Impact of Synbiotic Intake on Liver Metabolism in Metabolically Healthy Participants and Its Potential Preventive Effect on Metabolic-Dysfunction-Associated Fatty Liver Disease (MAFLD): A Randomized, Placebo-Controlled, Double-Blinded Clinical Trial.

Synbiotics modulate the gut microbiome and contribute to the prevention of liver diseases such as metabolic-dysfunction-associated fatty liver disease (MAFLD). This study aimed to evaluate the effect of a randomized, placebo-controlled, double-blinded seven-week intervention trial on the liver metabolism in 117 metabolically healthy male participants. Anthropometric data, blood parameters, and stool samples were analyzed using linear mixed models. After seven weeks of intervention, there was a significant reduction in alanine aminotransferase (ALT) in the synbiotic group compared to the placebo group (-14.92%, CI: -26.60--3.23%, p = 0.013). A stratified analysis according to body fat percentage revealed a significant decrease in ALT (-20.70%, CI: -40.88--0.53%, p = 0.045) in participants with an elevated body fat percentage. Further, a significant change in microbiome composition (1.16, CI: 0.06-2.25, p = 0.039) in this group was found, while the microbial composition remained stable upon intervention in the group with physiological body fat. The 7-week synbiotic intervention reduced ALT levels, especially in participants with an elevated body fat percentage, possibly due to modulation of the gut microbiome. Synbiotic intake may be helpful in delaying the progression of MAFLD and could be used in addition to the recommended lifestyle modification therapy.

Impact of the gut microbiome composition on social decision-making.

There is increasing evidence for the role of the gut microbiome in the regulation of socio-affective behavior in animals and clinical conditions. However, whether and how the composition of the gut microbiome may influence social decision-making in health remains unknown. Here, we tested the causal effects of a 7-week synbiotic (vs. placebo) dietary intervention on altruistic social punishment behavior in an ultimatum game. Results showed that the intervention increased participants' willingness to forgo a monetary payoff when treated unfairly. This change in social decision-making was related to changes in fasting-state serum levels of the dopamine-precursor tyrosine proposing a potential mechanistic link along the gut-microbiota-brain-behavior axis. These results improve our understanding of the bidirectional role body-brain interactions play in social decision-making and why humans at times act "irrationally" according to standard economic theory.

Effect of replacing soybean meal with Hermetia illucens meal on cecal microbiota, liver transcriptome, and plasma metabolome of broilers.

Despite the existence of a number of studies investigating the effect of insect meal on the growth performance of broilers, knowledge about the metabolic effects of insect meal in broilers is still scarce. Thus, the present study investigated the effect of partial replacement of soybean meal with Hermetia illucens (HI) larvae meal on the liver transcriptome, the plasma metabolome, and the cecal microbiota in broilers. For the study, 72 male one-day-old Cobb 500 broilers were divided into three groups and fed 3 different diets with either 0% (HI0), 7.5% (HI7.5), or 15% (HI15) defatted HI meal for 35 d. Each group consisted of 6 cages (replicates) with 4 broilers/cage. While body weight (BW) gain, feed intake, and feed:gain ratio did not differ between groups, breast muscle weight, carcass yield, and apparent ileal digestibility (AID) of 5 amino acids were higher in group HI15 than in group HI0 (P < 0.05). Indicators of α-diversity (Chao1 and Observed) in the cecal digesta were higher in groups HI15 and HI7.5 than in group HI0 (P < 0.05). The abundance of 5 families and 18 genera, all of which belonged to the Firmicutes phylum, in the cecal digesta differed among groups (P < 0.05). Concentrations of butyric acid, valeric acid, and isobutyric acid in the cecal digesta were lower in group HI15 than in the other 2 groups (P < 0.05), whereas those of total and other short-chain fatty acids were not different between groups. Liver transcriptomics revealed a total of 70 and 61 differentially expressed transcripts between groups HI15 vs. HI0 and between groups HI7.5 vs. HI0, respectively, (P < 0.05). Targeted metabolomics identified 138 metabolites, most of which were triglyceride species, being different between the 3 groups (FDR < 0.05). According to this study, dietary inclusion of HI larvae meal has no detrimental impact but increases breast muscle weight and carcass weight in broilers suggesting that HI larvae meal can be recommended as a sustainable alternative protein source for broilers.

Epigenetic variation impacts individual differences in the transcriptional response to influenza infection.

Humans display remarkable interindividual variation in their immune response to identical challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we performed in-depth genetic, epigenetic and transcriptional profiling on primary macrophages derived from individuals of European and African ancestry before and after infection with influenza A virus. We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to influenza A virus across individuals. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation, with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape can be genetically controlled, even more than gene expression. Lastly, among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, while the remaining genetic variants impact epigenetic marks, stressing the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.

Antibiotic definitive treatment in ventilator associated pneumonia caused by AmpC-producing Enterobacterales in critically ill patients: a prospective multicenter observational study.

BACKGROUND: Ventilator associated pneumonia (VAP) due to wild-type AmpC-producing Enterobacterales (wtAE) is frequent in intensive care unit (ICU) patients. Despite a low level of evidence, definitive antimicrobial therapy (AMT) with third generation cephalosporins (3GCs) or piperacillin is discouraged. METHODS: Observational prospective study including consecutive wtAE VAP patients in 20 French ICUs. The primary objective was to assess the association of the choice of definitive AMT, i.e. piperacillin ± tazobactam (PTZ), 3GCs or other molecule (4GCs, carbapenems, quinolones, cotrimoxazole; control group), with treatment success at day-7. Recurrence of infection was collected as a secondary outcome, and analyzed accounting for the competing risk of death. RESULTS: From February 2021 to June 2022, 274 patients were included. Enterobacter cloacae was the most prevalent specie (31%). Seventy-eight patients (28%) had PTZ as definitive AMT while 44 (16%) had 3GCs and 152 (56%) were classified in the control group. Day-7 success rate was similar between the 3 groups (74% vs. 73% vs. 68% respectively, p = 0.814). Recurrence probability at day-28 was 31% (95% CI 21-42), 40% (95% CI 26-55) and 21% (95% CI 15-28) for PTZ, 3GCs and control groups (p = 0.020). In multivariable analysis, choice of definitive AMT was not associated with clinical success, but definitive AMT with 3GCs was associated with recurrence at day-28 [csHR(95%CI) 10.9 (1.92-61.91)]. CONCLUSION: Choice of definitive antimicrobial therapy was not associated with treatment success at day 7. However, recurrence of pneumonia at day-28 was higher in patients treated with third generation cephalosporins with no differences in mortality or mechanical ventilation duration.

Impact of Physiological Fluctuations of Sex Hormones During the Menstrual Cycle on Glucose Metabolism and the Gut Microbiota.

Diabetes mellitus is one of the most prevalent chronic diseases. Previous studies have shown differences in glucose metabolism between males and females. Moreover, difficulties in medication adherence have been reported in females with type 2 diabetes. These observations are believed to be caused by fluctuations in sex hormone concentrations during the menstrual cycle. Furthermore, gut microbiota is linked to female host metabolism and sex hormone production. Understanding the interactions between fluctuating hormone concentrations during the menstrual cycle, gut microbiota, and glucose metabolism in humans is significant because of the increasing prevalence of diabetes and the consequent need to expand preventive efforts. A literature search was performed to determine and summarize the existing evidence, deduce future research needs to maintain female health, and investigate the relationship between the physiological menstrual cycle and glucose metabolism. Studies from 1967 to 2020 have already examined the relationship between variations during the menstrual cycle and glucose metabolism in healthy female subjects using an oral-glucose tolerance test or intravenous glucose tolerance test. However, the overall number of studies is rather small and the results are contradictory, as some studies detected differences in glucose concentrations depending on the different cycle phases, whereas others did not. Some studies reported lower glucose levels in the follicular phase than in the luteal phase, whereas another study detected the opposite. Data on gut microbiota in relation to the menstrual cycle are limited. Conflicting results exist when examining the effect of hormonal contraceptives on the gut microbiota and changes in the course of the menstrual cycle. The results indicate that the menstrual cycle, especially fluctuating sex hormones, might impact the gut microbiota composition.The menstrual cycle may affect the gut microbiota composition and glucose metabolism. These results indicate that glucose tolerance may be the greatest in the follicular phase; however, further well-conducted studies are needed to support this assumption.

On the edge: how nuclear pore complexes rule genome stability.

Nuclear organization has emerged as a critical layer in the coordination of DNA repair activities. Distinct types of DNA lesions have notably been shown to relocate at the vicinity of nuclear pore complexes (NPCs), where specific repair pathways are favored, ultimately safeguarding genome integrity. Here, we review the most recent progress in this field, notably highlighting the increasingly diverse types of DNA structures undergoing repositioning, and the signaling pathways involved. We further discuss our growing knowledge of the molecular mechanisms underlying the choice of repair pathways at NPCs, and their conservation - or divergences. Intriguingly, a series of recent findings suggest that DNA metabolism may be coupled to NPC biogenesis and specialization, challenging our initial vision of these processes.

Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions - a narrative review.

Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters and G-protein-coupled receptors (GPCRs). GLP-1 secretion may be lower in adults with obesity/overweight (OW) or type 2 diabetes mellitus (T2DM) than in those with normal glucose tolerance (NGT), but these findings are inconsistent. Because of the actions of GLP-1 on stimulating insulin secretion and promoting weight loss, GLP-1 and its analogs are used in pharmacologic preparations for the treatment of T2DM. However, physiologically stimulated GLP-1 secretion through the diet might be a preventive or synergistic method for improving glucose metabolism in individuals who are OW, or have impaired glucose tolerance (IGT) or T2DM. This narrative review focuses on fasting and postprandial GLP-1 secretion in individuals with different metabolic conditions and degrees of glucose intolerance. Further, the influence of relevant diet-related factors (e.g., specific diets, meal composition, and size, phytochemical content, and gut microbiome) that could affect fasting and postprandial GLP-1 secretion are discussed. Some studies showed diminished glucose- or meal-stimulated GLP-1 response in participants with T2DM, IGT, or OW compared with those with NGT, whereas other studies have reported an elevated or unchanged GLP-1 response in T2DM or IGT. Meal composition, especially the relationship between macronutrients and interventions targeting the microbiome can impact postprandial GLP-1 secretion, although it is not clear which macronutrients are strong stimulants of GLP-1. Moreover, glucose tolerance, antidiabetic treatment, grade of overweight/obesity, and sex were important factors influencing GLP-1 secretion. The results presented in this review highlight the potential of nutritional and physiologic stimulation of GLP-1 secretion. Further research on fasting and postprandial GLP-1 concentrations and the resulting metabolic consequences under different metabolic conditions is needed.

Behavioural evidence for enhanced olfactory and trigeminal perception in congenital hearing loss.

Sensory deprivation, especially hearing loss (HL), offers a valuable model for studying neuroplasticity in the human brain and adaptive behaviours that support the daily lives of those with limited or absent sensory input. The study of olfactory function is particularly important as it is an understudied aspect of sensory deprivation. This study aimed to compare the effects of congenital HL on olfactory capacity by using psychophysical tasks. Methodological concerns from previous studies regarding the onset of HL and cognitive assessments were addressed. We recruited 11 individuals with severe-to-profound sensorineural HL (SNHL) since birth and 11 age- and sex-matched typical hearing non-signers. We used standardized neuropsychological tests to assess typical cognition among participants with SNHL. We evaluated olfactory functions by assessing olfactory detection threshold, odour discrimination and odour identification. Hearing-impaired participants outperformed their typical hearing counterparts in olfactory tasks. We further evaluated the accuracy and response time in identifying and localizing odours to disentangle olfactory sensitivity from trigeminal system sensitivity. Participants with SNHL demonstrated higher sensitivity to both the identification and localization tasks. These findings suggest that congenital SNHL is associated with enhanced higher-level olfactory processing and increased trigeminal sensitivity.

Fat from Hermetia illucens Alters the Cecal Gut Microbiome and Lowers Hepatic Triglyceride Concentration in Comparison to Palm Oil in Obese Zucker Rats.

BACKGROUND: Palm oil (PO) is the most widely utilized plant oil for food production. Owing to the great ecologic problems associated with PO production, sustainably produced fats, such as insect fat, might be a suitable alternative. OBJECTIVES: The hypothesis was tested that fat from Hermetia illucens larvae (HF) compared with PO and soybean oil (SO) has no adverse effects on hepatic lipid metabolism, plasma metabolome, and cecal microbiome in obese Zucker rats. METHODS: Thirty male obese Zucker rats were randomly assigned to 3 groups (SO, PO, HF; n = 10 rats/group) and fed 3 different semisynthetic diets containing either SO, PO, or HF as the main fat source for 4 wk. The effects were evaluated by measurement of liver and plasma lipid concentrations, liver transcriptomics, targeted plasma metabolomics, and cecal microbiomics. RESULTS: Supplementation of HF reduced hepatic triglyceride concentration and messenger ribonucleic acid concentrations of selected genes involved in fatty acid and triglyceride synthesis in comparison to PO (P < 0.05). Pairwise comparison of the Simpson index and Jaccard index showed a higher cecal microbial α- and ß-diversity in rats fed the HF diet than in rats fed the PO diet (P = 0.015 and P = 0.027), but no difference between rats fed the diets with SO or PO. Taxonomic analysis of the cecal microbial community revealed a lower abundance of Clostridium_sensu_stricto_1 and a higher abundance of Blautia, Mucispirillum, Anaerotruncus, Harryflintia, and Peptococcus in rats supplemented with HF than in rats supplemented with PO (P < 0.05). CONCLUSIONS: HF, compared with PO, has liver lipid-lowering effects in obese Zucker rats, which may be caused by a shift in the gut microbial community. Thus, HF might serve as a sustainably produced fat alternative to PO for food production.

Factors associated with short- and long-term outcomes in lung cancer patients requiring unplanned invasive mechanical ventilation.

OBJECTIVE: Unplanned invasive mechanical ventilation (IMV) is associated with high mortality in lung cancer patients. We aimed to identify factors associated with weaning from IMV, intensive care unit (ICU) survival and 1-year survival in lung cancer patients requiring unplanned IMV. DESIGN: Retrospective observational study (2007-2017). SETTING: University-affiliated ICU. PATIENTS: Lung cancer patients requiring unplanned IMV. INTERVENTION: None. MAIN VARIABLES OF INTEREST: Weaning from IMV, ICU and 1-year survival. RESULTS: Of the 136 patients included in the analysis (age 64 (9) years, male 110 (81%), metastatic disease 97 (62%)), 52 (38%) were weaned from IMV, 51 (38%) were discharged from ICU and 22 (16%) were alive at 1year. The main indication for intubation was acute respiratory failure. In multivariate analysis, PaO2/FiO2 >175mmHg at ICU admission and intubation before ICU admission were associated with successful weaning from IMV while intubation for cardiac arrest was associated with weaning failure. Same factors were associated with ICU survival. Absence of metastasis at ICU admission and lung resection surgery were independently associated with 1-year survival. CONCLUSIONS: A significant proportion of patients with lung cancer treated with unplanned IMV could be weaned from IMV and survived to ICU discharge, especially in the absence of severe hypoxemia at ICU admission. The low one-year survival was mostly driven by metastatic status.

A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes.

Nuclear pore complexes (NPCs) have increasingly recognized interactions with the genome, as exemplified in yeast, where they bind transcribed or damaged chromatin. By combining genome-wide approaches with live imaging of model loci, we uncover a correlation between NPC association and the accumulation of R-loops, which are genotoxic structures formed through hybridization of nascent RNAs with their DNA templates. Manipulating hybrid formation demonstrates that R-loop accumulation per se, rather than transcription or R-loop-dependent damages, is the primary trigger for relocation to NPCs. Mechanistically, R-loop-dependent repositioning involves their recognition by the ssDNA-binding protein RPA, and SUMO-dependent interactions with NPC-associated factors. Preventing R-loop-dependent relocation leads to lethality in hybrid-accumulating conditions, while NPC tethering of a model hybrid-prone locus attenuates R-loop-dependent genetic instability. Remarkably, this relocation pathway involves molecular factors similar to those required for the association of stalled replication forks with NPCs, supporting the existence of convergent mechanisms for sensing transcriptional and genotoxic stresses.

The place of new antibiotics for Gram-negative bacterial infections in intensive care: report of a consensus conference.

INTRODUCTION: New beta-lactams, associated or not with beta-lactamase inhibitors (NBs/BIs), can respond to the spread of carbapenemase-producing enterobacteriales and nonfermenting carbapenem-resistant bacteria. The risk of emergence of resistance to these NBs/BIs makes guidelines necessary. The SRLF organized a consensus conference in December 2022. METHODS: An ad hoc committee without any conflict of interest (CoI) with the subject identified the molecules (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, meropenem-vaborbactam and cefiderocol); defined 6 generic questions; drew up a list of subquestions according to the population, intervention, comparison and outcomes (PICO) model; and reviewed the literature using predefined keywords. The quality of the data was assessed using the GRADE methodology. Seven experts in the field proposed their own answers to the questions in a public session and answered questions from the jury (a panel of 10 critical-care physicians without any CoI) and the public. The jury then met alone for 48 h to write its recommendations. Due to the frequent lack of powerful studies that have used clinically important criteria of judgment, the recommendations were formulated as expert opinions as often as necessary. RESULTS: The jury provided 17 statements answering 6 questions: (1) Is there a place in the ICU for the probabilistic use of new NBs/IBs active against Gram-negative bacteria? (2) In the context of documented infections with sensitivity to several of these molecules, are there pharmacokinetic, pharmacodynamic, ecological or medico-economic elements for prioritization? (3) What are the possible combinations with these molecules and in what context? (4) Should we integrate these new molecules into a carbapenem-sparing strategy? (5) What pharmacokinetic and pharmacodynamic data are available to optimize their mode of administration in critically ill patients? (6) What are the dosage adaptations in cases of renal insufficiency, hepatocellular insufficiency or obesity? CONCLUSION: These recommendations should optimize the use of NBs/BIs in ICU patients.

NPCs and APBs: two HUBs of non-canonical homology-based recombination at telomeres?

Apart from a few rare exceptions, the maintenance of functional telomeres by recombination-based mechanisms is restricted to accidental and/or pathological situations. Originally described in the yeast S. cerevisiae, this mode of telomere repair has gained interest with the discovery of telomerase negative cancers that use alternative lengthening of telomeres (ALT cancer) dependent on homologous recombination. In both yeast and humans, it has been shown that recombination at telomeres is spatially regulated and occurs preferentially at the nuclear pore complexes (NPCs) in yeast and at ALT-associated promyelocytic leukemia nuclear bodies (APBs) in human cells. Here, we discuss the potential relationships between these two membrane-less structures and their role in enabling unconventional recombination pathways.

Genome graphs detect human polymorphisms in active epigenomic state during influenza infection.

Genetic variants, including mobile element insertions (MEIs), are known to impact the epigenome. We hypothesized that genome graphs, which encapsulate genetic diversity, could reveal missing epigenomic signals. To test this, we sequenced the epigenome of monocyte-derived macrophages from 35 ancestrally diverse individuals before and after influenza infection, allowing us to investigate the role of MEIs in immunity. We characterized genetic variants and MEIs using linked reads and built a genome graph. Mapping epigenetic data revealed 2.3%-3% novel peaks for H3K4me1, H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq), and ATAC-seq. Additionally, the use of a genome graph modified some quantitative trait loci estimates and revealed 375 polymorphic MEIs in an active epigenomic state. Among these is an AluYh3 polymorphism whose chromatin state changed after infection and was associated with the expression of TRIM25, a gene that restricts influenza RNA synthesis. Our results demonstrate that graph genomes can reveal regulatory regions that would have been overlooked by other approaches.

Transposable elements are associated with the variable response to influenza infection.

Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.