Bifidobacteriumbreve Bif195 Protects Against Small-Intestinal Damage Caused by Acetylsalicylic Acid in Healthy Volunteers.

BACKGROUND & AIMS: Enteropathy and small-intestinal ulcers are common adverse effects of nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (ASA). Safe, cytoprotective strategies are needed to reduce this risk. Specific bifidobacteria might have cytoprotective activities, but little is known about these effects in humans. We used serial video capsule endoscopy (VCE) to assess the efficacy of a specific Bifidobacterium strain in healthy volunteers exposed to ASA. METHODS: We performed a single-site, double-blind, parallel-group, proof-of-concept analysis of 75 heathy volunteers given ASA (300 mg) daily for 6 weeks, from July 31 through October 24, 2017. The participants were randomly assigned (1:1) to groups given oral capsules of Bifidobacterium breve (Bif195) (≥5 × 1010 colony-forming units) or placebo daily for 8 weeks. Small-intestinal damage was analyzed by serial VCE at 6 visits. The area under the curve (AUC) for intestinal damage (Lewis score) and the AUC value for ulcers were the primary and first-ranked secondary end points of the trial, respectively. RESULTS: Efficacy data were obtained from 35 participants given Bif195 and 31 given placebo. The AUC for Lewis score was significantly lower in the Bif195 group (3040 ± 1340 arbitrary units) than the placebo group (4351 ± 3195) (P = .0376). The AUC for ulcer number was significantly lower in the Bif195 group (50.4 ± 53.1 arbitrary units) than in the placebo group (75.2 ± 85.3 arbitrary units) (P = .0258). Twelve adverse events were reported from the Bif195 group and 20 from the placebo group. None of the events was determined to be related to Bif195 intake. CONCLUSIONS: In a randomized, double-blind trial of healthy volunteers, we found oral Bif195 to safely reduce the risk of small-intestinal enteropathy caused by ASA. ClinicalTrials.gov no: NCT03228589.

Identification of AICP as a GluN2C-Selective N-Methyl-d-Aspartate Receptor Superagonist at the GluN1 Glycine Site.

N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention as therapeutic targets. In this regard, administration of d-cycloserine (DCS), which is a glycine site NMDA receptor agonist, can enhance extinction of conditioned fear responses. The intriguing behavioral effects of DCS have been linked to its unique pharmacological profile among NMDA receptor subtypes (GluN1/2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared with glycine and a partial agonist at GluN2B-containing receptors. Here, we identify (R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) as a glycine site agonist with unique GluN2-dependent differences in agonist efficacy at recombinant NMDA receptor subtypes. AICP is a full agonist at GluN1/2A (100% response compared with glycine), a partial agonist at GluN1/2B and GluN1/2D (10% and 27%, respectively), and a highly efficacious superagonist at GluN1/2C receptors (353%). Furthermore, AICP potencies are enhanced compared with DCS with EC50 values in the low nanomolar range (1.7 nM at GluN1/2C). We show that GluN1/2C superagonism of AICP and DCS is mediated by overlapping but distinct mechanisms and that AICP selectively enhances responses from recombinant GluN1/2C receptors in the presence of physiological glycine concentrations. This functional selectivity of AICP for GluN2C-containing NMDA receptors is more pronounced compared with DCS, suggesting that AICP can be a useful tool compound for uncovering the roles of GluN2C subunits in neuronal circuit function and in the development of new therapeutic strategies.

Bifidobacterium breve Bif195 ameliorates aspirin-induced gastric mucosal damage: A randomised, double blind, placebo-controlled crossover trial.

BACKGROUND: Gastric and duodenal ulcerations are common during multiple-dosing aspirin treatment, such as for prevention of cardiovascular disease. On capsule endoscopy, oral administration of the bacterial strain Bifidobacterium breve Bif195 (DSM 33360) reduced the risk of aspirin-induced small intestinal damage, without affecting cyclo-oxygenase-2 (COX-2) inhibition. AIM: To evaluate endoscopically the effect of Bif195 on aspirin-induced stomach and duodenal mucosal damage METHODS: Twenty-five healthy volunteers underwent two intervention periods in a randomised, double-blind, placebo-controlled crossover design including four gastroduodenoscopies and 6 weeks washout. Each intervention was a 4-week oral co-treatment of aspirin 300 mg daily and Bif195 (≥1011 colony-forming units daily) or placebo. Primary endpoint was change in Lanza score - ranging from 0 (normal mucosa) to 4 (>10 erosions or ulcer). RESULTS: All 25 participants (56% females); age 27.3 (±4.8) years; BMI 23.2 (±3.4) kg/m2 , completed the trial exhibiting significant increases in Lanza scores during placebo treatment as compared to baseline. Bif195 reduced gastric Lanza score with an odds ratio of 7.2 (95% confidence interval 1.72-30.08, p = 0.009) compared to placebo with no related adverse events. There were no significant changes in Lanza scores in the duodenum. CONCLUSIONS: Bif195 reduces aspirin-induced gastric mucosal damage and may serve as a safe supplement during multiple-dosing aspirin treatment.

Efficacy and dose response of Lactiplantibacillus plantarum in diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Probiotics have shown promise in alleviating symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D); however, the certainty of evidence is low. Well-powered randomized controlled dose-ranging trials are warranted on promising single-strain candidates. AIM: To investigate the clinical efficacy of Lactiplantibacillus plantarum (L. plantarum) Lpla33 (DSM34428) in adults with IBS-D. METHODS: This is a randomized, double-blind, placebo-controlled, multi-center, and dose-ranging study. Three hundred and seven adults, 18-70 years of age, with IBS-D, according to Rome IV criteria, were allocated (1:1:1) to receive placebo or L. plantarum Lpla33 at 1 × 109 (1B) or 1 × 1010 (10B) colony-forming units/d over an 8-wk intervention period. The primary outcome was the change in IBS severity scoring system (IBS-SSS) total score after 8 wk, while secondary and exploratory outcomes included abdominal pain severity, IBS related quality of life, stool and microbial profile, and perceived stress. RESULTS: IBS-SSS was significantly reduced, after 8 wk, in participants receiving L. plantarum 1B (-128.45 ± 83.30; P < 0.001) and L. plantarum 10B (-156.77 ± 99.06; P < 0.001), compared to placebo (-58.82 ± 74.75). Further, a dose-ranging effect was observed, with a greater absolute reduction in the L. plantarum 10B group (P < 0.05). A reduction in sub-scores related to abdominal pain, abdominal distension, bowel habits, and quality of life was observed in both L. plantarum groups compared to placebo (P < 0.001). Further, 62.5% and 88.4% of participants administered L. plantarum 1B and 10B, respectively, were classified as stool consistency responders based on a reduction in diarrheal stool form, as compared to 26.3% in the placebo group (P < 0.001). In contrast, no significant shifts were observed in microbial diversity. CONCLUSION: L. plantarum Lpla33 (DSM34428) is well tolerated and improves IBS symptom severity with a dose-ranging effect and a corresponding normalization of bowel habits in adults with IBS-D.

Seeding the Infant Gut in Early Life-Effects of Maternal and Infant Seeding with Probiotics on Strain Transfer, Microbiota, and Gastrointestinal Symptoms in Healthy Breastfed Infants.

We investigated the effects of two dosing regimens of two multi-strain probiotic products on the gut microbiota of breastfed infants, including the transfer of the dosed strains and clinical outcomes. In forty-seven dyads, infants were either exposed through maternal intake (MS) of Lactobacillus acidophilus LA-5, Bifidobacterium animalis subsp. lactis BB-12, Lacticaseibacillus rhamnosus LGG, and Bifidobacterium longum subsp. infantis Bifin02 from gestational week thirty-three until four weeks after birth (n = 24) or dosed directly (IS) with the same strains except for LA-5 starting within 24 h after birth until day 28 (n = 23). Infant stool samples were collected on day 0, 14, 28, and 42 after birth. Gastrointestinal symptoms were assessed by parents using an electronic diary. Microbiota composition was determined using 16S rRNA sequencing, and strain recovery was analyzed by qPCR. Notably, 100% of the IS infants were colonized with Bifin02 after 14 days as opposed to only 25% of the MS infants. Mean stool frequency was significantly lower in IS infants compared to MS infants and IS infants had softer stools on day 14, 28, and 42. A significantly steeper slope of progression of inconsolable crying and fussing was observed in MS infants compared to IS infants. In conclusion, direct infant seeding induced a faster increase in fecal bifidobacteria abundancy and Bifin02 recovery compared to dosed through the maternal intake.

The effect of a lozenge combining prebiotic arginine and probiotics on caries increment in children during 10-12 months, a randomized clinical trial.

OBJECTIVES: To investigate the effect of daily use of a lozenge containing arginine and probiotics for 10-12 months on caries increment, gingivitis- and plaque occurrence in children aged 5-9 years. METHODS: In this placebo-controlled, double-blinded, parallel-grouped randomized clinical trial, 343 children were randomly assigned to one of the study arms (1:1). The intervention group (n = 172) received a lozenge containing Lacticaseibacillus rhamnosus, LGG® (DSM33156), Lactobacillus paracasei subsp. paracasei, L. CASEI 431® (DSM33451) and prebiotic (arginine 2%). The placebo group (n = 171) received an identical lozenge without arginine or probiotics. Primary canines and molars, and permanent first molars were examined clinically (d/D= ICDAS1-6) and radiographically (d/D = R1-6) at baseline and follow-up. Missing (m/M), sealed (s/S), and filled (f/F) surfaces (-s/-S) in both dentitions were also included. Utilizing clinical and radiographic scorings, caries experience was classified as dICDAS1-6msf-s (primary teeth), DICDAS1-6MSF-S (permanent teeth), d/DICDAS1-6 m/M-s/S-f/F-s/S (mixed dentition). A weighted and an unweighted score system was applied. RESULTS: The study was completed by 288 children. The dropout rate was 15%. The increase in ∆mean dICDAS3-6msf-s and ∆mean d/DICDAS3-6m/M-s/S-f/F-s/S was lower in the intervention group (p = 0.007). No differences were found for gingivitis- and plaque occurrence. No product-related side effects were reported. This study followed ICH-GCP including external monitoring. CONCLUSION: Daily consumption of a lozenge containing prebiotic arginine and two strains of probiotics showed safe use and statistically significantly reduction in caries incrementbut no effect on the mean plaque or gingivitis occurrence in children. The use of a lozenge with arginine and probiotics combined has a promising potential as a supplementary tool for future management of caries. www. CLINICALTRIALS: gov (NCT03928587). CLINICAL SIGNIFICANCE: The combination of prebiotic arginine and probiotics shows clinical potential as a supplementary approach to toothbrushing with fluoride toothpaste in managing caries increment in children. A new era in the management of caries may be emerging.

Effects of a 10-Strain Oral Probiotic on Parameters of Vaginal Health and Microbial Community: A Pilot Clinical Study.

OBJECTIVE: To investigate the clinical effects of a 10-strain probiotic on parameters of vaginal health in a pilot, open label study in women with intermediate Nugent score (NS) or vaginal pH >4.5. METHODOLOGY: A total of 43 healthy premenopausal women, ages 18 to 50 years, with NS of 4-6 or vaginal pH >4.5 were enrolled. Participants consumed a probiotic formulation (Feminine Support™), containing 8 lactobacilli and 2 bifidobacteria strains, with a daily dose of 2.5×1010 CFU for 28 (subgroup 1) or 42 (subgroup 2) days. Investigational visits occurred at day 0, 14, 28 and 42 with assessment of vaginal pH, NS and vaginal microbiota, via next-generation sequencing. RESULTS: A total of 36 participants were included in the analysis set, with 24 and 12 participants included in subgroups 1 and 2, respectively. In the analysis set, there was a significant reduction in vaginal pH, from baseline, at day 28 (mean change=-0.19, P = 0.047). Participants in subgroup 1 achieved a significant reduction in vaginal pH from baseline, at day 28 (mean change=-0.23, P = 0.029) and day 42 (mean change=-0.29, P = 0.008), while participants in subgroup 2 achieved a significant and quantitatively greater reduction in vaginal pH from baseline to day 42 (mean change=-0.64, P = 0.008). No significant changes in NS were reported, due in part to highly diverse baseline levels. Vaginal microbial abundance exhibited a majority lactobacilli abundance at baseline, which was maintained over the study period. Vaginal pH was inversely associated with lactobacilli abundance throughout the study (P < 0.005). The product was well tolerated with high compliance. Two participants reported adverse events with suspected causality, which were mild and resolved during the study. CONCLUSION: This 10-strain probiotic formulation was well tolerated and helped reduce vaginal pH in women with intermediate NS or elevated vaginal pH. The study product warrants a randomized controlled trial to further assess efficacy.

A Convolutional Neural Network Deep Learning Model Trained on CD Ulcers Images Accurately Identifies NSAID Ulcers.

Background and Study Aims: Deep learning (DL) for video capsule endoscopy (VCE) is an emerging research field. It has shown high accuracy for the detection of Crohn's disease (CD) ulcers. Non-steroidal anti-inflammatory drugs (NSAIDS) are commonly used medications. In the small bowel, NSAIDs may cause a variety of gastrointestinal adverse events including NSAID-induced ulcers. These ulcers are the most important differential diagnosis for small bowel ulcers in patients evaluated for suspected CD. We evaluated a DL network that was trained using CD VCE ulcer images and evaluated its performance for NSAID ulcers. Patients and Methods: The network was trained using CD ulcers and normal mucosa from a large image bank created from VCE of diagnosed CD patients. NSAIDs-induced enteropathy images were extracted from the prospective Bifidobacterium breve (BIf95) trial dataset. All images were acquired from studies performed using PillCam SBIII. The area under the receiver operating curve (AUC) was used as a metric. We compared the network's AUC for detecting NSAID ulcers to that of detecting CD ulcers. Results: Overall, the CD training dataset included 17,640 CE images. The NSAIDs testing dataset included 1,605 CE images. The DL network exhibited an AUC of 0.97 (95% CI 0.97-0.98) for identifying images with NSAID mucosal ulcers. The diagnostic accuracy was similar to that obtained for CD related ulcers (AUC 0.94-0.99). Conclusions: A network trained on VCE CD ulcers similarly identified NSAID findings. As deep learning is transforming gastrointestinal endoscopy, this result should be taken into consideration in the future design and analysis of VCE deep learning applications.

Transient receptor potential ankyrin 1 channel localized to non-neuronal airway cells promotes non-neurogenic inflammation.

BACKGROUND: The transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1. METHODOLOGY/PRINCIPAL FINDINGS: By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide substance P (SP), which is released from sensory nerve terminals by capsaicin, acrolein or CS), produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue) in bronchoalveolar lavage (BAL) fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves. CONCLUSIONS: Our results demonstrate that, although either TRPV1 or TRPA1 activation causes airway neurogenic inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not neurogenic. This finding suggests that non-neuronal TRPA1 in the airways is functional and potentially capable of contributing to inflammatory airway diseases.