The effect of an acute aspirin challenge on intestinal permeability in healthy adults with and without prophylactic probiotic consumption: a double-blind, placebo-controlled, randomized trial.

BACKGROUND: Healthy individuals may experience increases in intestinal permeability after chronic or acute use of non-steroidal anti-inflammatory drugs, which may be attenuated by probiotics. This study investigates the effects of an acute aspirin challenge on gastroduodenal barrier function with or without prophylactic probiotic consumption. METHODS: Twenty-nine generally healthy participants (26 ± 6 years) completed a 14-week randomized, double-blind, crossover trial. A probiotic containing 2 Lactobacilli strains or placebo was administered for 3 weeks, with a 4-week washout period between crossover phases. Daily and weekly questionnaires assessing gastrointestinal function were completed for 2 weeks before until 2 weeks after each intervention to assess gastrointestinal function. Gastroduodenal permeability was assessed by urinary excretion of orally administered sucrose after 1, 2, and 3 weeks of each intervention with a 1950 mg-aspirin challenge after 2 weeks of supplementation. Stool samples were collected weekly during supplementation for detection of species of interest. RESULTS: Gastroduodenal permeability increased with aspirin challenge (Week 1: 3.4 ± 0.6 µmol vs Week 2: 9.9 ± 1.0 µmol urinary sucrose; p < 0.05). There were no differences in the change in permeability after the aspirin challenge or gastrointestinal function between interventions. CONCLUSION: The acute aspirin challenge significantly increased intestinal permeability similarly in both groups, and prophylactic probiotic consumption was unable to prevent the loss in this particular model.

Intermittent vs continuous ketogenic diet: Impact on seizures, gut microbiota, and mitochondrial metabolism.

We have shown previously that the ketogenic diet (KD) is effective in reducing seizures associated with infantile spasms syndrome (ISS) and that this benefit is related to alterations in the gut microbiota. However, it remains unclear whether the efficacy of the KD persists after switching to a normal diet. Employing a neonatal rat model of ISS, we tested the hypothesis that the impact of the KD would diminish when switched to a normal diet. Following epilepsy induction, neonatal rats were divided into two groups: continuous KD for 6 days; and a group fed with KD for 3 days and then a normal diet for 3 days. Spasms frequency, mitochondrial bioenergetics in the hippocampus, and fecal microbiota were evaluated as major readouts. We found that the anti-epileptic effect of the KD was reversible, as evidenced by the increased spasms frequency in rats that were switched from the KD to a normal diet. The spasms frequency was correlated inversely with mitochondrial bioenergetic function and a set of gut microbes, including Streptococcus thermophilus and Streptococcus azizii. These findings suggest that the anti-epileptic and metabolic benefits of the KD decline rapidly in concert with gut microbial alterations in the ISS model.

Lacticaseibacillus rhamnosus HA-114 improves eating behaviors and mood-related factors in adults with overweight during weight loss: a randomized controlled trial.

Background: Gut microbiota has emerged as a modifiable factor influencing obesity and metabolic diseases. Interventions targeting this microbial community could attenuate biological and psychological comorbidities of excess weight. Objective: Our aim was to determine if Lacticaseibacillus rhamnosus HA-114 supplementation accentuated beneficial impact of weight loss on metabolic and cognitive health. Methods: This 12-week randomized, double-blind, placebo-controlled trial assessed biological markers of energy metabolism, eating behaviors and mood-related factors in 152 adults with overweight receiving L. rhamnosus HA-114 supplementation or placebo, that were also on a dietary intervention inducing a controlled weight loss. Results: Although probiotic supplementation did not potentiate the reduction in body weight or fat mass, a significant decrease in plasma insulin, HOMA-IR, LDL-cholesterol and triglycerides was observed in the probiotic-supplemented group only. With respect to eating behaviors and mood-related factors, beneficial effects were either observed only in the group receiving probiotic supplementation or were significantly greater in this group, including decrease in binge eating tendencies, disinhibition and food-cravings. Conclusion: This study demonstrates the clinical relevance of probiotic supplementation to induce beneficial metabolic and psychological outcomes in individuals with overweight undergoing weight loss.Trial registration: ClinicalTrials.gov identifier: NCT02962583.

Evidence of the Dysbiotic Effect of Psychotropics on Gut Microbiota and Capacity of Probiotics to Alleviate Related Dysbiosis in a Model of the Human Colon.

Growing evidence indicates that non-antibiotic therapeutics significantly impact human health by modulating gut microbiome composition and metabolism. In this study, we investigated the impact of two psychotropic drugs, aripiprazole and (S)-citalopram, on gut microbiome composition and its metabolic activity, as well as the potential of probiotics to attenuate related dysbiosis using an ex vivo model of the human colon. After 48 h of fermentation, the two psychotropics demonstrated distinct modulatory effects on the gut microbiome. Aripiprazole, at the phylum level, significantly decreased the relative abundances of Firmicutes and Actinobacteria, while increasing the proportion of Proteobacteria. Moreover, the families Lachnospiraceae, Lactobacillaceae, and Erysipelotrichaceae were also reduced by aripiprazole treatment compared to the control group. In addition, aripiprazole lowered the levels of butyrate, propionate, and acetate, as measured by gas chromatography (GC). On the other hand, (S)-citalopram increased the alpha diversity of microbial taxa, with no differences observed between groups at the family and genus level. Furthermore, a probiotic combination of Lacticaseibacillus rhamnosus HA-114 and Bifidobacterium longum R0175 alleviated gut microbiome alterations and increased the production of short-chain fatty acids to a similar level as the control. These findings provide compelling evidence that psychotropics modulate the composition and function of the gut microbiome, while the probiotic can mitigate related dysbiosis.

Secretome-Mediated Interactions with Intestinal Epithelial Cells: A Role for Secretome Components from Lactobacillus rhamnosus R0011 in the Attenuation of Salmonella enterica Serovar Typhimurium Secretome and TNF-α-Induced Proinflammatory Responses.

Recent evidence suggests that lactic acid bacteria communicate with host cells via secretome components to influence immune responses but less is known about gut-pathogen secretomes, impact of lactic acid bacteria secretomes on host-pathogen interactions, and the mechanisms underlying these interactions. Genome-wide microarrays and cytokine profiling were used to interrogate the impact of the Lactobacillus rhamnosus R0011 secretome (LrS) on TNF-α and Salmonella enterica subsp. enterica serovar Typhimurium secretome (STS)-induced outcomes in human intestinal epithelial cells. The LrS attenuated both TNF-α- and STS-induced gene expression involved in NF-κB and MAPK activation, as well as expression of genes involved in other immune-related signaling pathways. Specifically, the LrS induced the expression of dual specificity phosphatase 1 (DUSP1), activating transcription factor 3 (ATF3), and tribbles pseudokinase 3 (TRIB3), negative regulators of innate immune signaling, in HT-29 intestinal epithelial cells challenged with TNF-α or STS. TNF-α- and STS-induced acetylation of H3 and H4 histones was attenuated by the LrS, as was the production of TNF-α- and STS-induced proinflammatory cytokines and chemokines. Interestingly, the LrS induced production of macrophage migration inhibitory factor (MIF), a cytokine involved in host-microbe interactions at the gut interface. We propose that the LrS attenuates proinflammatory mediator expression through increased transcription of negative regulators of innate immune activity and changes in global H3 and H4 histone acetylation. To our knowledge, these findings provide novel insights into the complex multifaceted mechanisms of action behind secretome-mediated interdomain communication at the gut-mucosal interface.

In Vitro Framework to Assess the Anti-Helicobacter pylori Potential of Lactic Acid Bacteria Secretions as Alternatives to Antibiotics.

Helicobacter pylori is a prevalent bacterium that can cause gastric ulcers and cancers. Lactic acid bacteria (LAB) ameliorate treatment outcomes against H. pylori, suggesting that they could be a source of bioactive molecules usable as alternatives to current antibiotics for which resistance is mounting. We developed an in vitro framework to compare the anti-H. pylori properties of 25 LAB and their secretions against H. pylori. All studies were done at acidic and neutralized pH, with or without urea to mimic various gastric compartments. Eighteen LAB strains secreted molecules that curtailed the growth of H. pylori and the activity was urea-resistant in five LAB. Several LAB supernatants also reduced the urease activity of H. pylori. Pre-treatment of H. pylori with acidic LAB supernatants abrogated its flagella-mediated motility and decreased its ability to elicit pro-inflammatory IL-8 cytokine from human gastric cells, without reverting the H. pylori-induced repression of other pro-inflammatory cytokines. This study identified the LAB that have the most anti-H. pylori effects, decreasing its viability, its production of virulence factors, its motility and/or its ability to elicit pro-inflammatory IL-8 from gastric cells. Once identified, these molecules can be used as alternatives or complements to current antibiotics to fight H. pylori infections.

Fecal Microbial Transplants Reduce Antibiotic-resistant Genes in Patients With Recurrent Clostridium difficile Infection.

BACKGROUND: Recurrent Clostridium difficile infection (RCDI) is associated with repeated antibiotic treatment and the enhanced growth of antibiotic-resistant microbes. This study tested the hypothesis that patients with RCDI would harbor large numbers of antibiotic-resistant microbes and that fecal microbiota transplantation (FMT) would reduce the number of antibiotic-resistant genes. METHODS: In a single center study, patients with RCDI (n = 20) received FMT from universal donors via colonoscopy. Stool samples were collected from donors (n = 3) and patients prior to and following FMT. DNA was extracted and shotgun metagenomics performed. Results as well as assembled libraries from a healthy cohort (n = 87) obtained from the Human Microbiome Project were aligned against the NCBI bacterial taxonomy database and the Comprehensive Antibiotic Resistance Database. Results were corroborated through a DNA microarray containing 354 antibiotic resistance (ABR) genes. RESULTS: RCDI patients had a greater number and diversity of ABR genes compared with donors and healthy controls. Beta-lactam, multidrug efflux pumps, fluoroquinolone, and antibiotic inactivation ABR genes were increased in RCDI patients, although donors primarily had tetracycline resistance. RCDI patients were dominated by Proteobacteria with Escherichia coli and Klebsiella most prevalent. FMT resulted in a resolution of symptoms that correlated directly with a decreased number and diversity of ABR genes and increased Bacteroidetes and Firmicutes with reduced Proteobacteria. ABR gene profiles were maintained in recipients for up to a year following FMT. CONCLUSIONS: RCDI patients have increased numbers of antibiotic-resistant organisms. FMT is effective in the eradication of pathogenic antibiotic-resistant organisms and elimination of ABR genes.

Effectiveness of Lactobacillus helveticus and Lactobacillus rhamnosus for the management of antibiotic-associated diarrhoea in healthy adults: a randomised, double-blind, placebo-controlled trial.

Broad-spectrum antibiotic use can disrupt the gastrointestinal microbiota resulting in diarrhoea. Probiotics may be beneficial in managing this type of diarrhoea. The aim of this 10-week randomised, double-blind, placebo-controlled, parallel study was to investigate the effect of Lactobacillus helveticus R0052 and Lactobacillus rhamnosus R0011 supplementation on antibiotic-associated diarrhoea in healthy adults. Subjects were randomised to receive 1 week of amoxicillin-clavulanic acid (875 mg/125 mg) once per day, plus a daily dose of 8×109 colony-forming units of a multi-strain probiotic (n 80) or placebo (n 80). The probiotic or placebo intervention was maintained for 1 week after completion of the antibiotic. Primary study outcomes of consistency and frequency of bowel movements were not significantly different between the probiotic and placebo groups. The secondary outcomes of diarrhoea-like defecations, Gastrointestinal Symptoms Rating Scale scores, safety parameters and adverse events were not significantly different between the probiotic intervention and the placebo. A post hoc analysis on the duration of diarrhoea-like defecations showed that probiotic intervention reduced the length of these events by 1 full day (probiotic, 2·70 (sem 0·36) d; placebo, 3·71 (sem 0·36) d; P=0·037; effect size=0·52). In conclusion, this study provides novel evidence that L. helveticus R0052 and L. rhamnosus R0011 supplementation significantly reduced the duration of diarrhoea-like defecations in healthy adults receiving antibiotics.

Multistrain probiotic modulation of intestinal epithelial cells' immune response to a double-stranded RNA ligand, poly(i·c).

A commercially available product containing three probiotic bacterial strains (Lactobacillus helveticus R0052, Bifidobacterium longum subsp. infantis R0033, and Bifidobacterium bifidum R0071) was previously shown in animal trials to modulate both TH1 and TH2 immune responses. Clinical studies on this combination of bacteria have also shown positive health effects against seasonal winter diseases and rotavirus infection. The goal of this study was to use a well-established in vitro intestinal epithelial (HT-29) cell model that has been shown to constitutively express double-stranded RNA (dsRNA) sensors (Toll-like receptor 3 [TLR3], retinoic acid-inducible gene I, melanoma differentiation-associated gene 5, and dsRNA-activated protein kinase). By using the HT-29 cell model, we wanted to evaluate whether or not this combination of three bacteria had the capacity to immune modulate the host cell response to a dsRNA ligand, poly(I·C). Using a custom-designed, two-color expression microarray targeting genes of the human immune system, we investigated the response of HT-29 cells challenged with poly(I·C) both in the presence and in the absence of the three probiotic bacteria. We observed that the combination of the three bacteria had a major impact on attenuating the expression of genes connected to proinflammatory TH1 and antiviral innate immune responses compared to that obtained by the poly(I·C)-only challenge. Major pathways through which the multistrain combination may be eliciting its immune-modulatory effect include the TLR3 domain-containing adapter-inducing beta interferon (TRIF), mitogen-activated protein kinase, and NF-κB signaling pathways. Such a model may be useful for selecting potential biomarkers for the design of future clinical trials.

Profiling of Metabolites in a Fermented Soy Dietary Supplement Reinforces its Role in the Management of Intestinal Inflammation.

SCOPE: Gastro-AD (GAD) is a soy flour derived product that undergoes an industrial fermentation with Lactobacillus delbrueckii R0187 and has demonstrated clinical effects in gastroesophageal reflux and peptic ulcer symptom resolution. The aim of this study is to describe and link GAD's metabolomic profile to plausible mechanisms that manifest and explain the documented clinical outcomes. METHODS AND RESULTS: 1H NMR spectroscopy with multivariate statistical analysis is used to characterize the prefermented soy flour and GAD products. The acquired spectra are screened using various resources and the molecular assignments are confirmed using total correlation spectroscopy (TOCSY). Peaks corresponding to different metabolites are integrated and compared between the two products for relative changes. HPLC and GC are used to quantify some specific molecules. NMR analyses demonstrate significant changes in the composition of various assigned bioactive moieties. HPLC and GC analysis demonstrate deglycation of isoflavones after fermentation, resulting in estrogenically active secondary metabolites that have been previously shown to help to reduce inflammation. CONCLUSION: The identification of bioactive molecules, such as genistein and SCFAs, capable of modulating anti-inflammatory signaling cascades in the stomach's gastric and neuroendocrine tissues can explain the reported biological effects in GAD and is supported by in vivo data.

Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-ß Toxicity in C. elegans via Distinct Mechanisms.

Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aß-induced paralysis. Methods: Using C. elegans expressing human amyloid-ß (Aß)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-ß aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.

A Lacticaseibacillus rhamnosus secretome induces immunoregulatory transcriptional, functional and immunometabolic signatures in human THP-1 monocytes.

Macrophage responses to activation are fluid and dynamic in their ability to respond appropriately to challenges, a role integral to host defence. While bacteria can influence macrophage differentiation and polarization into pro-inflammatory and alternatively activated phenotypes through direct interactions, many questions surround indirect communication mechanisms mediated through secretomes derived from gut bacteria, such as lactobacilli. We examined effects of secretome-mediated conditioning on THP-1 human monocytes, focusing on the ability of the Lacticaseibacillus rhamnosus R0011 secretome (LrS) to drive macrophage differentiation and polarization and prime immune responses to subsequent challenge with lipopolysaccharide (LPS). Genome-wide transcriptional profiling revealed increased M2-associated gene transcription in response to LrS conditioning in THP-1 cells. Cytokine and chemokine profiling confirmed these results, indicating increased M2-associated chemokine and cytokine production (IL-1Ra, IL-10). These cells had increased cell-surface marker expression of CD11b, CD86, and CX3CR1, coupled with reduced expression of the M1 macrophage-associated marker CD64. Mitochondrial substrate utilization assays indicated diminished reliance on glycolytic substrates, coupled with increased utilization of citric acid cycle intermediates, characteristics of functional M2 activity. LPS challenge of LrS-conditioned THP-1s revealed heightened responsiveness, indicative of innate immune priming. Resting stage THP-1 macrophages co-conditioned with LrS and retinoic acid also displayed an immunoregulatory phenotype with expression of CD83, CD11c and CD103 and production of regulatory cytokines. Secretome-mediated conditioning of macrophages into an immunoregulatory phenotype is an uncharacterized and potentially important route through which lactic acid bacteria and the gut microbiota may train and shape innate immunity at the gut-mucosal interface.

Attenuation of post-myocardial infarction depression in rats by n-3 fatty acids or probiotics starting after the onset of reperfusion.

Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFA n-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high- or low-PUFA n-3 diet, combined or not with one billion live bacteria of L. helveticus and B. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2'-deoxyuridine, 5'-triphosphate (dUTP) nick-end labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus (DG) and amygdala with the high-PUFA n-3 diet, as compared to the three other diets. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the DG and the medial amygdala. At 2 weeks post-MI, depression-like behaviour was observed in the low-PUFA n-3 diet without probiotics-group, and this behaviour was attenuated with the high-PUFA n-3 diet or/and probiotics. These results indicate that a high-PUFA n-3 diet or the administration of probiotics, starting after the onset of reperfusion, are beneficial to attenuate apoptosis in the limbic system and post-MI depression in the rat.

Tryptophan-synthesizing bacteria enhance colonic motility.

BACKGROUND: An emerging strategy to treat symptoms of gastrointestinal (GI) dysmotility utilizes the administration of isolated bacteria. However, the underlying mechanisms of action of these bacterial agents are not well established. Here, we elucidate a novel approach to promote intestinal motility by exploiting the biochemical capability of specific bacteria to produce the serotonin (5-HT) precursor, tryptophan (Trp). METHODS: Mice were treated daily for 1 week by oral gavage of Bacillus (B.) subtilis (R0179), heat-inactivated R0179, or a tryptophan synthase-null strain of B. subtilis (1A2). Tissue levels of Trp, 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured and changes in motility were evaluated. KEY RESULTS: Mice treated with B. subtilis R0179 exhibited greater colonic tissue levels of Trp and the 5-HT breakdown product, 5-HIAA, compared to vehicle-treated mice. Furthermore, B. subtilis treatment accelerated colonic motility in both healthy mice as well as in a mouse model of constipation. These effects were not observed with heat-inactivated R0179 or the live 1A2 strain that does not express tryptophan synthase. Lastly, we found that the prokinetic effects of B. subtilis R0179 were blocked by coadministration of a 5-HT4 receptor (5-HT4 R) antagonist and were absent in 5-HT4 R knockout mice. CONCLUSIONS AND INFERENCES: Taken together, these data demonstrate that intestinal motility can be augmented by treatment with bacteria that synthesize Trp, possibly through increased 5-HT signaling and/or actions of Trp metabolites, and involvement of the 5-HT4 R. Our findings provide mechanistic insight into a transient and predictable bacterial strategy to promote GI motility.

Total Transit Time and Probiotic Persistence in Healthy Adults: A Pilot Study.

Background/Aims: Motility, stool characteristics, and microbiota composition are expected to modulate probiotics' passage through the gut but their effects on persistence after intake cessation remain uncharacterized. This pilot, open-label study aims at characterizing probiotic fecal detection parameters (onset, persistence, and duration) and their relationship with whole gut transit time (WGTT). Correlations with fecal microbiota composition are also explored. Methods: Thirty healthy adults (30.4 ± 13.3 years) received a probiotic (30 × 109 CFU/capsule/day, 2 weeks; containing Lactobacillus helveticus R0052, Lacticaseibacillus paracasei HA-108, Bifidobacterium breve HA-129, Bifidobacterium longum R0175, and Streptococcus thermophilus HA-110). Probiotic intake was flanked by 4-week washout periods, with 18 stool collections throughout the study. WGTT was measured using 80% recovery of radio-opaque markers. Results: Tested strains were detected in feces ~1-2 days after first intake and persistence after intake cessation was not significantly different for R0052, HA-108, and HA-129 (~3-6 days). We identified 3 WGTT subgroups within this population (named Fast, Intermediate, and Slow), which could be classified by machine learning with high accuracy based on differentially abundant taxa. On average, R0175 persisted significantly longer in the intermediate WGTT subgroup (~8.5 days), which was mainly due to 6 of the 13 Intermediate participants for whom R0175 persisted ≥ 15 days. Machine learning classified these 13 participants according to their WGTT cluster (≥ 15 days or < 5 days) with high accuracy, highlighting differentially abundant taxa potentially associated with R0175 persistence. Conclusion: These results support the notion that host-specific parameters such as WGTT and microbiota composition should be considered when designing studies involving probiotics, especially for the optimization of washout duration in crossover studies but also for the definition of enrollment criteria or supplementation regimen in specific populations.

PRKN/parkin-mediated mitophagy is induced by the probiotics Saccharomyces boulardii and Lactococcus lactis.

Mitochondrial impairment is a hallmark feature of neurodegenerative disorders, such as Parkinson disease, and PRKN/parkin-mediated mitophagy serves to remove unhealthy mitochondria from cells. Notably, probiotics are used to alleviate several symptoms of Parkinson disease including impaired locomotion and neurodegeneration in preclinical studies and constipation in clinical trials. There is some evidence to suggest that probiotics can modulate mitochondrial quality control pathways. In this study, we screened 49 probiotic strains and tested distinct stages of mitophagy to determine whether probiotic treatment could upregulate mitophagy in cells undergoing mitochondrial stress. We found two probiotics, Saccharomyces boulardii and Lactococcus lactis, that upregulated mitochondrial PRKN recruitment, phospho-ubiquitination, and MFN degradation in our cellular assays. Administration of these strains to Drosophila that were exposed to paraquat, a mitochondrial toxin, resulted in improved longevity and motor function. Further, we directly observed increased lysosomal degradation of dysfunctional mitochondria in the treated Drosophila brains. These effects were replicated in vitro and in vivo with supra-physiological concentrations of exogenous soluble factors that are released by probiotics in cultures grown under laboratory conditions. We identified methyl-isoquinoline-6-carboxylate as one candidate molecule, which upregulates mitochondrial PRKN recruitment, phospho-ubiquitination, MFN degradation, and lysosomal degradation of damaged mitochondria. Addition of methyl-isoquinoline-6-carboxylate to the fly food restored motor function to paraquat-treated Drosophila. These data suggest a novel mechanism that is facilitated by probiotics to stimulate mitophagy through a PRKN-dependent pathway, which could explain the potential therapeutic benefit of probiotic administration to patients with Parkinson disease.

An Isolate of Streptococcus mitis Displayed In Vitro Antimicrobial Activity and Deleterious Effect in a Preclinical Model of Lung Infection.

Microbiota studies have dramatically increased over these last two decades, and the repertoire of microorganisms with potential health benefits has been considerably enlarged. The development of next generation probiotics from new bacterial candidates is a long-term strategy that may be more efficient and rapid with discriminative in vitro tests. Streptococcus strains have received attention regarding their antimicrobial potential against pathogens of the upper and, more recently, the lower respiratory tracts. Pathogenic bacterial strains, such as non-typable Haemophilus influenzae (NTHi), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus), are commonly associated with acute and chronic respiratory diseases, and it could be interesting to fight against pathogens with probiotics. In this study, we show that a Streptococcus mitis (S. mitis) EM-371 strain, isolated from the buccal cavity of a human newborn and previously selected for promising anti-inflammatory effects, displayed in vitro antimicrobial activity against NTHi, P. aeruginosa or S. aureus. However, the anti-pathogenic in vitro activity was not sufficient to predict an efficient protective effect in a preclinical model. Two weeks of treatment with S. mitis EM-371 did not protect against, and even exacerbated, NTHi lung infection.

Intestinal microRNAs and bacterial taxa in juvenile mice are associated, modifiable by allochthonous lactobacilli, and affect postnatal maturation.

The interplay between the intestinal microbiota and host is critical to intestinal ontogeny and homeostasis. MicroRNAs (miRNAs) may be an underlying link. Intestinal miRNAs are microbiota-dependent and, when shed in the lumen, affect resident microorganisms. Yet, longitudinal relationships between intestinal tissue miRNAs, luminal miRNAs, and luminal microorganisms have not been elucidated, especially in early life. Here, we investigated the postnatal cecal miRNA and microbiota populations, their relationship, and their impact on intestinal maturation in specific pathogen-free mice; we also assessed if they can be modified by intervention with allochthonous probiotic lactobacilli. We report that cecal and cecal content miRNA and microbiota signatures are temporally regulated, correlated, and modifiable by probiotics with implications for intestinal maturation. These findings help understand causal relationships within the gut ecosystem and provide a basis for preventing and managing their alterations in diseases throughout life. IMPORTANCE The gut microbiota affects intestinal microRNA (miRNA) signatures and is modified by host-derived luminal miRNA. This suggests the existence of close miRNA-microbiota relationships that are critical to intestinal homeostasis. However, an integrative analysis of these relationships and their evolution during intestinal postnatal maturation is lacking. We provide a system-level longitudinal analysis of miRNA-microbiota networks in the intestine of mice at the weaning transition, including tissue and luminal miRNA and luminal microbiota. To address causality and move toward translational applications, we used allochthonous probiotic lactobacilli to modify these longitudinal relationships and showed that they are critical for intestinal maturation in early life. These findings contribute to understand mechanisms that underlie the maturation of the intestinal ecosystem and suggest that interventions aiming at maintaining, or restoring, homeostasis cannot prescind from considering relationships among its components.

Complete genome sequence of Lactobacillus helveticus R0052, a commercial probiotic strain.

Lactobacillus helveticus R0052 is a commercially available strain that is widely used in probiotic preparations. The genome sequence consisted of 2,129,425 bases. Comparative analysis showed that it was unique among L. helveticus strains in that it contained genes encoding mucus-binding proteins similar to those found in Lactobacillus acidophilus.