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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
Amare, A, Thalamuthu, A, Schubert, KO, Fullerton, J, Ahmed, M, Hartmann, S, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, et al
Research square. 2023
Abstract
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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Randomized, Double-Blind, Placebo-Controlled Study to Assess the Effect of Two Probiotics on the Preterms' Gut Microbiota.
Moreno-Sanz, B, Montes, MT, Manzano, S, Espinosa-Martos, I, Cárdenas, N, Esteban, S, Cruz, M, Jiménez, E, de Pipaón, MS
Journal of pediatric gastroenterology and nutrition. 2022;(6):e153-e159
Abstract
OBJECTIVE To evaluate the effect of a new probiotic strain combination, Ligilactobacillus salivarius subsp infantis PS11603 and Bifidobacterium longum PS10402, on gut bacterial colonization of preterm infants. METHODS A randomized, double-blind, placebo-controlled study was conducted in preterm infants from 28 weeks + 0days to 30 weeks + 6days of gestation. Thirty preterm infants were randomly selected after birth to receive either probiotics or placebo. Stool samples were collected before product intake and then sequentially during the first weeks of their admission. Classical microbiological, metagenomics and multiplex immunological analyses were performed to assess the bacterial and immune profile of the samples. RESULTS Twenty-seven infants completed the study (14 vs 13, probiotic and placebo groups). A higher number of participants were colonized by Lactobacilli in the probiotic group than in the placebo group (93% vs 46%; P = 0.013). Similar results were obtained when analysing bifidobacterial colonization (100% vs 69%; P = 0.041). Earlier colonization was observed in the probiotics group versus the placebo group, specifically 5 weeks for Lactobacillus and 1 week for Bifidobacterium. Although no effect was observed in the faecal immunological profile, a decreasing trend could be observed in Th17 response during the first week of probiotic treatment. None of the adverse events (AEs) registered were related to product intake. CONCLUSION Probiotic supplementation with L salivarius PS11603 and B longum subsp. infantis PS10402 enhanced an earlier colonization of Lactobacillus and Bifidobacterium in preterm infants' guts in 5 and 1 week, respectively. A higher number of infants were colonized by Lactobacilli with the probiotics' intake at the end of the study.
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Ligilactobacillus salivarius PS2 Supplementation during Pregnancy and Lactation Prevents Mastitis: A Randomised Controlled Trial.
Jiménez, E, Manzano, S, Schlembach, D, Arciszewski, K, Martin, R, Ben Amor, K, Roelofs, M, Knol, J, Rodríguez, JM, Abou-Dakn, M, et al
Microorganisms. 2021;(9)
Abstract
Mastitis is considered one of the main reasons for unwanted breastfeeding cessation. This study aimed to investigate the preventive effect of the probiotic strain Ligilactobacillus salivarius PS2 on the occurrence of mastitis in lactating women. In this multicountry, multicenter, randomized, double-blind, placebo-controlled trial, 328 women were assigned to the probiotic or the placebo group. The intervention started from the 35th week of pregnancy until week 12 post-partum. The primary outcome was the incidence (hazard) rate of mastitis, defined as the presence of at least two of the following symptoms: breast pain, breast erythema, breast engorgement not relieved by breastfeeding, and temperature > 38 °C. The probability of being free of mastitis during the study was higher in the probiotic than in the placebo group (p = 0.022, Kaplan-Meier log rank test) with 9 mastitis cases (6%) vs. 20 mastitis cases (14%), respectively. The hazard ratio of the incidence of mastitis between both study groups was 0.41 (0.190-0.915; p = 0.029), indicating that women in the probiotic group were 58% less likely to experience mastitis. In conclusion, supplementation of L. salivarius PS2 during late pregnancy and early lactation was safe and effective in preventing mastitis, which is one of the main barriers for continuing breastfeeding.
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Maternal and Perinatal Factors Associated with the Human Milk Microbiome.
Demmelmair, H, Jiménez, E, Collado, MC, Salminen, S, McGuire, MK
Current developments in nutrition. 2020;(4):nzaa027
Abstract
Microbes are present in human milk regardless of the mother's health. The origins of the milk microbiota likely include the mother's skin, infant's mouth, and transfer from the maternal gastrointestinal (GI) tract. Prominent bacterial taxa in human milk are Staphylococcus and Streptococcus, but many other genera are also found including anaerobic Lactobacillus, Bifidobacterium, and Bacteroides. The milk microbiome is highly variable and potentially influenced by geographic location, delivery mode, time postpartum, feeding mode, social networks, environment, maternal diet, and milk composition. Mastitis alters the milk microbiome, and the intake of Lactobacilli has shown potential for mastitis treatment and prevention. Although milk and infant fecal microbiomes are different, their variations appear to be related - suggesting that milk is an important contributor of early GI colonization. Nonetheless, nothing is known regarding whether the milk microbiome influences infant health. Further research and clinical interventions are needed to determine if changes in the microbiomes of human milk and infant formula/food impact health.
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Prevention of Recurrent Acute Otitis Media in Children Through the Use of Lactobacillus salivarius PS7, a Target-Specific Probiotic Strain.
Cárdenas, N, Martín, V, Arroyo, R, López, M, Carrera, M, Badiola, C, Jiménez, E, Rodríguez, JM
Nutrients. 2019;11(2)
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20–30% of infants suffer from recurrent acute otitis media (rAOM) which is usually treated with antibiotics, leading to increasing antimicrobial resistance rates. A bacterial strain, Lactobacillus salivarius PS7, was identified and characterised by in vitro studies which showed antimicrobial activity against most of otitis-related organisms. It was shown to be safe in rat toxicity studies. The investigators then carried out this prospective pilot study to test the efficacy and safety of L. Salivarius PS7 in infants and children with rAOM. 61 subjects completed the study and received the probiotic for the duration of 6 months. Oral intakes of L. salivarius PS7 over 6 months led to a statistically significant reduction (84%) in the number of episodes of AOM in comparison to those observed in the same children during the 6 months preceding probiotic intake. When AOM occurred, the duration of AOM episodes was shorter than in control children not receiving the probiotic. Ear samples showed that the probiotic treatment led to a statistically significant decrease in potential otopathogens. Limitations of this preliminary “proof of concept” trial were lack of placebo group and randomisation.
Abstract
Acute otitis media (AOM) is one of the most common bacterial infections in children. Empiric antibiotherapy leads to increasing antimicrobial resistance rates among otopathogens and may impair the correct development of the microbiota in early life. In this context, probiotics seem to be an attractive approach for preventing recurrent AOM (rAOM) through the restoration of the middle ear and nasopharyngeal microbiota. The aim of this study was the selection of a probiotic strain (Lactobacillus salivarius PS7), specifically tailored for its antagonism against otopathogens. Since L. salivarius PS7 was safe and displayed a strong antimicrobial activity against otopathogens, its efficacy in preventing rAOM was assessed in a trial involving 61 children suffering from rAOM. Children consumed daily ~1 × 10⁸ CFU of L. salivarius PS7, and the number of AOM episodes were registered and compared with that observed in the previous 6 and 12 months. The microbiota of samples collected from the external auditory canal samples was quantitatively and qualitatively assessed. The number of AOM episodes during the intervention period decreased significantly (84%) when compared to that reported during the 6 months period before the probiotic intervention. In conclusion, L. salivarius PS7 is a promising strain for the prevention of rAOM in infants and children.
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An Exploratory Search for Potential Molecular Targets Responsive to the Probiotic Lactobacillus salivarius PS2 in Women With Mastitis: Gene Expression Profiling vs. Interindividual Variability.
de Andrés, J, Jiménez, E, Espinosa-Martos, I, Rodríguez, JM, García-Conesa, MT
Frontiers in microbiology. 2018;:2166
Abstract
Probiotics constitute an attractive alternative in the battle against microbial infections. Oral administration of certain strains of lactobacilli isolated from human milk has resulted in an effective reduction of the bacterial load as well as an improvement of the mastitis-associated symptoms. Nevertheless, little is yet known about the potential molecular mechanisms and specific targets implicated in these effects. Transcriptomic profiling has been used to search for disease-associated and therapy-responsive molecules in different disorders and experimental models. We have applied for the first time a gene expression-based molecular approach to explore for potential targets responsive to intervention with a probiotic in: (i) breast milk somatic cells (n = 17) and (ii) blood leukocytes (n = 19). Women with mastitis ingested a new strain of lactobacilli, Lactobacillus salivarius PS2 (3 × capsules per day, each capsule contained ~9.5 log10 CFU) for 21 days. We applied Affymetrix microarrays and Taqman one-step quantitative reverse transcription PCR (RT-qPCR) to analyze and compare gene expression changes between samples pre- and post-treatment. Our results substantiate the involvement of inflammatory and cell-growth related pathways and genes in the breast milk somatic cells following the intake of L. salivarius PS2. Individual analyses of selected genes: (1) supported the upregulation of STC1 and IL19 and the downregulation of PLAUR and IFNGR1 in the somatic cells of the patients as potential targets responsive to the probiotic, (2) detected a lack of a relationship between the gene expression responses in the two types of cells, and (3) evidenced a substantial interindividual variability in the gene expression changes in both types of cells. Our study provides an insight into the essentiality of incorporating the study of tissue-specific interindividual molecular responsivity into future clinical intervention trials to further understand the complexity of human gene expression responses to therapy and the potentiality of selecting appropriate responsive targets.
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Modulatory effect of three probiotic strains on infants' gut microbial composition and immunological parameters on a placebo-controlled, double-blind, randomised study.
De Andrés, J, Manzano, S, García, C, Rodríguez, JM, Espinosa-Martos, I, Jiménez, E
Beneficial microbes. 2018;(4):573-584
Abstract
The gut microbiota plays a crucial role in gastrointestinal health. Current use of probiotics is aimed at modulating the bacterial gut composition to alleviate specific diseases. The safety and tolerance of three probiotic strains (Bifidobacterium longum subsp. infantis R0033, Lactobacillus helveticus R0052 and Bifidobacterium bifidum R0071) has recently been described. The objective of the present study was to analyse the microbiological composition and immunological parameters of faecal samples obtained from healthy infants from 3 to 12 months of age after receiving either one of the three probiotic strains or placebo for 8 weeks. 16S ribosomal RNA gene sequencing and multiplexing technology was used for analysis. Faecal sample analysis showed that the most abundant genus in all four groups of infants pre- and post-intervention was Bifidobacterium, representing approximately 50% of the sequences. After the intervention period the microbial composition of faecal samples in the probiotic groups did not display notable changes. In contrast, a decrease in different Bifidobacterium species, such as B. bifidum and Bifidobacterium breve and an increase in Bacteroides, Blautia, Clostridium, Coprococcus and Faecalibacterium genera was observed in the placebo group. The analysis of a wide range of immune factors in faecal samples suggests a modulatory effect by these three probiotic strains during the intervention period. The anti-inflammatory ratio interleukin (IL)-10/IL-12 increased at the end of the intervention period in the B. infantis R0033 group while the TNF-α/IL-10 ratio increased in the L. helveticus R0052 group. The decrease of the IL-10/IL-12 ratio together with the increase of the tumour necrosis factor alpha (TNF-α)/IL-10 ratio demonstrated a pro-inflammatory profile in the placebo group. In conclusion, the species profile of the microbiome observed in all three probiotic groups resembled that of a younger infant, similar to an unweaned infant, when compared to the placebo group which may also be related with an anti-inflammatory effect.
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Impact of childhood trauma on cognitive profile in bipolar disorder.
Jiménez, E, Solé, B, Arias, B, Mitjans, M, Varo, C, Reinares, M, Bonnín, CDM, Ruíz, V, Saiz, PA, García-Portilla, MP, et al
Bipolar disorders. 2017;(5):363-374
Abstract
OBJECTIVES Bipolar Disorder (BD) is associated with cognitive impairment even during remission periods. Nonetheless, this impairment seems to adjust to different profiles of severity. Our aim was to examine the potential impact of childhood trauma (CT) on cognitive performance and, more specifically, on neurocognitive profile membership. METHODS Using a data-driven strategy, 113 euthymic bipolar patients were grouped according to their cognitive performance using a hierarchical clustering technique. Patients from the three resulting clusters, the so-called "low", "average", and "high performance" groups, were then compared in terms of main sociodemographic, clinical and functioning variables, including CT measures. One-way ANOVA, a chi-square test and partial correlations were used for this purpose, as appropriate. A multinomial logistic regression model was used to determine which variables contributed to neurocognitive clustering membership. RESULTS Patients from the three neurocognitive clusters differed in terms of sociodemographic, clinical, functioning and CT variables. Scores on the Childhood Trauma Questionnaire (CTQ), especially on the physical negligence subscale, were also associated with a poor cognitive performance. The multinomial regression model indicated that CTQ total scores and the estimated intelligence quotient (IQ) significantly contributed to differentiation among the three neurocognitive groups. CONCLUSIONS Our results confirmed that CT significantly impacts on cognitive performance during adulthood in BD. The data obtained suggest that a history of CT could act as a liability marker for cognitive impairment. A higher estimated IQ may act as a protective factor against cognitive decline in this group of patients.
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Phylogenetic profile of gut microbiota in healthy adults after moderate intake of red wine.
Barroso, E, Muñoz-González, I, Jiménez, E, Bartolomé, B, Moreno-Arribas, MV, Peláez, C, Del Carmen Martínez-Cuesta, M, Requena, T
Molecular nutrition & food research. 2017;(3)
Abstract
SCOPE There is growing interest in understanding how human colonic microbiota can be modified by dietary habits. We examined the influence of moderate red wine intake on the colonic microbiota of 15 healthy volunteers, related to the high concentration of polyphenols present in this beverage. The volunteers were classified into high, moderate, and low polyphenol metabolizers (metabotypes) due to their ability to metabolize polyphenols and the results were compared with that of five control (no wine intake) subjects. METHODS AND RESULTS We analyzed the composition, diversity, and dynamics of their fecal microbiota before and after 1 month of wine consumption. The 16S rDNA sequencing allowed detection of 2324 phylotypes, of which only 30 were found over the 0.5% of mean relative frequency, representing 84.6% of the total taxonomical assignments. The samples clustered more strongly by individuals than by wine intake or metabotypes, however an increase in diversity, after the wine intake, was observed. CONCLUSION The results of this study suggest an increase in the global fecal microbial diversity associated to the consumption of red wine, confirm the high variability of the microbiota from different individuals, and show the stability of their singular microbiota composition to small and short-term dietary changes.
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Probiotics for human lactational mastitis.
Fernández, L, Arroyo, R, Espinosa, I, Marín, M, Jiménez, E, Rodríguez, JM
Beneficial microbes. 2014;(2):169-83
Abstract
The use of culture-dependent and -independent techniques to study the human milk microbiota and microbiome has revealed a complex ecosystem with a much greater diversity than previously anticipated. The potential role of the milk microbiome appears to have implications not only for short- and long-term infant health but also for mammary health. In fact, mammary disbiosis, which may be triggered by a variety of host, microbial and medical factors, often leads to acute, subacute or subclinical mastitis, a condition that represents the first medical cause for undesired weaning. Multiresistance to antibiotics, together with formation of biofilms and mechanisms for evasion of the host immune response, is a common feature among the bacterial agents involved. This explains why this condition uses to be elusive to antibiotic therapy and why the development of new strategies for mastitis management based on probiotics is particularly appealing. In fact, selected lactobacilli strains isolated from breast milk have already shown a high efficacy for treatment.