
Wauters, L, Van Oudenhove, L, Accarie, A, Geboers, K, Geysen, H, Toth, J, Luypaerts, A, Verbeke, K, Smokvina, T, Raes, J, et al
Gut microbes. 2022;14(1):2031695
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Previous research has shown a bidirectional relationship between the gut and psychological stress, which could be mediated by intestinal permeability followed by an immune and inflammatory response. However, the exact mechanisms of this relationship are yet to be elucidated. This randomised, double-blind, placebo-controlled trial evaluated the beneficial effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal permeability and stress markers during a public speech in healthy students. Participants consumed either milk containing Lactobacillus rhamnosus CNCM I-3690 or acidified milk twice daily for four weeks to assess subjective and objective stress markers and markers of intestinal permeability. Lactobacillus rhamnosus CNCM I-3690 reduced the stress-induced hyperpermeability to mannitol and subjective stress markers (State-Trait Anxiety Inventory/ STAI). A subgroup of healthy students with stress-induced cortisol >P90 of baseline showed a reduction in perceived stress score following Lactobacillus rhamnosus CNCM I-3690 intervention. To evaluate the additional effects of Lactobacillus rhamnosus CNCM I-3690 on stress and gut health, further robust studies are needed. Healthcare professionals can use the findings of this study to understand the anxiolytic effects of Lactobacillus rhamnosus CNCM I-3690.
Abstract
Psychological stress negatively affects the intestinal barrier function in animals and humans. We aimed to study the effect of Lactobacillus rhamnosus CNCM I-3690 on intestinal permeability and stress-markers during public speech. Healthy students were randomized to L. rhamnosus-containing (test) or acidified (placebo) milk consumed twice daily for 4 weeks, with 46 subjects per treatment group. Small intestinal permeability was quantified by a 2 h urinary lactulose-mannitol ratio (LMR, primary outcome), fractional excretion of lactulose (FEL) and mannitol (FEM). Salivary cortisol, State-Trait Anxiety Inventory (STAI) and Perceived Stress scores (PSS) were collected. No between-treatment differences were found for LMR (p = .71), FEL or FEM. Within-treatment analyses showed similar LMR and FEL but a stress-induced increase of FEM with the placebo (p < .05) but not test product. Despite a similar increase in salivary cortisol, the stress-induced increase in STAI was significantly lower with the test product vs. placebo (p = .01). Moreover, a stress-preventative effect of the probiotic was found for PSS and more pronounced in subjects with high stress-induced cortisol (p = .01). While increased FEM was mediated by salivary cortisol levels, the effect of the test product on subjective stress was not mediated by changes in FEM. No serious adverse events occurred. In conclusion, we demonstrated that L. rhamnosus CNCM I-3690 prevented stress-induced hyperpermeability to mannitol. Subjective but not objective stress-markers were reduced with L. rhamnosus vs. placebo, suggesting anxiolytic effects, which were independent of barrier stabilization and attractive for the reduction of stress in both health and disease. Clinicaltrials.gov, number NCT03408691.
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Structural factors governing starch digestion and glycemic responses and how they can be modified by enzymatic approaches: A review and a guide.
Korompokis, K, Verbeke, K, Delcour, JA
Comprehensive reviews in food science and food safety. 2021;(6):5965-5991
Abstract
Starch is the most abundant glycemic carbohydrate in the human diet. Consumption of starch-rich food products that elicit high glycemic responses has been linked to the occurrence of noncommunicable diseases such as cardiovascular disease and diabetes mellitus type II. Understanding the structural features that govern starch digestibility is a prerequisite for developing strategies to mitigate any negative health implications it may have. Here, we review the aspects of the fine molecular structure that in native, gelatinized, and gelled/retrograded starch directly impact its digestibility and thus human health. We next provide an informed guidance for lowering its digestibility by using specific enzymes tailoring its molecular and three-dimensional supramolecular structure. We finally discuss in vivo studies of the glycemic responses to enzymatically modified starches and relevant food applications. Overall, structure-digestibility relationships provide opportunities for targeted modification of starch during food production and improving the nutritional profile of starchy foods.
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Dietary fibre and the gut-brain axis: microbiota-dependent and independent mechanisms of action.
La Torre, D, Verbeke, K, Dalile, B
Gut microbiome (Cambridge, England). 2021;:e3
Abstract
Dietary fibre is an umbrella term comprising various types of carbohydrate polymers that cannot be digested nor absorbed by the human small intestine. Consumption of dietary fibre is linked to beneficial effects on cognitive and affective processes, although not all fibres produce the same effects. Fibres that increase short-chain fatty acid (SCFA) production following modulation of the gut microbiota are thought to be the most potent fibres to induce effects on cognitive and affective processes. SCFAs can exert their effects by improving central, peripheral and systemic immunity, lowering hypertension and enhancing intestinal barrier integrity. Here, we propose additional mechanisms by which dietary fibres may contribute to improvements in affective and cognitive processes. Fibre-induced modulation of the gut microbiota may influence affective processes and cognition by increasing brain-derived neurotrophic factor levels. Depending on the physicochemical properties of dietary fibre, additional effects on affect and cognition may occur via non-microbiota-related routes, such as enhancement of the immune system and lowering cholesterol levels and subsequently lowering blood pressure. Mechanistic randomised placebo-controlled trials are needed to establish the effects of dietary fibre consumption and the magnitude of explained variance in affect and cognition when incorporating measurements of microbiota-dependent and microbiota-independent mechanisms in humans.
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European guideline on indications, performance and clinical impact of 13 C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC.
Keller, J, Hammer, HF, Afolabi, PR, Benninga, M, Borrelli, O, Dominguez-Munoz, E, Dumitrascu, D, Goetze, O, Haas, SL, Hauser, B, et al
United European gastroenterology journal. 2021;(5):598-625
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Abstract
INTRODUCTION 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed. RESULTS The guideline gives an overview over general methodology of 13 C-breath testing and provides recommendations for the use of 13 C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of 13 C-breath testing are summarized briefly. The recommendations specifically detail when and how individual 13 C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results. CONCLUSION This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of 13 C-breath tests.
