Associations between various markers of intestinal barrier and immune function after a high-intensity exercise challenge.

Strenuous exercise can result in disruption of intestinal barrier function and occurrence of gastrointestinal symptoms. The aim of this exploratory study was to elucidate systemic effects of increased intestinal permeability after high-intensity exercise. Forty-one endurance-trained subjects performed a 60-min treadmill run at 80% VO2max. Small intestinal permeability was measured as urinary excretion ratio of lactulose/rhamnose (L/R). Blood, saliva and feces were analyzed for gut barrier and immune-related biomarkers. The exercise challenge increased several markers of intestinal barrier disruption, immune function and oxidative stress. We found a negative correlation between L/R ratio and uric acid (r = -0.480), as well as a positive correlation between the L/R ratio and fecal chromogranin A in male participants (r = 0.555). No significant correlations were found between any of the markers and gastrointestinal symptoms, however, perceived exertion correlated with the combination of IL-6, IL-10 and salivary cortisol (r = 0.492). The lack of correlation between intestinal permeability and gastrointestinal symptoms could be due to minor symptoms experienced in lab settings compared to real-life competitions. The correlation between L/R ratio and uric acid might imply a barrier-protective effect of uric acid, and inflammatory processes due to strenuous exercise seem to play an important role regarding physical exhaustion.

Hospital-treated infections and subsequent Parkinson's disease risk: a register-based sibling comparison study.

Serious infections may result in greater risk of Parkinson's disease. However, high-quality cohort studies focusing on a potential causal role of different types and sites of infection are lacking. Gastrointestinal infections are of a particular interest due to growing evidence implicating gut dysbiosis in Parkinson's disease aetiology. This population-based cohort study used the Swedish Total Population Register to identify individuals born during 1944-77 and resident in Sweden between 1990 and 2018 (N = 3 698 319). Hospital-treated infections at ages 21-30 and 31-40 years were identified from the National Patient Register. Participants were followed to identify Parkinson's disease diagnoses from age 41 years up to December 31, 2018, when the oldest individual reached 75 years. Cox regression with a sibling comparison design to tackle familial genetic and environmental confounding was used to derive hazard ratios and 95% confidence intervals for each infection site, type, or any infections at ages 21-30 and 31-40 years. During a median follow-up of 15.4 years, 8815 unique Parkinson's disease diagnoses were accrued, with a crude rate of 17.3 (95% confidence interval 17.0, 17.7) per 100 000 person-years. After controlling for shared familial factors, hospital-treated gastrointestinal and respiratory infections between 21 and 30 years of age were associated with a greater risk of Parkinson's disease [hazard ratios 1.35 (95% confidence interval: 1.05, 1.75) and 1.45 (95% confidence interval: 1.08, 1.95), respectively]; no association was found for any infections at age 31-40 [hazard ratio 1.05 (95% confidence interval: 0.93, 1.19)]. After adjustment, no statistically significant associations were observed for other sites including genitourinary and skin. These findings suggest that hospital-treated infections of the gastrointestinal tract and lungs, both of which may have an influence on the gut microbiome, by age 30 years may be risk factors for Parkinson's disease.

Limosilactobacillus reuteri DSM 17938 supplementation and SARS-CoV-2 specific antibody response in healthy adults: a randomized, triple-blinded, placebo-controlled trial.

Studies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 µg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 µg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168-1480] BAU/ml vs 111 [36.1-1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212-3449] BAU/ml vs (83.7 [22.8-2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9-976] BAU/ml vs 61.3 [26.7-97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.

Fecal microbiota transplantation for the treatment of irritable bowel syndrome: A systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is the most prevalent gastrointestinal disorder in developed countries and reduces patients' quality of life, hinders their ability to work, and increases health care costs. A growing number of trials have demonstrated an aberrant gut microbiota composition in IBS, also known as 'gut dysbiosis'. Fecal microbiota transplantation (FMT) has been suggested as a treatment for IBS. AIM: To assess the efficacy and safety of FMT for the treatment of IBS. METHODS: We searched Cochrane Central, MEDLINE, EMBASE and Web of Science up to 24 October 2022 for randomised controlled trials (RCTs) investigating the effectiveness of FMT compared to placebo (including autologous FMT) in treating IBS. The primary outcome was the number of patients with improvements of symptoms measured using a validated, global IBS symptoms score. Secondary outcomes were changes in quality-of-life scores, non-serious and serious adverse events. Risk ratios (RR) and corresponding 95%CI were calculated for dichotomous outcomes, as were the mean differences (MD) and 95%CI for continuous outcomes. The Cochrane risk of bias tool was used to assess the quality of the trials. GRADE criteria were used to assess the overall quality of the evidence. RESULTS: Eight RCTs (484 participants) were included in the review. FMT resulted in no significant benefit in IBS symptoms three months after treatment compared to placebo (RR 1.19, 95%CI: 0.68-2.10). Adverse events were reported in 97 participants in the FMT group and in 45 participants in the placebo group (RR 1.17, 95%CI: 0.63-2.15). One serious adverse event occurred in the FMT group and two in the placebo group (RR 0.42, 95%CI: 0.07-2.60). Endoscopic FMT delivery resulted in a significant improvement in symptoms, while capsules did not. FMT did not improve the quality of life of IBS patients but, instead, appeared to reduce it, albeit non significantly (MD -6.30, 95%CI: -13.39-0.79). The overall quality of the evidence was low due to moderate-high inconsistency, the small number of patients in the studies, and imprecision. CONCLUSION: We found insufficient evidence to support or refute the use of FMT for IBS. Larger trials are needed.

Potential Modulation of Inflammation and Physical Function by Combined Probiotics, Omega-3 Supplementation and Vitamin D Supplementation in Overweight/Obese Patients with Chronic Low-Grade Inflammation: A Randomized, Placebo-Controlled Trial.

Obesity is characterized by low-grade inflammation and increased gut permeability. Here, we aim to evaluate the effect of a nutritional supplement on these parameters in subjects with overweight and obesity. A double-blinded, randomized clinical trial was conducted in 76 adults with overweight or obesity (BMI 28 to 40) and low-grade inflammation (high-sensitivity C-reactive protein (hs-CRP) between 2 and 10 mg/L). The intervention consisted of a daily intake of a multi-strain probiotic of Lactobacillus and Bifidobacterium, 640 mg of omega-3 fatty acids (n-3 FAs), and 200 IU of vitamin D (n = 37) or placebo (n = 39), administered for 8 weeks. hs-CRP levels did not change post-intervention, other than an unexpected slight increase observed in the treatment group. Interleukin (IL)-6 levels decreased in the treatment group (p = 0.018). The plasma fatty acid (FA) levels of the arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio and n-6/n-3 ratio (p < 0.001) decreased, and physical function and mobility improved in the treatment group (p = 0.006). The results suggest that hs-CRP may not be the most useful inflammatory marker, but probiotics, n-3 FAs, and vitamin D, as non-pharmaceutical supplements, may exert modest effects on inflammation, plasma FA levels, and physical function in patients with overweight and obesity and associated low-grade inflammation.

Reviewing the state of the art of probiotics as clinical modalities for brain-gut-microbiota axis associated disorders.

The rise in prevalence of mental and neurological disorders is causing a high burden on society, however adequate interventions are not always available. The brain-gut-microbiota axis (BGMA) may provide a new angle for the development of clinical modalities. Due to the intricate bi-directional signaling between the brain and the gut, it may be helpful to look into interventions that target the gut, such as probiotics. Therefore, this review aimed to investigate the state of the art of probiotics and their potential as clinical modalities for BGMA-associated indications by gaining insight into patents and clinical trials that have been applied for and executed since 1999. A total of 565 patents and 390 clinical trials were found, focusing on probiotic applications for 83 indications. Since the start of the 21st century, the highest numbers of patents and clinical trials were related to primary neuropsychological, affective (depression, anxiety) and cognitive disorders, neurodegenerative and/or inflammatory brain disorders (Alzheimer's disease, Parkinson's disease, amongst others), and gastrointestinal disorders (irritable bowel syndrome). The locations where the most patents and clinical trials were registered included China, the United States, and Iran. From 1999 to ~2013 a slight growth could be seen in the numbers of patents and clinical trials, followed by an almost exponential growth from ~2013 onwards. Overall, the developments of the state of the art were in accordance with previous research, however it appeared that clinical trials showed a slightly slower growth compared to patents, which may have implications for the future implementation of probiotics as clinical modalities for BGMA-associated indications.

Potential Modulation of Inflammation by Probiotic and Omega-3 Supplementation in Elderly with Chronic Low-Grade Inflammation-A Randomized, Placebo-Controlled Trial.

Probiotic and omega-3 supplements have been shown to reduce inflammation, and dual supplementation may have synergistic health effects. We investigated if the novel combination of a multi-strain probiotic (containing B. lactis Bi-07, L. paracasei Lpc-37, L. acidophilus NCFM, and B. lactis Bl-04) alongside omega-3 supplements reduces low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) in elderly participants in a proof-of-concept, randomized, placebo-controlled, parallel study (NCT04126330). In this case, 76 community-dwelling elderly participants (median: 71.0 years; IQR: 68.0-73.8) underwent an intervention with the dual supplement (n = 37) or placebo (n = 39) for eight weeks. In addition to hs-CRP, cytokine levels and intestinal permeability were also assessed at baseline and after the eight-week intervention. No significant difference was seen for hs-CRP between the dual supplement group and placebo. However, interestingly, supplementation did result in significant increases in the level of the anti-inflammatory marker IL-10. In addition, dual supplementation increased levels of valeric acid, further suggesting the potential of the supplements in reducing inflammation and conferring health benefits. Together, the results suggest that probiotic and omega-3 dual supplementation exerts modest effects on inflammation and may have potential use as a non-pharmacological treatment for low-grade inflammation in the elderly.

Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism.

Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.

Multi-Strain Probiotic Mixture Affects Brain Morphology and Resting State Brain Function in Healthy Subjects: An RCT.

Probiotics can alter brain function via the gut-brain axis. We investigated the effect of a probiotic mixture containing Bifidobacterium longum, Lactobacillus helveticus and Lactiplantibacillus plantarum. In a randomized, placebo-controlled, double-blinded crossover design, 22 healthy subjects (6 m/16 f; 24.2 ± 3.4 years) underwent four-week intervention periods with probiotics and placebo, separated by a four-week washout period. Voxel-based morphometry indicated that the probiotic intervention affected the gray matter volume of a cluster covering the left supramarginal gyrus and superior parietal lobule (p < 0.0001), two regions that were also among those with an altered resting state functional connectivity. Probiotic intervention resulted in significant (FDR < 0.05) functional connectivity changes between regions within the default mode, salience, frontoparietal as well as the language network and several regions located outside these networks. Psychological symptoms trended towards improvement after probiotic intervention, i.e., the total score of the Hospital Anxiety and Depression Scale (p = 0.056) and its depression sub-score (p = 0.093), as well as sleep patterns (p = 0.058). The probiotic intervention evoked distinct changes in brain morphology and resting state brain function alongside slight improvements of psycho(bio)logical markers of the gut-brain axis. The combination of those parameters may provide new insights into the modes of action by which gut microbiota can affect gut-brain communication and hence brain function.

Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses Toward an Emotional Task in Healthy Subjects: A Randomized Clinical Trial.

Background: Evidence from preclinical studies suggests that probiotics affect brain function via the microbiome-gut-brain axis, but evidence in humans remains limited. Objective: The present proof-of-concept study investigated if a probiotic product containing a mixture of Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 (in total 3 × 109 CFU/day) affected functional brain responses in healthy subjects during an emotional attention task. Design: In this double-blinded, randomized, placebo-controlled crossover study (Clinicaltrials.gov, NCT03615651), 22 healthy subjects (24.2 ± 3.4 years, 6 males/16 females) were exposed to a probiotic intervention and a placebo for 4 weeks each, separated by a 4-week washout period. Subjects underwent functional magnetic resonance imaging while performing an emotional attention task after each intervention period. Differential brain activity and functional connectivity were assessed. Results: Altered brain responses were observed in brain regions implicated in emotional, cognitive and face processing. Increased activation in the orbitofrontal cortex, a region that receives extensive sensory input and in turn projects to regions implicated in emotional processing, was found after probiotic intervention compared to placebo using a cluster-based analysis of functionally defined areas. Significantly reduced task-related functional connectivity was observed after the probiotic intervention compared to placebo. Fecal microbiota composition was not majorly affected by probiotic intervention. Conclusion: The probiotic intervention resulted in subtly altered brain activity and functional connectivity in healthy subjects performing an emotional task without major effects on the fecal microbiota composition. This indicates that the probiotic effects occurred via microbe-host interactions on other levels. Further analysis of signaling molecules could give possible insights into the modes of action of the probiotic intervention on the gut-brain axis in general and brain function specifically. The presented findings further support the growing consensus that probiotic supplementation influences brain function and emotional regulation, even in healthy subjects. Future studies including patients with altered emotional processing, such as anxiety or depression symptoms are of great interest. Clinical Trial Registration: [http://clinicaltrials.gov/], identifier [NCT03615651].

Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses to an Arithmetic Stress Task in Healthy Subjects: A Randomised Clinical Trial and Proof-of-Concept Study.

Probiotics are suggested to impact physiological and psychological stress responses by acting on the gut-brain axis. We investigated if a probiotic product containing Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 affected stress processing in a double-blinded, randomised, placebo-controlled, crossover proof-of-concept study (NCT03615651). Twenty-two healthy subjects (24.2 ± 3.4 years, 6 men/16 women) underwent a probiotic and placebo intervention for 4 weeks each, separated by a 4-week washout period. Subjects were examined by functional magnetic resonance imaging while performing the Montreal Imaging Stress Task (MIST) as well as an autonomic nervous system function assessment during the Stroop task. Reduced activation in regions of the lateral orbital and ventral cingulate gyri was observed after probiotic intervention compared to placebo. Significantly increased functional connectivity was found between the upper limbic region and medioventral area. Interestingly, probiotic intervention seemed to predominantly affect the initial stress response. Salivary cortisol secretion during the task was not altered. Probiotic intervention did not affect cognitive performance and autonomic nervous system function during Stroop. The probiotic intervention was able to subtly alter brain activity and functional connectivity in regions known to regulate emotion and stress responses. These findings support the potential of probiotics as a non-pharmaceutical treatment modality for stress-related disorders.

Nutritional status in older people - An explorative analysis.

BACKGROUND & AIMS: The nutritional status is seldom defined in general, but is considered to be important throughout life span, especially in times of diseases and disabilities. We previously proposed a theoretical model of the nutritional status from a functional perspective [1], however without proposing a definition of the nutritional status. The model comprises four domains that might affect the nutritional and functional status in a bidirectional way. These four domains are: Food and nutrition; Health and somatic disorders; Physical function and capacity; and Cognitive, affective, and sensory function. This study contributes to the existing literature and knowledge by empirically analysing patterns and relationships of possible nutritional status indicators within and between the four domains. METHODS: This study is based on a sample of 69 men and women; older than 65 years, receiving home health care. They were followed up for three years. A broad set of nutritional status indicators in the participants were assessed in their home yearly. Given the small sample size and large number of variables, we used both correlation and factor analysis to explore patterns of nutritional status indicators within the four domains and relationships between the four domains suggested by the theoretical model of nutritional status which we proposed earlier. RESULTS: At baseline, between 4 and 18 components were extracted from the four domains, separately, using factor analysis. The first three components of each domain (called main components) were correlated (p < 0.05) with at least one of the main components of each of the other three domains (r = -0.34-0.79 at baseline, 0.38-0.74 at year 1, 0.40-0.77 at year 2 and 0.47-0.71 at year 3). At baseline, these main components explained, respectively, 31%, 52%, 57% and 63% of the sample variation in the four domains. This remained stable throughout all three years of follow up. In all four domains, there were statistically significant differences in prevalence of malnutrition, frailty, sarcopenia, and dehydration (all different inadequate nutritional status) between individuals' individual component scores. CONCLUSIONS: This study provides empirical evidence for the relationship between nutritional status indicators within and between the four domains suggested by our theoretical model of nutritional status. Components in all four domains were associated with inadequate nutritional status, highlighting that a wide perspective of the nutritional status assessment is necessary to be applied in clinical practice.

The use of Faecal Microbiota Transplantation (FMT) in Europe: A Europe-wide survey.

BACKGROUND: Faecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe. METHODS: We invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT. FINDINGS: In 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10-64) FMT procedures; 1,077 (57%) with Clostridioides difficile infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0•3%) unaccounted for. Adjusted to population size, 0•257 per 100,000 population received FMT for CDI and 0•189 per 100,000 population for experimental indications. With estimated 12,400 (6,100-28,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres. INTERPRETATION: FMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need. FUNDING: NordForsk under the Nordic Council and Innovation Fund Denmark (j.no. 8056-00006B).

Sauna dehydration as a new physiological challenge model for intestinal barrier function.

The intestinal barrier plays a crucial role in maintaining gut health, and an increased permeability has been linked to several intestinal and extra-intestinal disorders. There is an increasing demand for interventions aimed at strengthening this barrier and for in vivo challenge models to assess their efficiency. This study investigated the effect of sauna-induced dehydration on intestinal barrier function (clinicaltrials.gov: NCT03620825). Twenty healthy subjects underwent three conditions in random order: (1) Sauna dehydration (loss of 3% body weight), (2) non-steroidal anti-inflammatory drug (NSAID) intake, (3) negative control. Intestinal permeability was assessed by a multi-sugar urinary recovery test, while intestinal damage, bacterial translocation and cytokines were assessed by plasma markers. The sauna dehydration protocol resulted in an increase in gastroduodenal and small intestinal permeability. Presumably, this increase occurred without substantial damage to the enterocytes as plasma intestinal fatty acid-binding protein (I-FABP) and liver fatty acid-binding protein (L-FABP) were not affected. In addition, we observed significant increases in levels of lipopolysaccharide-binding protein (LBP), IL-6 and IL-8, while sCD14, IL-10, IFN-É£ and TNF-α were not affected. These results suggest that sauna dehydration increased intestinal permeability and could be applied as a new physiological in vivo challenge model for intestinal barrier function.

Dehydration and loss of appetite: Key nutrition features in older people receiving home health care.

OBJECTIVES: The aim was to describe a population of older people in home health care based on what is probably a novel theoretical model, previously published, and to analyze longitudinal changes in different dimensions of nutritional status. METHODS: This explorative and longitudinal study examines nutritional status based on four domains in the novel theoretical model: health and somatic disorders; cognitive, affective, and sensory function; physical function and capacity; and food and nutrition. Inclusion criteria were age ≥65 y and need of home health care for more than three months. A total of 69 men and women were enrolled in the study. Participants' nutritional status was studied at baseline and regularly during the following three years. RESULTS: At baseline, 44% (n = 27) reported one or more severe symptoms and 83% had polypharmacy (≥5 prescribed medications). The prevalence of malnutrition, sarcopenia, frailty, and dehydration at baseline were, respectively, 83% (n = 35), 44% (n = 24), 34% (n = 18), and 45% (n = 25). Participants that died during the 3-y follow-up (n = 14) differed from survivors in the following aspects: more reduced appetite, lower quality of life, worse cognitive function, lower physical activity, and less intake of dietary fiber and water. Dehydration at baseline was associated with lower function in several domains and with general decline over time. CONCLUSIONS: Most participants had poor nutritional status. Dehydration and reduced appetite were important indicators of worsening nutritional and overall status and mortality.

Short intense psychological stress induced by skydiving does not impair intestinal barrier function.

BACKGROUND AND AIM: Psychological stress has been shown to increase intestinal permeability and is associated with the development of gastrointestinal disorders. This study aimed to investigate skydiving as an alternative model to analyse the effect of acute psychological stress on intestinal barrier function. MATERIALS AND METHODS: Twenty healthy subjects participated in a tandem skydive followed by a negative control visit, of which 19 (9 females and 10 males, 25.9 ± 3.7 years) were included in the study. Intestinal permeability was assessed by a multi-sugar urinary recovery test. Sucrose recovery and lactulose/rhamnose ratio in 0-5h urine indicated gastroduodenal and small intestinal permeability, respectively, and sucralose/erythritol ratio in 5-24h urine indicated colonic permeability. Blood samples were taken to assess markers associated with barrier function. This study has been registered at ClinicalTrials.gov (NCT03644979) on August 23, 2018. RESULTS: Skydiving resulted in a significant increase in salivary cortisol levels directly after skydiving compared to the control visit. Cortisol levels were still increased two hours after landing, while cortisol levels before skydiving were not significantly different from the baseline at the control visit. Skydiving did not induce a significant increase in gastroduodenal, small intestinal or colonic permeability. There was also no significant increase in plasma intestinal and liver fatty acid-binding proteins, suggesting no damage to the enterocytes. DISCUSSION: These results show that the acute intense psychological stress induced by skydiving does not affect intestinal permeability in healthy subjects. Future models aiming to investigate the effect of stress on human intestinal barrier function should consider a more sustained exposure to the psychological stressor.

Using naso- and oro-intestinal catheters in physiological research for intestinal delivery and sampling in vivo: practical and technical aspects to be considered.

Intestinal catheters have been used for decades in human nutrition, physiology, pharmacokinetics, and gut microbiome research, facilitating the delivery of compounds directly into the intestinal lumen or the aspiration of intestinal fluids in human subjects. Such research provides insights about (local) dynamic metabolic and other intestinal luminal processes, but working with catheters might pose challenges to biomedical researchers and clinicians. Here, we provide an overview of practical and technical aspects of applying naso- and oro-intestinal catheters for delivery of compounds and sampling luminal fluids from the jejunum, ileum, and colon in vivo. The recent literature was extensively reviewed, and combined with experiences and insights we gained through our own clinical trials. We included 60 studies that involved a total of 720 healthy subjects and 42 patients. Most of the studies investigated multiple intestinal regions (24 studies), followed by studies investigating only the jejunum (21 studies), ileum (13 studies), or colon (2 studies). The ileum and colon used to be relatively inaccessible regions in vivo. Custom-made state-of-the-art catheters are available with numerous options for the design, such as multiple lumina, side holes, and inflatable balloons for catheter progression or isolation of intestinal segments. These allow for multiple controlled sampling and compound delivery options in different intestinal regions. Intestinal catheters were often used for delivery (23 studies), sampling (10 studies), or both (27 studies). Sampling speed decreased with increasing distance from the sampling syringe to the specific intestinal segment (i.e., speed highest in duodenum, lowest in ileum/colon). No serious adverse events were reported in the literature, and a dropout rate of around 10% was found for these types of studies. This review is highly relevant for researchers who are active in various research areas and want to expand their research with the use of intestinal catheters in humans in vivo.

Feasibility and Acceptability of a Healthy Nordic Diet Intervention for the Treatment of Depression: A Randomized Controlled Pilot Trial.

Healthy diet interventions have been shown to improve depressive symptoms, but there is a need for randomized controlled trials (RCTs) that are double blind and investigate biological mechanisms. The primary objectives of this randomized controlled pilot trial were to test the palatability of the meals and the acceptability of the intervention in preparation for an 8-week RCT in the future, which will investigate whether a healthy Nordic diet improves depressive symptoms in individuals with major depressive disorder, and associated biological mechanisms. Depressed (n = 10) and non-depressed (n = 6) women and men were randomized to receive either a healthy Nordic diet (ND) or a control diet (CD) for 8 days. Participants were blinded to their diet allocation and the study hypotheses. Health questionnaires were completed before and after the intervention and, throughout the study, questionnaires assessed participants' liking for the meals, their sensory properties, adherence, and open-ended feedback. In the ND group, 75% of participants consumed only the provided foods, as instructed, compared to 50% of CD participants. The meals of both diets, on average, received good ratings for liking and sensory properties, though the ND ratings were somewhat higher. Overall, results were positive and informative, indicating that the planned RCT will be feasible and well-accepted, with some proposed modifications.

Butyrate Rescues Oxidative Stress-Induced Transport Deficits of Tryptophan: Potential Implication in Affective or Gut-Brain Axis Disorders.

INTRODUCTION: Butyrate is a short-chain fatty acid metabolite produced by microbiota in the colon. With its antioxidant properties, butyrate has also been shown to alter the neurological functions in affective disorder models, suggesting it as a key mediator in gut-brain interactions. OBJECTIVE: Here, we evaluated the negative effect of oxidative stress on the transport of the serotonin precursor tryptophan as present in affective disorders. Butyrate was hypothesized to be able to rescue these deficits due to its antioxidative capacities and its effect on transmembrane transport of tryptophan. Human skin-derived fibroblasts were used as cellular models to address these objectives. METHODS: Human fibroblasts were treated with hydrogen peroxide to induce oxidative stress. Stressed as well as control cells were treated with different concentrations of butyrate. Tryptophan (3H) was used as a tracer to measure the transport of tryptophan across the cell membranes (n = 6). Furthermore, gene expression profiles of different amino acid transporters were analyzed (n = 2). RESULTS: As hypothesized,oxidative stress significantly decreased the uptake of tryptophan in fibroblast cells, while butyrate counteracted this effect. Oxidative stress did not alter the gene expression profile of amino acid transporters. However, treatment of stressed and control cells with different concentrations of butyrate differentially regulated the gene expression of large amino acid transporters 1 and 2, which are the major transporters of tryptophan. CONCLUSIONS: Gut microbiota-derived butyrate may have therapeutic potential in affective disorders characterized by either aberrant serotonergic activity or neuroinflammation due to its role in rescuing the oxidative stress-induced perturbations of tryptophan transport.