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Abstract Current treatments for chronic diarrhea have limited efficacy and several side effects. Probiotics have the potential to alleviate symptoms of diarrhea. This randomized, double-blind, placebo-controlled trial evaluates the effects of administering the probiotic Lactiplantibacillus plantarum P9 (P9) strain in young adults with chronic diarrhea (Clinical Trial Registration Number: ChiCTR2000038410). The intervention period lasts for 28 days, followed by a 14-day post-intervention period. Participants are randomized into the P9 (n = 93) and placebo (n = 96) groups, with 170 individuals completing the double-blind intervention phase (n = 85 per group). The primary endpoint is the diarrhea symptom severity score. Both intention-to-treat (n = 189) and per-protocol (n = 170) analyses reveal a modest yet statistically significant reduction in diarrhea severity compared to the placebo group (20.0%, P = 0.050; 21.4%, P = 0.048, respectively). In conclusion, the results of this study support the use of probiotics in managing chronic diarrhea in young adults. However, the lack of blood parameter assessment and the short intervention period represent limitations of this study.

Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine (TCM) for over 13 centuries. However, the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare. Here, we present a new approach for creating artificial bear bile (ABB) as a high-quality and sustainable alternative to natural bear bile. This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields, including resources, chemistry, biology, medicine, pharmacology, and TCM. A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established, allowing for the systematic screening of therapeutic constituents. Through the utilization of chemical synthesis and enzyme engineering technologies, our research has achieved the environmentally friendly, large-scale production of bear bile therapeutic compounds, as well as the optimization and recomposition of ABB formulations. The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality, availability of raw materials, and independence from threatened or wild resources. Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile (DBB). Furthermore, preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB. This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs, thereby strengthening the integrity and sustainability of TCM.

Abstract Background Gut microbes play an important role in the growth and health of neonatal piglets. Probiotics can promote the healthy growth of neonatal piglets by regulating their gut microbes. The study investigated the effects of spraying Lactiplantibacillus plantarum P-8 (L. plantarum P-8) fermentation broth on the growth performance and gut microbes of neonatal piglets. Results The animals were randomly divided into probiotics groups (109 neonatal piglets) and control groups (113 neonatal piglets). The probiotics group was sprayed with L. plantarum P-8 fermented liquid from 3 day before the expected date of the sow to the 7-day-old of piglets, while the control group was sprayed with equal dose of PBS. Average daily gain (ADG), immune and antioxidant status and metagenome sequencing were used to assess the changes in growth performance and gut microbiota of neonatal piglets. The results showed that L. plantarum P-8 treatment significantly improved the average daily gain (P

Abstract Background Early identification of high-risk individuals with cisplatin-induced nephrotoxicity (CIN) is crucial for avoiding CIN and improving prognosis. In this study, we developed and validated a CIN prediction model based on general clinical data, laboratory indications, and genetic features of lung cancer patients before chemotherapy. Methods We retrospectively included 696 lung cancer patients using platinum chemotherapy regimens from June 2019 to June 2021 as the traing set to construct a predictive model using Absolute shrinkage and selection operator (LASSO) regression, cross validation, and Akaike’s information criterion (AIC) to select important variables. We prospectively selected 283 independent lung cancer patients from July 2021 to December 2022 as the test set to evaluate the model’s performance. Results The prediction model showed good discrimination and calibration, with AUCs of 0.9217 and 0.8288, sensitivity of 79.89% and 45.07%, specificity of 94.48% and 94.81%, in the training and test sets respectively. Clinical decision curve analysis suggested that the model has value for clinical use when the risk threshold ranges between 0.1 and 0.9. Precision-Recall (PR) curve shown in recall interval from 0.5 to 0.75: precision gradually declines with increasing Recall, up to 0.9. Conclusions Predictive models based on laboratory and demographic variables can serve as a beneficial complementary tool for identifying high-risk populations with CIN.

ABSTRACT: Probiotics are increasingly used as starter cultures to produce fermented dairy products; however, few studies have investigated the role of probiotics in milk fermentation metabolism. The current study aimed to investigate whether adding Bifidobacterium animalis ssp. lactis Probio-M8 (Probio-M8) as a starter culture strain could improve milk fermentation by comparing the physicochemical characteristics and metabolomes of fermented milks produced by a commercial starter culture with and without Probio-M8. Our results showed that adding Probio-M8 shortened the milk fermentation time and improved the fermented milk texture and stability. Metabolomics analyses revealed that adding Probio-M8 affected mostly organic acid, AA, and fatty acid metabolism in milk fermentation. Targeted quantitative analyses revealed significant increases in various metabolites related to the sensory quality, nutritive value, and health benefits of the probiotic fermented milk, including 5 organic acids (acetic acid, lactic acid, citric acid, succinic acid, and tartaric acid), 5 EAA (valine, arginine, leucine, isoleucine, and lysine), glutamic acid, and 2 essential fatty acids (α-linolenic acid and docosahexaenoic acid). Thus, applying probiotics in milk fermentation is desirable. This study has generated useful information for developing novel functional dairy products.

Abstract Background Cognitive impairment (CoI), chronic kidney disease (CKD), and depression are prevalent among older adults and are interrelated, imposing a significant disease burden. This study evaluates the association of CKD and depression with CoI and explores their potential interactions. Method Data for this study were sourced from the 2011–2014 National Health and Nutritional Examination Survey (NHANES). Multiple binary logistic regression models assessed the relationship between CKD, depression, and CoI while controlling for confounders. The interactions were measured using the relative excess risk of interaction (RERI), the attributable proportion of interaction (AP), and the synergy index (S). Results A total of 2,666 participants (weighted n = 49,251,515) were included in the study, of which 700 (16.00%) had CoI. After adjusting for confounding factors, the risk of CoI was higher in patients with CKD compared to non-CKD participants (odds ratio [OR] = 1.49, 95% confidence interval [CI]:1.12–1.99). The risk of CoI was significantly increased in patients with depression compared to those without (OR = 2.29, 95% CI: 1.73–3.03). Furthermore, there was a significant additive interaction between CKD and depression in terms of the increased risk of CoI (adjusted RERI = 2.01, [95% CI: 0.31–3.71], adjusted AP = 0.50 [95% CI: 0.25–0.75], adjusted S = 2.97 [95% CI: 1.27–6.92]). Conclusion CKD and depression synergistically affect CoI, particularly when moderate-to-severe depression co-occurs with CKD. Clinicians should be mindful of the combined impact on patients with CoI. Further research is needed to elucidate the underlying mechanisms and assess the effects specific to different CKD stages.

Camel milk is a nutrient-rich diet and fermentation affects its nutritional value and probiotic function. In this study, sour camel milk and oat jujube sour camel milk were prepared using fermentation bacteria agent TR1, and the metabolites of camel milk, sour camel milk and oat jujube sour camel milk were detected using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry (LC-MS).The results showed that the partial least squares discriminant analysis (PLS-DA) with 100 % accuracy and good predictive power detected 343 components in positive ion mode and 220 components in negative ion mode. The differential metabolites were mainly organic acids, amino acids, esters, vitamins and other substances contained in camel milk.It showed that there were significant differences in the metabolites of camel milk, sour camel milk and oat jujube sour camel milk. Based on the pathway enrichment analysis of the three dairy products in the KEGG database, 12 metabolic pathways mainly involved in the positive ion mode and 20 metabolic pathways mainly involved in the negative ion mode were identified. The main biochemical metabolic pathways and signal transduction pathways of the differential metabolites of the three dairy products were obtained. This study provides theoretical support for improving the nutritional quality and probiotic function of camel milk and fermented camel milk products and provides a basis for the development of relevant processing technologies and products for camel milk and fermented camel milk.

IntroductionThis study investigates the intricate relationship between parents’ education anxiety and children’s learning anxiety, examining the mediating role of parenting style and the moderating effect of extracurricular tutoring.MethodsUtilizing data from the “Survey of Parents and Students in Primary and Secondary Schools,” the study employs stratified sampling (n = 3,298) and various psychological scales to measure education anxiety, parenting styles, and extracurricular tutoring.ResultsThis study reveals that parents’ education anxiety significantly influences children’s learning anxiety, with a notable positive correlation (r = 0.301**). Parenting styles particularly rejection and overprotection style increase this anxiety, while emotional warmth style decreases it. Academic tutoring serves as a moderator, reducing the impact of parental anxiety on children’s learning anxiety (β = −0.033, p

ABSTRACT In view of the safety concerns of probiotics, more and more attention is paid to the beneficial effects of dead probiotics cells. Herein, we investigated and compared the alleviation effects of viable Bifidobacterium longum subsp. infantis B8762 (B. infantis B8762) and its heat-killed cells on dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) rats. Four groups of rats (n = 12 per group) were included: normal control, DSS-induced colitis rats without bacterial administration (DSS), DSS-induced colitis rats with viable B. infantis B8762 administration (VB8762), and DSS-induced colitis rats with dead B. infantis B8762 administration (DB8762). Our results showed that both VB8762 and DB8762 administration exerted significant protective effects on DSS-induced IBD rats, as evidenced by a reduction in mortality, disease activity index score, body weight loss, as well as decreased histology score, which were companied by a significant decrease in serum pro-inflammatory factors compared with DSS group, and a stronger effect on modulating the fecal microbiota alpha-diversity and beta-diversity compared with DSS group. Additionally, the fecal metabolome results showed that both VB8762 and DB8762 interventions indeed altered the fecal metabolome profile and related metabolic pathways of DSS-induced IBD rats. Therefore, given the alleviation effects on colitis, the DB8762 can be confirmed to be a postbiotic. Overall, our findings suggested that VB8762 and DB8762 had similar ability to alleviate IBD although with some differences. Due to the minimal safety concern of postbiotics, we propose that the postbiotic DB8762 could be a promising alternative to probiotics to be applied in the prevention and treatment of IBDs.IMPORTANCEInflammatory bowel disease (IBD) has emerged as a global disease because of the worldwide spread of western diets and lifestyles during industrialization. Up to now, many probiotic strains are used as a modulator of gut microbiota or an enhancer of gut barrier to alleviate or cure IBD. However, there are still many issues of using probiotics, which were needed to be concerned about, for instance, safety issues in certain groups like neonates and vulnerable populations, and the functional differences between viable and dead microorganisms. Therefore, it is of interest to investigate the beneficial effects of dead probiotics cells. The present study proved that both viable Bifidobacterium longum subsp. infantis B8762 and heat-killed cells could alleviate dextran sodium sulfate-induced colitis in rats. The findings help to support that some heat-killed probiotics cells can also exert relevant biological functions and can be used as a postbiotic.

Abstract Objectives The present body of evidence regarding the correlation between the estimated glomerular filtration rate (eGFR) and the reversal of impaired fasting glucose (IFG) to normoglycemia remains constrained. Consequently, the objective of our study is to examine the relationship between eGFR and the restoration of normoglycemia in individuals with IFG. Methods This retrospective cohort study consecutively collected data from 24,541 non-selective participants with IFG at Rich Healthcare Group in China from January 2010 to 2016. We aimed to investigate the association between baseline eGFR and reversion to normoglycemia using the Cox proportional-hazards regression model. Through the utilization of a Cox proportional hazards regression model featuring cubical spline smoothing, we were able to ascertain the non-linear correlation between eGFR and the return to normoglycemia. Furthermore, various sensitivity and subgroup analyses were carried out, and a competing risk multivariate Cox regression was employed to examine the progression to diabetes as a competing risk for the reversal of normoglycemic events. Results In our study, comprising 24,541 participants, the average age was 49.25 ± 13.77 years, with 66.28% being male. The baseline eGFR mean was 104.16 ± 15.78 ml/min per 1.73 m2. During a median follow-up period of 2.89 years, we observed a reversion rate to normoglycemia of 45.50%. Upon controlling for covariates, our findings indicated a positive correlation between eGFR and the probability of returning to normoglycemia (HR = 1.008, 95% CI 1.006–1.009). In addition, a non-linear association was observed between eGFR and the likelihood of transitioning from IFG to normoglycemia. The inflection point of eGFR was found to be 111.962 ml/min per 1.73 m2, with HRs of 1.003 (95% CI 1.001, 1.005) on the left side of the point and 1.019 (95% CI 1.015, 1.022) on the right side. Our robust results were supported by competing risks multivariate Cox's regression and sensitivity analysis. Conclusions The findings of our investigation indicate a favorable and non-linear correlation between eGFR and the restoration of normoglycemia in Chinese individuals with IFG. Specifically, a reduction in renal function at an early stage in these patients may considerably diminish the likelihood of attaining normoglycemia.

Abstract The goal of this study was to use a new interpretable machine-learning framework based on max-logistic competing risk factor models to identify a parsimonious set of differentially expressed genes (DEGs) that play a pivotal role in the development of colorectal cancer (CRC). Transcriptome data from nine public datasets were analyzed, and a new Chinese cohort was collected to validate the findings. The study discovered a set of four critical DEGs - CXCL8, PSMC2, APP, and SLC20A1 - that exhibit the highest accuracy in detecting CRC in diverse populations and ethnicities. Notably, PSMC2 and CXCL8 appear to play a central role in CRC, and CXCL8 alone could potentially serve as an early-stage marker for CRC. This work represents a pioneering effort in applying the max-logistic competing risk factor model to identify critical genes for human malignancies, and the interpretability and reproducibility of the results across diverse populations suggests that the four DEGs identified can provide a comprehensive description of the transcriptomic features of CRC. The practical implications of this research include the potential for personalized risk assessment and precision diagnosis and tailored treatment plans for patients.

Abstract Lactic acid bacteria (LAB) are widely used in the food industry, but little is known about their population genomics, hindering our understanding of their genetic background and evolution. To better understand the evolution of LAB and their potential applications to related food production, we conducted a scoping review of the literature focusing on genomic issues related to LAB. The research progress of LAB population and functional genomics was summarized by sorting the literature of LAB genomics research in the last 10–15 years. According to the existing evidence, the formation mechanism of characteristics of LAB and their habitat adaptive evolution directed by genome decay and horizontal gene transfer were elucidated. The major evolutionary driving forces of LAB are mutations and horizontal gene transfer (HGT) events with or without the involvement of mobile genetic elements instead of recombination. We also underline the application of LAB genome in food safety and properties. Collectively, this review paper provides up‐to‐date information of the population and functional genomics of LAB, current challenges in the field, and suggestions for improving the exploitation and application of LAB resources.

Spike architecture influences both grain weight and grain number per spike, which are the two major components of grain yield in bread wheat (Triticum aestivum L.). However, the complex wheat genome and the influence of various environmental factors pose challenges in mapping the causal genes that affect spike traits. Here, we systematically identified genes involved in spike trait formation by integrating information on genomic variation and gene regulatory networks controlling young spike development in wheat. We identified 170 loci that are responsible for variations in spike length, spikelet number per spike, and grain number per spike through genome-wide association study and meta-QTL analyses. We constructed gene regulatory networks for young inflorescences at the double ridge stage and the floret primordium stage, in which the spikelet meristem and the floret meristem are predominant, respectively, by integrating transcriptome, histone modification, chromatin accessibility, eQTL, and protein–protein interactome data. From these networks, we identified 169 hub genes located in 76 of the 170 QTL regions whose polymorphisms are significantly associated with variation in spike traits. The functions of TaZF-B1, VRT-B2, and TaSPL15-A/D in establishment of wheat spike architecture were verified. This study provides valuable molecular resources for understanding spike traits and demonstrates that combining genetic analysis and developmental regulatory networks is a robust approach for dissection of complex traits.

Background: Cognitive function impairment (CFI) is common in patients with chronic kidney disease (CKD) and significantly impacts treatment adherence and quality of life. This study aims to create a simplified nomogram for early CFI risk detection. Methods: Data were obtained from the National Health and Nutrition Examination Survey cycles spanning from 1999 to 2002 and again from 2011 to 2014. Stepwise logistic regression was used to select variables and construct a CFI risk prediction model. Furthermore, C-statistic and Brier Score (BS) assessed model performance. Additionally, Kaplan–Meier survival curves were utilised to assess risk group-death prognosis relationships. Results: Of the 545 participants in the CKD model development cohort, a total of 146 (26.8 %) had CFI. The final model included the variables of age, race, education, annual family income, body mass index, estimated glomerular filtration rate, serum albumin and uric acid. The model had a C-statistic of 0.808 (95 % confidence interval (CI): 0.769–0.847) and a BS of 0.149. Furthermore, the 5-fold cross-validation internal C-statistic was 0.764 (interquartile range: 0.763–0.807) and BS was 0.154. Upon external validation, the model's C-statistic decreased to 0.752 (95 % CI: 0.654–0.850) and its BS increased to 0.182. The Kaplan–Meier survival curves demonstrated that intermediate-to-high-risk participants had shorter overall survival time than low-risk participants (log-rank test: p = 0.00042). Conclusions: This study established an effective nomogram for predicting CFI in patients with CKD, which can be used for the early detection of CFI and guide the treatment of patients with CKD.

Respiratory tract infections constitute a significant global public health concern, accounting for around 20 % of child fatalities worldwide. Modulating the gut microbiota have the potential to serve as a promising strategy for both the prevention and treatment of respiratory infections. According to our prior research, the consumption of Bifidobacterium lactis Probio-M8 can notably enhance symptoms associated with respiratory tract infections in infants and young children. The current study is a follow-up work aimed at exploring the functional role of the gut microbes in the observed beneficial effects. We analyzed the fecal metagenomes of patients in both the probiotic group (n = 50) and the placebo group (n = 49). The results showed that Probio-M8 intervention may regulate the host inflammatory response by regulating the balance of intestinal microorganisms, bioactive metabolites and related pathways. Provides new insights into the study of probiotics in alleviating diseases related to the gut-lung axis.

Objective: To investigate the factors influencing hyperuricemia in children and adolescents and to provide a scientific basis for early prevention and treatment. Methods: A retrospective study (2017–2021) of the prevalence of hyperuricemia in children and adolescents was conducted, and the factors influencing hyperuricemia were analyzed by multi-factor logistic regression. Results: The overall prevalence of hyperuricemia in children and adolescents aged 6–17 years in northeast Sichuan Province was 55.12% (8676/15,739), of which 60.68% (5699/9392) in boys and 46.90% (2977/6347) in girls; the prevalence of hyperuricemia from 2017 to 2021 was 52.40% ( 1540/2939), 52.56% (1642/3124), 52.11% (1825/3502), 58.33% (1691/2899), and 60.40% (1978/3275), respectively; the prevalence rates of 6–12 years old were 48.92% (864/1766), 50.46% (769/1524), and 52.73% (685/1299), 56.99% (693/1216), 35.46% (444/1252), 46.33% (524/1131), 60.50% (720/1190), and 66.82% (739/1106), 58.95% (652/1106), and 62.17% (761/1106) for 13–17 years old, respectively, 62.17% (761/1224), 63.19% (855/1353), and 61.70% (970/1572), respectively. Logistic regression showed that the prevalence of male (OR = 1.451, 95% CI 1.034 to 2.035, p = 0.031), age (OR = 1.074, 95% CI 1.024 to 1.126, p = 0.003), overweight/obesity (OR = 1.733, 95% CI 1.204∼2.494, p = 0.003), blood creatinine (OR = 1.018, 95% CI 1.005∼1.031, p = 0.007), triglycerides (OR = 1.450, 95% CI 1.065∼1.972, p = 0.018), blood calcium (OR = 6.792, 95% CI 1.373∼33.594, p = 0.019), and systolic blood pressure (OR = 1.037, 95% CI 1.018∼1.057, p < 0.001) were influential factors for the development of hyperuricemia. Conclusion: The prevalence of hyperuricemia was higher in children and adolescents aged 6–17 years in northeastern Sichuan Province, with a higher prevalence in boys than in girls, and the prevalence increased with age.

Abstract Background Cisplatin is a widely used and effective chemotherapeutic agent against cancer. However, nephrotoxicity is one of the most common side effects of cisplatin, and it can proceed to acute kidney injury (AKI). Studies have reported that activation of transient receptor potential ankyrin-1 (TRPA1) mediates cisplatin-induced renal tubular cytotoxic injury. The aim of this study was to investigate the mechanism of TRPA1 in promoting cisplatin-induced AKI through modulation of the endoplasmic reticulum stress (ERS)-mitochondrial damage. Methods A cisplatin-induced HK-2 cell model in vitro and mouse model in vivo were established. The mechanism of TRPA1 promotes AKI was elucidated by H&E staining, TUNEL staining, transmission electron microscope (TEM), immunofluorescence, CCK-8 viability assays, flow cytometry, Western blotting, JC-1 assay, and enzyme linked immunosorbent assay (ELISA). Result In vivo and in vitro, HC-030031 reduced cisplatin-induced Scr and BUN level elevations; improved cisplatin-induced renal tissue injury, apoptosis, and mitochondrial dysfunction; elevated the reduced ERS-associated proteins glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), and C/EBP homologous protein (CHOP) levels induced by cisplatin; reduced the elevated optic atrophy 1 (OPA1), mito-fusion 1 (MFN1), and mito-fusion 2 (MFN2) protein levels, and elevated phospho-dynamin-related protein 1 (p-DRP1) and mitochondrial fission factor (MFF) protein levels. HC-030031 also reduced the mitochondria-associated endoplasmic reticulum membrane (MAM) structure. In addition, TRPA1 agonists also decreased cell proliferation, increased apoptosis, and triggered mitochondrial dysfunction and calcium overload in HK-2 cells via modulation of MAM. ERS inhibitors and GRP75 inhibitors reversed these changes caused by TRPA1 agonists. Conclusion Our findings suggest that TRPA1 enhances cisplatin-induced AKI via modulation of ERS and mitochondrial damage.

Abstract Constipation and systemic inflammation are common in late pregnant and lactating sows, which cause health problems like uteritis, mastitis, dystocia, or even stillbirth, further influencing piglets’ survival and growth. Probiotic supplementation can improve such issues, but the beneficial mechanism of relieving constipation and enhancing gut motility remains underexplored. This study aimed to investigate the effects and mechanism of probiotic supplementation in drinking water to late pregnant sows on constipation, inflammation, and piglets’ growth performance. Seventy-four sows were randomly allocated to probiotic (n = 36) and control (n = 38) groups. Probiotic treatment significantly relieved sow constipation, enhanced serum IL-4 and IL-10 levels while reducing serum IL-1β, IL-12p40, and TNF-α levels, and increased piglet daily gain and weaning weight. Furthermore, probiotic administration reshaped the sow gut bacteriome and phageome structure/diversity, accompanied by increases in some potentially beneficial bacteria. At 113 days of gestation, the probiotic group was enriched in several gut microbial bioactive metabolites, multiple carbohydrate-active enzymes that degrade pectin and starch, fecal butyrate and acetate, and some serum metabolites involved in vitamin and amino acid metabolism. Our integrated correlation network analysis revealed that the alleviation of constipation and inflammation was associated with changes in the sow gut bacteriome, phageome, bioactive metabolic potential, and metabolism.

Abstract To analyze the clinical significance of MATN1-AS1 as ceRNA of Mir-200b in the tissues and serum of cervical cancer patients. A total of 50 patients with cervical cancer admitted to our hospital from March 2018 to March 2019 were selected as the research objects. All patients underwent surgical resection of cancer tissues in our hospital, and cervical cancer tissues and adjacent tissues more than 2 cm away from the edge of cancer tissues were retained. Patients with cervical cancer were selected as the research group, and 50 patients with benign uterine lesions were selected as the control group. The expressions of MATN1-AS1 and Mir-200b in cervical cancer tissues and serum were detected by real-time PCR, and the correlation between MATN1-AS1 and Mir-200b was analyzed. The relationship between MATN1-AS1, Mir-200b and clinical features was analyzed, and the 3-year survival rate of cervical cancer patients was analyzed. Compared with adjacent tissues, the relative expression levels of MATN1-AS1 and Mir-200b in cancer tissues were significantly increased (P

Objective: To determine if moderate physical activity is associated with live birth rates in women with unexplained infertility and obesity. Design: Secondary analysis of the Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial. Setting: US fertility centers, 2015–2019. Patient(s): A total of 379 women participated in Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial, a lifestyle modification program with increased physical activity (phase I, 16 weeks) and up to three cycles of clomiphene citrate treatment and intrauterine insemination (phase II). Intervention(s): Participants were instructed to add 500 steps/day weekly until a maximum of 10,000 steps/day was reached and maintained. Participants were stratified as active (top third, N = 125) and less active (lower third, N = 125) on the basis of the average number of steps per day recorded using a FitBit activity tracker. Main Outcome Measure(s): Live birth rate. Result(s): Active participants were more physically active at the time of enrollment than less active participants (average baseline steps per day, 8,708 [7,079–10,000] vs. 4,695 [3,844–5,811]; P ≤ 0.001) and were more likely to reach 10,000 steps/day than less active participants (average steps per day, 10,526 [9,481–11,810] vs. 6,442 [4,644–7,747]; P ≤ 0.001), although both groups increased their average steps per day by a similar amount (1,818 vs.1,747; P = 0.57). There was no difference in live birth rates (24/125 [19.2%] vs. 25/125 [20%]; P = 0.87) between active and less active participants nor were there differences in clinical pregnancy rates (P = 0.45) or miscarriage rates (P = 0.49) between the two groups. Conclusion(s): Active participants were more likely to achieve the physical activity goal, although this was not associated with benefit or harm with respect to live birth. Clinical Trial Registration Number: ClinicalTrials.gov (NCT02432209), first posted: May 4, 2015.

Infant intestinal microbiome is closely linked with health and risk of disease. Bifidobacterium are important components of the infant gut and are known to confer various health effects on the host. However, few studies have described the precise composition and dynamics of early infant gut bifidobacterial communities. Thus, this was a pilot study aiming to describe the developmental trajectories and temporal dynamics of bifidobacterial communities in infants before 6 months of age. A total of 28 fecal samples from 4 infants (GF, ZZ, QM, TN, respectively) were collected and analyzed after 5, 15, 30, 60, 90, 120, 150, and 180 days of birth by a bifidobacteria-target method (based on single-molecule real-time sequencing of partial bifidobacterial rpsK genes) in conjunction with droplet digital polymerase chain reaction (ddPCR). The infant fecal microbiota comprised a total of 11 bifidobacterial species, including 4 major species, i.e., B. dentium (37.35 %), B. catenulatum (32.04 %), B. breve (22.24 %), and B. animalis (8.02 %). The infant microbiota showed highly individualized developmental trajectories. The leading species for GF was B. catenulatum, with a relatively stable developmental trajectory. In ZZ, B. breve was enriched, and the developmental trajectory was rather fluctuating. The most abundant species for QM and TN was B. dentium. The developmental trajectory of B. dentium in QM showed a trend of gradual decrease, whereas an opposite trend was seen in samples of TN. The results of ddPCR confirmed large variations in quantities of bifidobacteria between infants and suggested discordances in temporal dynamics of bifidobacterial communities during the first half year of infancy. In conclusion, our results suggested that the early infant gut bifidobacterial microbiota was highly complex and temporal dynamics, with individualized developmental trajectories, which should be considered in future research of infant gut microbiota.

ABSTRACTProbiotics can effectively improve a variety of neurological diseases, but there is little research on autism, and the specific mechanism is unclear. In this study, shotgun metagenomics analysis was used to investigate the preventive and therapeutic effects of Bifidobacterium animalis subsp. lactis Probio-M8 on autism. The results showed that Probio-M8 treatment significantly alleviated valproate (VPA)-induced autism in mice, with autistic symptoms characterized by increased stereotyped behaviors such as grooming, reduced learning ability, and decreased desire to socialize. Further studies have found that Probio-M8 can alleviate autism by optimizing gut microbiota diversity and regulating metabolic levels. Probio-M8 regulates gut microbiota structure by increasing the abundance of beneficial bacteria such as Bifidobacterium globosum and Akkermansia muciniphila. In addition, Probio-M8 regulates metabolic activity by increasing levels of choline, which corrects CAZy disorders. In conclusion, Probio-M8 is therapeutic in the VPA-induced autism mouse model by regulating the gut microbiome and metabolic levels.IMPORTANCEIndividuals with autism often exhibit symptoms of social invariance, obsessive-compulsive tendencies, and repetitive behaviors. However, early intervention and treatment can be effective in improving social skills and mitigating autism symptoms, including behaviors related to irritability. Although taking medication for autism may lead to side effects such as weight gain, probiotics can be an ideal intervention for alleviating these symptoms. In this study, we investigated the effects of Probio-M8 intervention on the behavior of autistic mice using an open-field test, a three-chamber sociability test, and a novel object recognition test. Metagenomic analysis revealed differences in gut microbiota diversity among groups, predicted changes in metabolite levels, and functionally annotated CAZy. Additionally, we analyzed serum neurotransmitter levels and found that probiotics were beneficial in mitigating neurotransmitter imbalances in mice with autism.

Introduction Uterine fibroids affect 30%–77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG’s efficacy in treating women with fibroids and unexplained infertility.Methods and analysis This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores.Ethics and dissemination The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial.Trial registration number NCT05364008.

ABSTRACT High-fructose intake is one of the high-risk factors for hypertension. Several probiotics have been reported to reduce high blood pressure (BP) via modulating gut microbiota, but the mechanism of the antihypertensive effect of probiotics is insufficiently understood. Herein, we investigated the antihypertensive effect of Bifidobacterium lactis M8 and Lactobacillus rhamnosus M9 based on the integrative analysis of gut metagenome and serum metabolome in high-fructose-treated mice. After 16-week intervention, M8 and M9 significantly reduced the median blood pressure by 16.92% and 15.39% in SBP, and 18.56% and 20.62% in DBP, respectively. Metagenomic analysis revealed that the increased Lawsonia and Pyrolobus, and reduced Alistipes and Alloprevotella levels were tightly correlated with lowered BP. Functionally, the decreased pathways of “base excision repair” (BER) and “D-glutamine and D-glutamate metabolism” were associated with BP reduction. Metabolomics data analysis further revealed that the probiotic interventions regulated vascular smooth muscle contraction, serotonergic synapse, cholinergic synapse, and lipid and vitamin metabolism in BP control. Additionally, association analyses indicated a strong negative correlation between Alistipes and “steroid hormone biosynthesis,” suggesting that Alistipes could affect blood pressure by changing steroid hormone levels. In conclusion, our findings indicate that the probiotic efficacies in alleviating hypertension are linked to specific gut microbes and metabolic pathways, which provide a potential mechanistic understanding of probiotics modulated blood pressure, paving the way for future assessment of the therapeutic potential of probiotics in hypertension management.IMPORTANCEElevated blood pressure affects 40% of the adult population, which accounts for high cardiovascular disease risk and further high mortality yearly. The global understanding of the gut microbiome for hypertension may provide important insights into the prevention. Bifidobacterium lactis M8 and Lactobacillus rhamnosus M9 originated from human breast milk, were able to decrease blood pressure, and modified metabolites in a high fructose-induced elevated blood pressure mouse model. Moreover, we found there was a close relationship between unexplored gut microbes and elevated blood pressure. Also, subsequently, the cross-link was explored among gut microbes, metabolites, and some metabolic pathways in gut microbial environment through introducing novel prediction methodology and bioinformatic analysis. It allowed us to hypothesize that probiotics can prevent elevated blood pressure via gut microbiota and related metabolism.Thus, utilization of dietary strategies (such as probiotics) to maintain the blood pressure level is of crucial importance.

Flowability greatly affects the application of ultrafine dry powder fire extinguishing systems, while hydrophobicity and acute inhalation toxicity are concerns for fire extinguishing agents. In the present study, we examined the impact of hydrophobic fumed silica on the hydrophobicity and flow properties of ammonium dihydrogen phosphate as the base. Our findings revealed that incorporating 6 wt.% of hydrophobic fumed silica resulted in optimal flowability, accompanied by a hydrophobicity angle of 126.48°. The excessive inclusion of hydrophobic fumed silica impeded powder flow within the ammonium dihydrogen phosphate particles. Furthermore, the investigations indicated that the incorporation of a small quantity of bentonite (0.5 wt.%) amongst the three functional additives—bentonite, magnesium stearate, and perlite—offered further enhancements in powder flowability. In fire extinguishing experiments’ total flooding conditions (1 m3), the designed UDPA exhibited a minimum required extinguishing concentration of merely 41.5 g/m3, which is better than the publicly reported value. Moreover, observations on the well-being of mice subjected to nearly three times the extinguishing concentration at 60 s, 10 min, and 3 days, respectively, demonstrated the absence of acute inhalation toxicity associated with the designed UDPA. Collectively, the developed ultrafine dry powder fire extinguishing agent displayed promising performance and possesses broad applicability.

The gut microbiota plays a significant role in tumor pathogenesis by regulating the host metabolism and immune response, and there are few studies focused on tracking changes in the gut microbiota from the onset of lung cancer. Therefore, the aim of our study is combining preclinical and clinical research to thoroughly analyze the signatures of fecal microbiota in lung cancer, which will be useful for early diagnosis and predicting the therapeutic efficacy of lung cancer. The first part of this study analyzed the fecal metagenomic differences between patients with non-small cell lung cancer and healthy subjects, and the second part of this work constructed a murine lung cancer model to monitor changes in mouse fecal metagenomics and T cell immunology during lung cancer progression. We found that the fecal microbiota was altered in both humans and mice with lung cancer, characterized by a significantly reduced microbial diversity and number of beneficial microbes, with increases in potential pathogens. The fecal level of Akkermansia muciniphila and the gut metabolic module of the secondary bile acid metabolism were diminished in both humans and mice with lung cancer compared with healthy subjects. Splenomegaly was observed in the lung cancer mice. Flow cytometer analysis of the splenocytes revealed substantial alterations in the proportions of T cell subsets in the lung cancer mice, characterized by significant increases in CD4+Foxp3+CD25+ T regulatory cells (p < 0.05) while significant decreases in CD3+ T cells (p < 0.001), CD4+ T cells (p < 0.001), and the CD4+/CD8+ ratio (p < 0.01). Vertical and longitudinal analyses of the fecal microbiota of the two mouse groups identified some lung cancer biomarkers (including Acutalibacter timonensis, Lachnospiraceae bacterium NSJ-38 sp014337195, etc.). The fecal microbiota of the lung cancer mice had a reduced metagenomic potential for neurotransmitters (melatonin, γ-aminobutyric acid, and histamine) compared with healthy mice. In summary, this study found that the diversity, structure, and composition of gut microbiota vary between cancer and healthy conditions, ultimately leading to changes in the potential for functional metagenomics.

Abstract Probiotic functional products have drawn wide attention because of their increasing popularity. However, few studies have analyzed probiotic-specific metabolism in the fermentation process. This study applied UPLC-QE-MS-based metabolomics to track changes in the milk metabolomes in the course of fermentation by two probiotic strains, Lacticaseibacillus paracasei PC-01 and Bifidobacterium adolescentis B8589. We observed substantial changes in the probiotic fermented milk metabolome between 0 and 36 h of fermentation, and the differences between the milk metabolomes at the interim period (36 h and 60 h) and the ripening stage (60 h and 72 h) were less obvious. A number of time point-specific differential metabolites were identified, mainly belonging to organic acids, amino acids, and fatty acids. Nine of the identified differential metabolites are linked to the tricarboxylic acid cycle, glutamate metabolism, and fatty acid metabolism. The contents of pyruvic acid, γ-aminobutyric acid, and capric acid increased at the end of fermentation, which can contribute to the nutritional quality and functional properties of the probiotic fermented milk. This time-course metabolomics study analyzed probiotic-specific fermentative changes in milk, providing detailed information of probiotic metabolism in a milk matrix and the potential beneficial mechanism of probiotic fermented milk.

Abstract Lacticaseibacillus paracasei is an economically important bacterial species, used in the food industry and as a probiotic. Here, we investigate the roles of N6-methyladenine (6mA) modification in L. paracasei using multi-omics and high-throughput chromosome conformation capture (Hi-C) analyses. The distribution of 6mA-modified sites varies across the genomes of 28 strains, and appears to be enriched near genes involved in carbohydrate metabolism. A pglX mutant, defective in 6mA modification, shows transcriptomic alterations but only modest changes in growth and genomic spatial organization.

Ovulation induction is a first-line medical treatment for infertility in polycystic ovary syndrome (PCOS). Poor ovulation responses are assumed to be due to insulin resistance and hyperandrogenism. In a prospective cohort (PCOSAct) of 1000 infertile patients with PCOS, whole-exome plus targeted single-nucleotide polymorphism (SNP) sequencing and comprehensive metabolomic profiling were conducted. Significant genome-wide common variants and rare mutations associated with anovulation were identified, and a prediction model was built using machine learning. Common variants in zinc-finger protein 438 gene (ZNF438) indexed by rs2994652 (p = 2.47 × 10–8) and a rare functional mutation in REC114 (rs182542888, p = 5.79 × 10–6) were significantly associated with failure of ovulation induction. Women carrying the A allele of rs2994652 and REC114 p.Val101Leu (rs182542888) had lower ovulation (odds ratio (OR) = 1.96, 95% confidence interval (95%CI) = 1.55–2.49; OR = 11.52, 95%CI = 3.08–43.05, respectively) and prolonged time to ovulation (mean = 56.7 versus (vs) 49.0 days, p

ABSTRACT: Streptococcus thermophilus has been extensively applied in fermented milk. This study used gas chromatography-ion mobility spectroscopy to determine and evaluate the volatile metabolites in raw milk, milk fermented at 37°C, and milk fermented at 42°C. Ten discriminatory volatile metabolites were identified at different incubation temperatures: acetone, 2-heptanone, 2-pentanone, 2-hexanone, butanal, hexanal, ethyl acetate, 3-methylbutanal, 3-methylbutanoic acid, and 2-methylpropanoic acid, indicating that fermentation temperature affected the spectrum of volatiles in milk fermented by different strains of S. thermophilus. Specifically, fermentation at 37°C led to accumulation of short-chain fatty acids, whereas fermentation at 42°C enriched ketones and other flavor substances in the fermented milk, enhancing the flavor of the product. This work examined the differences between the volatile metabolites produced by different S. thermophilus strains fermented at different temperatures to evaluate the effect of temperature on the metabolic pathways.

Recently, some research has utilized machine learning methods to identify critical nodes in complex networks. However, existing approaches often lack a comprehensive consideration of network structural features during node feature extraction. Benefiting from the powerful feature extraction capability of network representation learning methods, a simple and effective algorithm for identifying key nodes in complex networks, termed Network Representation Learning and Key Node Identification (NRL_KNI), is proposed. The NRL_KNI algorithm utilizes network embedding techniques for learning node feature representations, followed by clustering and the utilization of quota-based limited sampling to obtain sampled nodes. Subsequently, these sampled nodes are employed to train a regression model for predicting the diffusion capability of unsampled nodes. To rank node influences, a Local Structure Influence Score (LSIS) based on the local structure is introduced to evaluate nodes’ final impact. Experimental results on eight real-world datasets demonstrate that the NRL_KNI algorithm generally outperforms traditional centrality methods and network representation learning-based methods in terms of the Jaccard similarity coefficient and Kendall’s Tau correlation coefficient evaluation metrics.

Intestinal bacteria play important roles in the progression of colitis-associated carcinogenesis. Colostrum-derived Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9) has shown a protective effect in a colitis-associated cancer (CAC) model, but detailed metagenomic analysis had not been performed. Here, we investigated the preventive effects of the probiotic Probio-M9 on CAC-model mice, tracking the microbiota. Feces were obtained at four time points for evaluation of gut microbiota. The effect of Probio-M9 on tight junction protein expression was evaluated in co-cultured Caco-2 cells. Probio-M9 treatment decreased the number of tumors as well as stool consistency score, spleen weight, inflammatory score, and macrophage expression in the CAC model. Probio-M9 accelerated the recovery of the structure, composition, and function of the intestinal microbiota destroyed by azoxymethane (AOM)/dextran sulfate sodium (DSS) by regulating key bacteria (including Lactobacillus murinus, Muribaculaceae bacterium DSM 103720, Muribaculum intestinale, and Lachnospiraceae bacterium A4) and pathways from immediately after administration until the end of the experiment. Probio-M9 co-culture protected against lipopolysaccharide-induced impairment of tight junctions in Caco-2 cells. This study provides valuable insight into the role of Probio-M9 in correcting gut microbiota defects associated with inflammatory bowel disease carcinogenesis and may have clinical application in the treatment of inflammatory carcinogenesis.

Hepatocellular carcinoma (HCC) is one of the most fatal cancers in the world. There is an urgent need to understand the molecular background of HCC to facilitate the identification of biomarkers and discover effective therapeutic targets. Published transcriptomic studies have reported a large number of genes that are individually significant for HCC. However, reliable biomarkers remain to be determined. In this study, built on max-linear competing risk factor models, we developed a machine learning analytical framework to analyze transcriptomic data to identify the most miniature set of differentially expressed genes (DEGs). By analyzing 9 public whole-transcriptome datasets (containing 1184 HCC samples and 672 nontumor controls), we identified 5 critical differentially expressed genes (DEGs) (ie, CCDC107, CXCL12, GIGYF1, GMNN, and IFFO1) between HCC and control samples. The classifiers built on these 5 DEGs reached nearly perfect performance in identification of HCC. The performance of the 5 DEGs was further validated in a US Caucasian cohort that we collected (containing 17 HCC with paired nontumor tissue). The conceptual advance of our work lies in modeling gene-gene interactions and correcting batch effect in the analytic framework. The classifiers built on the 5 DEGs demonstrated clear signature patterns for HCC. The results are interpretable, robust, and reproducible across diverse cohorts/populations with various disease etiologies, indicating the 5 DEGs are intrinsic variables that can describe the overall features of HCC at the genomic level. The analytical framework applied in this study may pave a new way for improving transcriptome profiling analysis of human cancers.

Background: Bloodstream infection (BSI) is a prevalent cause of admission in hemodialysis (HD) patients and is associated with increased morbidity and mortality. This study aimed to establish a diagnostic, predictive model for the early identification of BSI in HD patients. Methods: HD patients who underwent blood culture testing between August 2018 and March 2022 were enrolled in this study. Machine learning algorithms, including stepwise logistic regression (SLR), Lasso logistic regression (LLR), support vector machine (SVM), decision tree, random forest (RF), and gradient boosting machine (XGboost), were used to predict the risk of developing BSI from the patient's clinical data. The accuracy (ACC) and area under the subject working curve (AUC) were used to evaluate the performance of such models. The Shapley Additive Explanation (SHAP) values were used to explain each feature's predictive value on the models' output. Finally, a simplified nomogram for predicting BSI was devised. Results: A total of 391 HD patients were enrolled in this study, of whom 74 (18.9%) were diagnosed with BSI. The XGboost model achieved the highest AUC (0.914, 95% confidence interval [CI]: 0.861–0.964) and ACC (86.3%) for BSI prediction. The four most significant co-variables in both the significance matrix plot of the XGboost model variables and the SHAP summary plot were body temperature, dialysis access via a non-arteriovenous fistula (non-AVF), the procalcitonin levels (PCT), and neutrophil-lymphocyte ratio (NLR). Conclusions: This study created an effective machine-learning model for predicting BSI in HD patients. The model could be used to detect BSI at an early stage and hence guide antibiotic treatment in HD patients.

ABSTRACT Hyperlipidemia is a key risk factor for cardiovascular disease, and it is associated with lipid metabolic disorders and gut microbiota dysbiosis. Here, we aimed to investigate the beneficial effects of 3-month intake of a mixed probiotic formulation in hyperlipidemic patients (n = 27 and 29 in placebo and probiotic groups, respectively). The blood lipid indexes, lipid metabolome, and fecal microbiome before and after the intervention were monitored. Our results showed that probiotic intervention could significantly decrease the serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol (P

BackgroundThe purpose of this study is to establish a novel nomogram model for accurate detection of non-alcoholic fatty liver disease (NAFLD) in the Chinese population based on sex hormone binding globulin (SHBG) and other routine laboratory tests.MethodsA total of 1417 participants (1003 testing and 414 validations) were enrolled into the study. Risk factors independently associated with NAFLD were identified and incorporated in the new nomogram, SFI. The performance of nomogram was assessed by analysis of receiver operating characteristic (ROC) curve, calibration curve, and decision curve.ResultsWe formulated a new nomogram incorporating four independent factors: SHBG, body mass index (BMI), ALT/AST, and triglycerides (TG). The nomogram achieved good indexes of area under ROC 0.898 (95% confidence interval 0.865–0.926) in predicting NAFLD, which was significantly superior to previously reported models of FLI, HSI, LFS, and LAP. The calibration curve and decision curve demonstrated high performance and clinical utility of the nomogram in predicting NAFLD.ConclusionThe nomogram SFI has high performance in predicting NAFLD in Chinese population and may be used as a cost-effective screening model to assess NAFLD in the general population.

Chronic diarrhea has a considerable impact on quality of life. This randomized, double-blind, placebo-controlled crossover intervention trial was conducted with 69 participants (36 in Group A, 33 in Group B), aiming to investigate the potential of postbiotics in alleviating diarrhea-associated symptoms. Participants received postbiotic Probio-Eco® and placebo for 21 days each in alternating order, with a 14-day washout period between interventions. The results showed that postbiotic intake resulted in significant improvements in Bristol stool scale score, defecation frequency, urgency, and anxiety. Moreover, the postbiotic intervention increased beneficial intestinal bacteria, including Dysosmobacter welbionis and Faecalibacterium prausnitzii, while reducing potential pathogens like Megamonas funiformis. The levels of gut Microviridae notably increased. Non-targeted metabolomics analysis revealed postbiotic-driven enrichment of beneficial metabolites, including α-linolenic acid and p-methoxycinnamic acid, and reduction of diarrhea-associated metabolites, including theophylline, piperine, capsaicin, and phenylalanine. Targeted metabolomics confirmed a significant increase in fecal butyric acid after postbiotic intervention. The levels of aromatic amino acids, phenylalanine and tryptophan, and their related metabolites, 5-hydroxytryptophan and kynurenine, decreased after the postbiotic intervention, suggesting diarrhea alleviation was through modulating the tryptophan-5-hydroxytryptamine and tryptophan-kynurenine pathways. Additionally, chenodeoxycholic acid, a diarrhea-linked primary bile acid, decreased substantially. In conclusion, postbiotics have shown promise in relieving chronic diarrhea.

Background: The optimal protocol for minimal stimulation in vitro fertilization (IVF) has yet to be established. This study aims to determine if the use of gonadotropin-releasing hormone (GnRH) antagonist during minimal stimulation improves outcomes. Materials and Methods: All cycles designated as minimal stimulation from 2014 to 2016 from the Society for Assisted Reproductive Technology Clinic Online Reporting System were identified. Cycles in which GnRH antagonist was administered (n?=?5984) were compared to those that did not receive it (n?=?7066). Wilcoxon's rank-sum test and chi-square test were used to analyze continuous and categorical variables. Results: A total of 6750 patients undergoing 13,050 cycles were included. GnRH antagonist use was associated with a significantly higher total gonadotropin dosage (median 975.0 [interquartile range, IQR, 600.0, 1575.0] vs. median 660.0 [IQR 375.0, 975.0], p?0.001), lower cycle cancelation rate (11.3% vs. 13.6%, p?

Abstract Background Most previous studies attempting to prove the phenomenon of mother-to-infant microbiota transmission were observational, performed only at genus/species-level resolution, and relied entirely on non-culture-based methodologies, impeding interpretation. Results This work aimed to use a biomarker strain, Bifidobacterium animalis subsp. lactis Probio-M8 (M8), to directly evaluate the vertical transmission of maternally ingested bacteria by integrated culture-dependent/-independent methods. Our culture and metagenomics results showed that small amounts of maternally ingested bacteria could translocate to the infant gut via oral-/entero-mammary routes through lactation. Interestingly, many mother-infant-pair-recovered M8 homologous isolates exhibited high-frequency nonsynonymous mutations in a sugar transporter gene (glcU) and altered carbohydrate utilization preference/capacity compared with non-mutant isolates, suggesting that M8 underwent adaptive evolution for better survival in simple sugar-deprived lower gut environments. Conclusions This study presented direct and strain-level evidence of mother-to-infant bacterial transmission through lactation and provided insights into the impact of milk microbiota on infant gut colonization. Video Abstract

ABSTRACT: The addition of Bifidobacterium to goat milk has dual effects on health, for which various inherent nutrients of goat milk are retained and live probiotics are provided. We explored the effect of Bifidobacterium animalis ssp. lactis Probio-M8 (Probio-M8) on fermentation characteristics, formation of organic acid, sensory properties, and storage characteristics of fermented goat milk (with added 4.0% sucrose). Addition of Probio-M8 decreased the fermentation time and significantly increased the content of functional organic acids, such as acetic acid, and functional long-chain unsaturated fatty acids, including linoleic acid, α-linolenic acid, and docosahexaenoic acid. Furthermore, the contents of medium-chain and short-chain fatty acids, which are related to “goaty” flavor, were significantly lower in the Probio-M8 treatment compared with the control. The number of living Probio-M8 decreased from 8.27 log cfu/mL (1.80 × 108 cfu/mL) to 7.94 log cfu/mL (0.79 × 108 cfu/mL) after 28 d of storage. Titratable acidity and pH value did not differ between the control group and experimental group (containing Probio-M8). Sensory evaluation indicated a lower goaty flavor and odor in the Probio-M8 fermented milk. Our results suggest that the addition of the probiotic Probio-M8 could improve the sensory, physicochemical, and functional properties of fermented goat milk.

ABSTRACT: We evaluated the potential of whey protein hydrolysate as a lyoprotectant for maintaining the cell viability of Bifidobacterium animalis ssp. lactis Probio-M8 during freeze-drying and subsequent storage. The moisture content and water activity of the lyophilized samples treated by different concentrations of whey protein hydrolysate were ≤5.23 ± 0.33 g/100 g and ≤0.102 ± 0.003, respectively. During storage at 25°C and 30°C, whey protein hydrolysate had a stronger protective effect on B. lactis Probio-M8 than the same concentration of whey protein. Using the Excel tool GinaFit, we estimated the microbial inactivation kinetics during storage. Whey protein hydrolysate reduced cell damage caused by an increase in temperature. Whey protein hydrolysate could protect cells by increasing the osmotic pressure as a compatible solute. Whey protein hydrolysate improved cell membrane integrity and reduced the amounts of reactive oxygen species and malondialdehyde produced. The findings indicated that whey protein hydrolysate was a novel antioxidant lyoprotectant that could protect probiotics during freeze-drying and storage.

ABSTRACT: Probiotic fermented milk is more and more popular due to their positive health associated properties. However, fermentation temperature and other process conditions may affect the growth and metabolism of probiotic strains, thereby affecting quality of the final products. In this study, the growth behaviors and metabolomic profiles of yogurts induced by Lactobacillus casei Zhang at fermentation termination (FT) and d 10 of storage (S10d) under different fermentation temperatures at 37°C (low) and 42°C (high) were analyzed and compared using liquid chromatography-mass spectrometry (MS)- and gas chromatography-MS-based metabolomics approaches. At 37°C, the growth of L. casei Zhang at FT and S10d was significantly increased, and the potential relationship between riboflavin, starch, and sucrose metabolism and growth of L. casei Zhang may be mutually promoting. Fermentation temperature (37°C and 42°C) affected volatile and nonvolatile metabolomic profiles and pathways. The levels of acetaldehyde, 2,3-butanedione, acetoin, butyric acid, decanoic acid, hexanoic acid, and octanoic acid were significantly higher at 37°C than at 42°C at FT and S10d. This indicates that the low temperature (37°C) most likely contributes more to the formation of important flavor compounds during the fermentation process and production of short-chain fatty acids during storage.

Abstract Background Microbial communities in the human body, also known as human microbiota, impact human health, such as colorectal cancer (CRC). However, the different roles that microbial communities play in healthy and disease hosts remain largely unknown. The microbial communities are typically recorded through the taxa counts of operational taxonomic units (OTUs). The sparsity and high correlations among OTUs pose major challenges for understanding the microbiota-disease relation. Furthermore, the taxa data are structured in the sense that OTUs are related evolutionarily by a hierarchical structure. Results In this study, we borrow the idea of super-variant from statistical genetics, and propose a new concept called super-taxon to exploit hierarchical structure of taxa for microbiome studies, which is essentially a combination of taxonomic units. Specifically, we model a genus which consists of a set of OTUs at low hierarchy and is designed to reflect both marginal and joint effects of OTUs associated with the risk of CRC to address these issues. We first demonstrate the power of super-taxon in detecting highly correlated OTUs. Then, we identify CRC-associated OTUs in two publicly available datasets via a discovery-validation procedure. Specifically, four species of two genera are found to be associated with CRC: Parvimonas micra, Parvimonas sp., Peptostreptococcus stomatis, and Peptostreptococcus anaerobius. More importantly, for the first time, we report the joint effect of Parvimonas micra and Parvimonas sp. (p = 0.0084) as well as that of Peptostrepto-coccus stomatis and Peptostreptococcus anaerobius (p = 8.21e-06) on CRC. The proposed approach provides a novel and useful tool for identifying disease-related microbes by taking the hierarchical structure of taxa into account and further sheds new lights on their potential joint effects as a community in disease development. Conclusions Our work shows that proposed approaches are effective to study the microbiota-disease relation taking into account for the sparsity, hierarchical and correlated structure among microbes.

Abstract Background The two subspecies of Bifidobacterium catenulatum, B. catenulatum subsp. kashiwanohense and B. catenulatum subsp. catenulatum, are usually from the infant and adult gut, respectively. However, the genomic analysis of their functional difference and genetic divergence has been rare. Here, 16 B. catenulatum strains, including 2 newly sequenced strains, were analysed through comparative genomics. Results A phylogenetic tree based on 785 core genes indicated that the two subspecies of B. catenulatum were significantly separated. The comparison of genomic characteristics revealed that the two subspecies had significantly different genomic sizes (p

Chronic constipation (CC) is a common gastrointestinal condition associated with intestinal inflammation, and the condition considerably impairs patients’ quality of life. We conducted a large-scale 42-day randomized, double-blind, placebo-controlled trial to investigate the effect of probiotics in alleviating CC. 163 patients diagnosed with CC (following Rome IV criteria) were randomly divided into probiotic (n = 78; received Lactiplantibacillus plantarum P9 [P9]; 1 ×1011 CFU/day) and placebo (n = 85; received placebo material) groups. Ingesting P9 significantly improved the weekly mean frequency of complete spontaneous bowel movements (CSBMs) and spontaneous bowel movements (SBMs), while significantly reducing the level of worries and concerns (WO; P

Summary: Background: Probiotics have been increasingly proposed for enhancing immune checkpoint blockade (ICB) treatments against cancer. However, its causal relationship with immunotherapeutic efficacy remains unclear, which promoted us to explore if and how probiotic Lacticaseibacillus rhamnosus Probio-M9 manipulates gut microbiome for expected outcomes. Methods: We evaluated the effects of Probio-M9 on the anti-PD-1 treatment against colorectal cancer in mice via a multi-omics approach. We defined the mechanisms of Probio-M9-mediated antitumor immunity by comprehensive analyses of metagenome and metabolites of commensal gut microbes as well as the immunologic factors and serum metabolome of the host. Findings: The results indicated that Probio-M9 intervention strengthened the anti-PD-1-based tumor inhibition. Both prophylactic and therapeutic administration of Probio-M9 showed conspicuous performance in controlling tumor growth with ICB treatment. The supplement of Probio-M9 modulated enhanced immunotherapy response through promoting beneficial microbes (e.g., Lactobacillus and Bifidobacterium animalis), producing beneficial metabolites including butyric acids in the gut, and accumulating blood-derived α-ketoglutaric acid, N-acetyl-l-glutamic acid and pyridoxine in particular, which promoted the infiltration and activation of cytotoxic T lymphocytes (CTLs) and suppressing the function of regulatory T cells (Tregs) in the tumor microenvironment (TME). Subsequently, we found that enhanced immunotherapeutic response was transmissible by transplanting either post-probiotic-treatment gut microbes or intestinal metabolites to new tumor-bearing mice. Interpretation: This study offered valuable insight into the causal role of Probio-M9 in correcting the defects in gut microbiota that compromised anti-PD-1 therapeutic efficacy, which can be used as an alternative synergetic agent with ICB for clinical cancer treatment. Funding: This research was supported by Research Fund for the National Key R&D Program of China (2022YFD2100702), Inner Mongolia Science and Technology Major Projects (2021ZD0014), and China Agriculture Research System of MOF and MARA.

Cuproptosis is a kind of cell death dependent on copper. We aimed to explore the functions of the cuproptosis in the tumor microenvironment (TME) and construct a cuproptosis-related prognosis signature in bladder cancer (BCa). Using BCa patients in the public cohort, the cuproptosis-related molecular subtypes and cuproptosis-related prognosis signature were developed. Three cuproptosis-related molecular subtypes, with different prognoses and TME characteristics, were identified in BCa. The cuproptosis-related prognosis signature can divide patients into high- and low-risk groups with different prognoses, TME characteristics, chemotherapeutic drug susceptibility and immunotherapeutic response. Low risk group patients had a favored prognosis and response to immunotherapy. The dysregulation of cuproptosis-related genes expression levels was validated in multiple BCa cells using in vitro experiments. Cuproptosis has an important role in the tumor progression and the characterization of TME in BCa. The cuproptosis-related prognosis signature is a useful biomarker that can reflect the prognosis, TME characteristics, immunotherapeutic response and chemotherapeutic drug susceptibility in BCa patients.

Background: Probiotics may be an ideal choice for these patients, given it can improve the defecation and quality of life of individuals with chronic diarrhoea. However, evidence-based medical research is still limited to support its use as a diarrhoea agent. Method: A randomized, double-blind, placebo-controlled clinical trial is designed to pinpoint the efficiency and possible action modes of probiotics for chronic diarrhoea. 200 eligible volunteers with chronic diarrhoea are randomly assigned to a probiotic group (orally taking Lactobacillus plantarum p9 probiotics powder) or a placebo group. Except an independent project administrator who will be responsible for unblinding, the other researchers are blinded. Primary outcome is diarrhoea severity score, and secondary outcomes include weekly mean frequency of defecation, weekly mean stool appearance score, weekly mean stool urgency score, emotional state score, gut microbiome, and faecal metabolome. Each outcome measure will be assessed at the timepoints of pre-administration (day 0), administration (day 14 and/or 28), and post-administration (day 42) to identity inter- and intra-groups differences. Adverse events will be recorded to evaluate the safety of L. plantarum p9. Discussion: The study protocol will provide high-quality evidence for the use of probiotics as a diarrhoea agent when it is strictly conducted out, providing evidence regarding whether and to what extent L. plantarum p9 can improve the defecation and well-being of individuals with chronic diarrhoea. Trial registration: Chinese Clinical Trial Registry (ChiCTR) (NO. ChiCTR2000038410). Registered on November 22, 2020, https://www.chictr.org.cn/showproj.aspx?proj=56542.