Signals from intestinal microbiota mediate the crosstalk between the lung-gut axis in an influenza infection mouse model.

Introduction: Introduction: The influenza virus primarily targets the respiratory tract, yet both the respiratory and intestinal systems suffer damage during infection. The connection between lung and intestinal damage remains unclear. Methods: Our experiment employs 16S rRNA technology and Liquid Chromatography-Mass Spectrometry (LC-MS) to detect the impact of influenza virus infection on the fecal content and metabolites in mice. Additionally, it investigates the effect of influenza virus infection on intestinal damage and its underlying mechanisms through HE staining, Western blot, Q-PCR, and flow cytometry. Results: Our study found that influenza virus infection caused significant damage to both the lungs and intestines, with the virus detected exclusively in the lungs. Antibiotic treatment worsened the severity of lung and intestinal damage. Moreover, mRNA levels of Toll-like receptor 7 (TLR7) and Interferon-b (IFN-b) significantly increased in the lungs post-infection. Analysis of intestinal microbiota revealed notable shifts in composition after influenza infection, including increased Enterobacteriaceae and decreased Lactobacillaceae. Conversely, antibiotic treatment reduced microbial diversity, notably affecting Firmicutes, Proteobacteria, and Bacteroidetes. Metabolomics showed altered amino acid metabolism pathways due to influenza infection and antibiotics. Abnormal expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon disrupted the balance between helper T17 cells (Th17) and regulatory T cells (Treg cells) in the intestine. Mice infected with the influenza virus and supplemented with tryptophan and Lactobacillus showed reduced lung and intestinal damage, decreased Enterobacteriaceae levels in the intestine, and decreased IDO1 activity. Discussion: Overall, influenza infection caused damage to lung and intestinal tissues, disrupted intestinal microbiota and metabolites, and affected Th17/Treg balance. Antibiotic treatment exacerbated these effects. Supplementation with tryptophan and Lactobacillus improved lung and intestinal health, highlighting a new understanding of the lung-intestine connection in influenza-induced intestinal disease.

Barcoded overexpression screens in gut Bacteroidales identify genes with roles in carbon utilization and stress resistance.

A mechanistic understanding of host-microbe interactions in the gut microbiome is hindered by poorly annotated bacterial genomes. While functional genomics can generate large gene-to-phenotype datasets to accelerate functional discovery, their applications to study gut anaerobes have been limited. For instance, most gain-of-function screens of gut-derived genes have been performed in Escherichia coli and assayed in a small number of conditions. To address these challenges, we develop Barcoded Overexpression BActerial shotgun library sequencing (Boba-seq). We demonstrate the power of this approach by assaying genes from diverse gut Bacteroidales overexpressed in Bacteroides thetaiotaomicron. From hundreds of experiments, we identify new functions and phenotypes for 29 genes important for carbohydrate metabolism or tolerance to antibiotics or bile salts. Highlights include the discovery of a D-glucosamine kinase, a raffinose transporter, and several routes that increase tolerance to ceftriaxone and bile salts through lipid biosynthesis. This approach can be readily applied to develop screens in other strains and additional phenotypic assays.

Large-scale genetic correlation studies explore the causal relationship and potential mechanism between gut microbiota and COVID-19-associated risks.

Recent observational studies suggest that gut microorganisms are involved in the onset and development of coronavirus disease 2019 (COVID-19), but the potential causal relationship behind them remains unclear. Exposure data were derived from the MiBioGen consortium, encompassing 211 gut microbiota (n = 18,340). The outcome data were sourced from the COVID-19 host genetics initiative (round 7), including COVID-19 severity (n = 1,086,211), hospitalization (n = 2,095,324), and susceptibility (n = 2,597,856). First, a two-sample Mendelian randomization (TSMR) was performed to investigate the causal effect between gut microbiota and COVID-19 outcomes. Second, a two-step MR was used to explore the potential mediators and underlying mechanisms. Third, several sensitivity analyses were performed to verify the robustness of the results. Five gut microbes were found to have a potential causality with COVID-19 severity, namely Betaproteobacteria (beta = 0.096, p = 0.034), Christensenellaceae (beta = -0.092, p = 0.023), Adlercreutzia (beta = 0.072, p = 0.048), Coprococcus 1 (beta = 0.089, p = 0.032), Eisenbergiella (beta = 0.064, p = 0.024). Seven gut microbes were found to have a potential causality with COVID-19 hospitalization, namely Victivallaceae (beta = 0.037, p = 0.028), Actinomyces (beta = 0.047, p = 0.046), Coprococcus 2 (beta = -0.061, p = 0.031), Dorea (beta = 0.067, p = 0.016), Peptococcus (beta = -0.035, p = 0.049), Rikenellaceae RC9 gut group (beta = 0.034, p = 0.018), and Proteobacteria (beta = -0.069, p = 0.035). Two gut microbes were found to have a potential causality with COVID-19 susceptibility, namely Holdemanella (beta = -0.024, p = 0.023) and Lachnospiraceae FCS020 group (beta = 0.026, p = 0.027). Multi-omics mediation analyses indicate that numerous plasma proteins, metabolites, and immune factors are critical mediators linking gut microbiota with COVID-19 outcomes. Sensitivity analysis suggested no significant heterogeneity or pleiotropy. These findings revealed the causal correlation and potential mechanism between gut microbiota and COVID-19 outcomes, which may improve our understanding of the gut-lung axis in the etiology and pathology of COVID-19 in the future.

Ameliorative effects of mesenchymal stromal cells on senescence associated phenotypes in naturally aged rats.

BACKGROUND: Aging is a multifaceted process that affects all organ systems. With the increasing trend of population aging, aging-related diseases have resulted in significant medical challenges and socioeconomic burdens. Mesenchymal stromal cells (MSCs), due to their antioxidative stress, immunoregulatory, and tissue repair capabilities, hold promise as a potential anti-aging intervention. METHODS: In this study, we transplanted MSCs into naturally aged rats at 24 months, and subsequently examined levels of aging-related factors such as ß-galactosidase, superoxide dismutase, p16, p21 and malondialdehyde in multiple organs. Additionally, we assessed various aging-related phenotypes in these aged rats, including immune senescence, lipid deposition, myocardial fibrosis, and tissue damage. We also conducted a 16 S ribosomal ribonucleic acid (rRNA) analysis to study the composition of gut microbiota. RESULTS: The results indicated that MSCs significantly reduced the levels of aging-associated and oxidative stress-related factors in multiple organs such as the heart, liver, and lungs of naturally aging rats. Furthermore, they mitigated chronic tissue damage and inflammation caused by aging, reduced levels of liver lipid deposition and myocardial fibrosis, alleviated aging-associated immunodeficiency and immune cell apoptosis, and positively influenced the gut microbiota composition towards a more youthful state. This research underscores the diverse anti-aging effects of MSCs, including oxidative stress reduction, tissue repair, metabolic regulation, and improvement of immune functions, shedding light on the underlying anti-aging mechanisms associated with MSCs. CONCLUSIONS: The study confirms that MSCs hold great promise as a potential anti-aging approach, offering the possibility of extending lifespan and improving the quality of life in the elderly population.

Relationship between deltamethrin resistance and gut symbiotic bacteria of Aedes albopictus by 16S rDNA sequencing.

BACKGROUND: Aedes albopictus is an important vector for pathogens such as dengue, Zika, and chikungunya viruses. While insecticides is the mainstay for mosquito control, their widespread and excessive use has led to the increased resistance in Ae. albopictus globally. Gut symbiotic bacteria are believed to play a potential role in insect physiology, potentially linking to mosquitoes' metabolic resistance against insecticides. METHODS: We investigated the role of symbiotic bacteria in the development of resistance in Ae. albopictus by comparing gut symbiotic bacteria between deltamethrin-sensitive and deltamethrin-resistant populations. Adults were reared from field-collected larvae. Sensitive and resistant mosquitoes were screened using 0.03% and 0.09% deltamethrin, respectively, on the basis of the World Health Organization (WHO) tube bioassay. Sensitive and resistant field-collected larvae were screened using 5 × LC50 (lethal concentration at 50% mortality) and 20 × LC50 concentration of deltamethrin, respectively. Laboratory strain deltamethrin-sensitive adults and larvae were used as controls. The DNA of gut samples from these mosquitoes were extracted using the magnetic bead method. Bacterial 16S rDNA was sequenced using BGISEQ method. We isolated and cultured gut microorganisms from adult and larvae mosquitoes using four different media: Luria Bertani (LB), brain heart infusion (BHI), nutrient agar (NA), and salmonella shigella (SS). RESULTS: Sequencing revealed significantly higher gut microbial diversity in field-resistant larvae compared with field-sensitive and laboratory-sensitive larvae (P < 0.01). Conversely, gut microorganism diversity in field-resistant and field-sensitive adults was significantly lower compared with laboratory-sensitive adults (P < 0.01). At the species level, 25 and 12 bacterial species were isolated from the gut of field resistant larvae and adults, respectively. The abundance of Flavobacterium spp., Gemmobacter spp., and Dysgonomonas spp. was significantly higher in the gut of field-resistant larvae compared with sensitive larvae (all P < 0.05). Furthermore, the abundance of Flavobacterium spp., Pantoea spp., and Aeromonas spp. was significantly higher in the gut of field-resistant adults compared with sensitive adults (all P < 0.05). The dominant and differentially occurring microorganisms were also different between resistant larval and adult mosquitoes. These findings suggest that the gut commensal bacteria of Ae. albopictus adults and larvae may play distinct roles in their deltamethrin resistance. CONCLUSIONS: This study provides an empirical basis for further exploration of the mechanisms underlying the role of gut microbial in insecticide resistance, potentially opening a new prospect for mosquito control strategies.

Gut microbial composition is altered in sarcopenia: A systematic review and meta-analysis of clinical studies.

Increasing evidence has shown that gut microbiota (GM) was involved in the pathophysiology of musculoskeletal disorders through multiple pathways such as protein anabolism, chronic inflammation and immunity, and imbalanced metabolism. We performed a systematic review and meta-analysis of human studies to evaluate GM diversity differences between individuals with and without sarcopenia, and explore bacteria with potential to become biomarkers. PubMed, Embase and Cochrane library were systematically searched from inception to February 16, 2024. Studies were included if they (1) sampled adults with sarcopenia, and (2) performed GM analysis and reported α-diversity, ß-diversity or relative abundance. The methodological quality of included studies and the certainty of evidence were assessed through the Joanna Briggs Institute critical appraisal checklist for analytical cross-sectional studies and the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group system, respectively. Weighted standardized mean differences (SMDs) and corresponding 95% confidence intervals (CIs) were estimated for α-diversity indices using a fixed-effects and a random-effects model. Beta diversity and the relative abundance of GM were summarized qualitatively. A total of 19 studies involving 6,565 participants were included in this study. Compared with controls, significantly moderate decrease in microbial richness in participants with sarcopenia were found (Chao1: SMD = -0.44; 95%CI, -0.64 to -0.23, I2 = 57.23%, 13 studies; observed species: SMD = -0.68; 95%CI, -1.00 to -0.37, I2 = 66.07%, 5 studies; ACE index: SMD = -0.30; 95%CI, -0.56 to -0.04, I2 = 8.12%, 4 studies), with very low certainty of evidence. Differences in ß-diversity were consistently observed in 84.6% of studies and 97.3% of participants. The detailed analysis of the gut microbial differential abundance identified a loss of Prevotellaceae, Prevotella, and Megamonas in sarcopenia compared with non-sarcopenia. In conclusion, sarcopenia was found to be associated with reduced richness of GM, and supplementing intestinal bacteria described above may contribute to preventing and treating this muscle disease. The research protocol was registered and approved in PROSPERO (CRD42023412849).

Gut bacteria are essential for development of an invasive bark beetle by regulating glucose transport.

Insects and their gut bacteria form a tight and beneficial relationship, especially in utilization of host nutrients. The red turpentine beetle (RTB), a destructive and invasive pine pest, employs mutualistic microbes to facilitate its invasion success. However, the molecular mechanism underlying the utilization of nutrients remains unknown. In this study, we found that gut bacteria are crucial for the utilization of D-glucose, a main carbon source for RTB development. Downstream assays revealed that gut bacteria-induced gut hypoxia and the secretion of riboflavin are responsible for RTB development by regulating D-glucose transport via the activation of a hypoxia-induced transcription factor 1 (Hif-1α). Further functional investigations confirmed that Hif-1α mediates glucose transport by direct upregulation of two glucose transporters (ST10 and ST27), thereby promoting RTB development. Our findings reveal how gut bacteria regulate the development of RTB, and promote our understanding of the mutualistic relationship of animals and their gut bacteria.

[Effect of umbilical moxibustion on intestinal flora in patients with subthreshold depression].

OBJECTIVE: To observe the clinical efficacy of umbilical moxibustion for subthreshold depression (SD) and its effect on intestinal flora, and to explore its mechanism. METHODS: Thirty-six SD patients were recruited as the SD group (1 case dropped out, 2 cases excluded), and 36 healthy subjects were recruited as the healthy control group (1 case excluded). The SD group was treated with umbilical moxibustion, once a week, a total of 8 times were required. The healthy control group did not receive any intervention. Hamilton depression scale 17-item (HAMD-17) and Center for Epidemiologic Studies depression scale (CES-D) scores were observed in the SD group before and after treatment, and the clinical efficacy was evaluated. Fecal samples were collected in the SD group before and after treatment and in the healthy control group when enrolled, the intestinal flora was analyzed by 16S rRNA sequencing technology. RESULTS: The HAMD-17 and CES-D scores after treatment in the SD group were reduced compared with those before treatment (P<0.05), and the total effective rate was 90.9% (30/33). Compared with the healthy control group, Sobs index, Shannon index and Ace index were reduced in the SD group before treatment (P<0.05), Simpson index was increased (P<0.05), the relative abundance of Escherichia-Shigella was increased (P<0.01), the relative abundance of Eubacterium_hallii_group, Ruminococcus, Christensenellaceae_R-7_ group, Paraprevotella was decreased (P<0.05, P<0.01). Compared before treatment, the relative abundance of Escherichia- Shigella after treatment in the SD group was decreased (P<0.01), the relative abundance of Ruminococcus, Christensenaceae_R-7_group, Paraprevotella was increased (P<0.01, P<0.05). Christensenellaceae_R-7_group and Paraprevotella were negatively correlated with the CES-D score (P<0.01, P<0.05). Escherichia-Shigella was positively correlated with the HAMD-17 score (P<0.05). Christensenellaceae_R-7_group was negatively correlated with the HAMD-17 score (P<0.01). CONCLUSION: Patients with subthreshold depression have dysbiosis of intestinal flora, and umbilical moxibustion may exert therapeutic effect by regulating the abundance and diversity of intestinal flora, increasing beneficial bacteria, and reducing harmful bacteria.

Early-life gut bacterial community structure predicts disease risk and athletic performance in horses bred for racing.

Gut bacterial communities have a profound influence on the health of humans and animals. Early-life gut microbial community structure influences the development of immunological competence and susceptibility to disease. For the Thoroughbred racehorse, the significance of early-life microbial colonisation events on subsequent health and athletic performance is unknown. Here we present data from a three-year cohort study of horses bred for racing designed to explore interactions between early-life gut bacterial community structure, health events in later life and athletic performance on the racetrack. Our data show that gut bacterial community structure in the first months of life predicts the risk of specific diseases and athletic performance up to three years old. Foals with lower faecal bacterial diversity at one month old had a significantly increased risk of respiratory disease in later life which was also associated with higher relative abundance of faecal Pseudomonadaceae. Surprisingly, athletic performance up to three years old, measured by three different metrics, was positively associated with higher faecal bacterial diversity at one month old and with the relative abundance of specific bacterial families. We also present data on the impact of antibiotic exposure of foals during the first month of life. This resulted in significantly lower faecal bacterial diversity at 28 days old, a significantly increased risk of respiratory disease in later life and a significant reduction in average prize money earnings, a proxy for athletic performance. Our study reveals associations between early-life bacterial community profiles and health events in later life and it provides evidence of the detrimental impact of antimicrobial treatment in the first month of life on health and performance outcomes in later life. For the first time, this study demonstrates a relationship between early-life gut bacterial communities and subsequent athletic performance that has implications for athletes of all species including humans.

Engineered fungus containing a caterpillar gene kills insects rapidly by disrupting their ecto- and endo-microbiomes.

Similar to the physiological importance of gut microbiomes, recent works have shown that insect ectomicrobiotas can mediate defensive colonization resistance against fungal parasites that infect via cuticle penetration. Here we show that engineering the entomopathogenic fungus Metarhizium robertsii with a potent antibacterial moricin gene from silkworms substantially enhances the ability of the fungus to kill mosquitos, locusts, and two Drosophila species. Further use of Drosophila melanogaster as an infection model, quantitative microbiome analysis reveals that engineered strains designed to suppress insect cuticular bacteria additionally disrupt gut microbiomes. An overgrowth of harmful bacteria such as the opportunistic pathogens of Providencia species is detected that can accelerate insect death. In support, quantitative analysis of antimicrobial genes in fly fat bodies and guts indicates that topical fungal infections result in the compromise of intestinal immune responses. In addition to providing an innovative strategy for improving the potency of mycoinsecticides, our data solidify the importance of both the ecto- and endo-microbiomes in maintaining insect wellbeing.

Vitamin A carotenoids, but not retinoids, mediate the impact of a healthy diet on gut microbial diversity.

BACKGROUND: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). METHODS: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. RESULTS: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10-6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. CONCLUSIONS: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern.

Effect of ß-lactam antibiotics on the gut microbiota of term neonates.

ß-Lactam antibiotics are a class of antibiotics commonly used to treat bacterial infections. However, the effects of ß-lactam antibiotics on term neonatal intestinal flora have not been fully elucidated. Hospitalized full-term newborns receiving ß-lactam antibiotics formed the antibiotic group (n = 67), while those without antibiotic treatment comprised the non-antibiotic group (n = 47). A healthy group included healthy full-term newborns (n = 16). Stool samples were collected for 16 S rDNA sequencing to analyze gut microbiota variations. Further investigation was carried out within the ß-lactam antibiotic group, exploring the effects of antibiotic use on the newborns' gut microbiota in relation to the duration and type of antibiotic administration, delivery method, and feeding practices. The antibiotic group exhibited significant difference of microbial community composition compared to the other groups. Genera like Klebsiella, Enterococcus, Streptococcus, Alistipes, and Aeromonas were enriched, while Escherichia-Shigella, Clostridium sensu stricto 1, Bifidobacterium, and Parabacteroides were reduced. Klebsiella negatively correlated with Escherichia-Shigella, positively with Enterobacter, while Escherichia-Shigella negatively correlated with Enterococcus and Streptococcus. Regardless of neonatal age, ß-lactam antibiotics induced an elevated abundance of Klebsiella and Enterococcus. The impact on gut microbiota varied with the duration and type of antibiotic (cefotaxime or ampicillin/sulbactam). Compared to vaginal delivery, cesarean delivery after ß-lactam treatment heightened the abundance of Klebsiella, Enterobacteriaceae_Unclassified, Lactobacillales_Unclassified, and Pectobacterium. Feeding patterns minimally influenced ß-lactam-induced alterations. In conclusion, ß-lactam antibiotic treatment for neonatal pneumonia and sepsis markedly disrupted intestinal microbiota, favoring Klebsiella, Enterococcus, Streptococcus, Alistipes, and Aeromonas. The impact of ß-lactam varied by duration, type, and delivery method, emphasizing heightened disruptions post-cesarean delivery.

Multi-omics analysis reveals a feedback loop amplifying immune responses in acute graft-versus-host disease due to imbalanced gut microbiota and bile acid metabolism.

Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.

Exploring the resilience and stability of a defined human gut microbiota consortium: An isothermal microcalorimetric study.

The gut microbiota significantly contributes to human health and well-being. The aim of this study was to evaluate the stability and resilience of a consortium composed of three next-generation probiotics (NGPs) candidates originally found in the human gut. The growth patterns of Akkermansia muciniphila, Bacteroides thetaiotaomicron, and Faecalibacterium prausnitzii were studied both individually and consortium. The growth kinetics of Akkermansia muciniphila (A. muciniphila), Bacteroides thetaiotaomicron (B. thetaiotaomicron), and Faecalibacterium prausnitzii (F. prausnitzii) were characterized both individually and in consortium using isothermal microcalorimetry and 16S ribosomal RNA next-generation sequencing. The consortium reached stability after three passages and demonstrated resilience to changes in its initial composition. The concentration of butyrate produced was nearly twice as high in the consortium compared to the monoculture of F. prausnitzii. The experimental conditions and methodologies used in this article are a solid foundation for developing further complex consortia.

Importance of underlying mechanisms for interpreting relative risk of Clostridioides difficile infection among antibiotic-exposed patients in healthcare facilities.

Clostridioides difficile infection (CDI) is a significant public health threat, associated with antibiotic-induced disruption of the normally protective gastrointestinal microbiota. CDI is thought to occur in two stages: acquisition of asymptomatic colonization from ingesting C. difficile bacteria followed by progression to symptomatic CDI caused by toxins produced during C. difficile overgrowth. The degree to which disruptive antibiotic exposure increases susceptibility at each stage is uncertain, which might contribute to divergent published projections of the impact of hospital antibiotic stewardship interventions on CDI. Here, we model C. difficile transmission and CDI among hospital inpatients, including exposure to high-CDI-risk antibiotics and their effects on each stage of CDI epidemiology. We derive the mathematical relationship, using a deterministic model, between those parameters and observed equilibrium levels of colonization, CDI, and risk ratio of CDI among certain antibiotic-exposed patients relative to patients with no recent antibiotic exposure. We then quantify the sensitivity of projected antibiotic stewardship intervention impacts to alternate assumptions. We find that two key parameters, the antibiotic effects on susceptibility to colonization and to CDI progression, are not identifiable given the data frequently available. Furthermore, the effects of antibiotic stewardship interventions are sensitive to their assumed values. Thus, discrepancies between different projections of antibiotic stewardship interventions may be largely due to model assumptions. Data supporting improved quantification of mechanistic antibiotic effects on CDI epidemiology are needed to understand stewardship effects better.

Gut mycobiome alterations and implications for liver diseases.

Chronic liver disease and its complications are a significant global health burden. Changes in fungal communities (mycobiome), an integral component of the gut microbiome, are associated with and contribute to the development of liver disease. Fungal dysbiosis can induce intestinal barrier dysfunction and allow fungal products to translocate to the liver causing progression of disease. This review explores recent progress in understanding the compositional and functional diversity of gut mycobiome signatures across different liver diseases. It delves into causative connections between gut fungi and liver diseases. We emphasize the significance of fungal translocation, with a particular focus on fungal-derived metabolites and immune cells induced by fungi, as key contributors to liver disease. Furthermore, we review the potential impact of the intrahepatic mycobiome on the progression of liver diseases.

Gut microbiota and pancreatic cancer risk, and the mediating role of immune cells and inflammatory cytokines: a Mendelian randomization study.

Introduction: Gut microbiota (GM) influences the occurrence and development of pancreatic cancer (PC), potentially through the involvement of inflammatory cytokines (IC) and immune cells (IM). We aimed to investigate the causal impact of the gut microbiota (GM) on pancreatic cancer (PC) and identify potential IC and IM mediators. Methods: The summary statistics data from whole-genome association studies of gut microbiota, immune cells, inflammatory cytokines, and four types of pancreatic tumors (MNP: Malignant neoplasm of pancreas; BNP: Benign neoplasm of pancreas; ADCP: Adenocarcinoma and ductal carcinoma of pancreas; NTCP: Neuroendocrine tumor and carcinoma of pancreas). Two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis were employed to assess the causal relationship between gut microbiota (GM) and pancreatic cancer (PC), as well as potential IC and IM mediators. Results: The two-sample UVMR analysis showed causal relationships between 20 gut microbiota species and pancreatic cancer, with pancreatic cancer affecting the abundance of 37 gut microbiota species. Mediation analysis revealed that Interleukin-6 (IL-6), "CD4 on naive CD4+ T cell" and "SSC-A on HLA DR+ Natural Killer" mediated the causal effects of gut microbiota on pancreatic cancer. Conclusion: This Mendelian randomization study demonstrates causal relationships between several specific gut microbiota and pancreatic cancer, as well as potential mediators (IC, IM).

Fetal growth restriction induced by maternal gal-3 deficiency is associated with altered gut-placenta axis.

Adverse intrauterine conditions may cause fetal growth restriction (FGR), a pregnancy complication frequently linked to perinatal morbidity and mortality. Although many studies have focused on FGR, the pathophysiological processes underlying this disorder are complex and incompletely understood. We have recently determined that galectin-3 (gal-3), a ß-galactoside-binding protein, regulates pregnancy-associated processes, including uterine receptibility, maternal vascular adaptation and placentation. Because gal-3 is expressed at both sides of the maternal-fetal interface, we unraveled the contribution of maternal- and paternal-derived gal-3 on fetal-placental development in the prenatal window and its effects on the post-natal period. Deficiency of maternal gal-3 induced maternal gut microbiome dysbiosis, resulting in a sex-specific fetal growth restriction mainly observed in female fetuses and offspring. In addition, poor placental metabolic adaptions (characterized by decreased trophoblast glycogen content and insulin-like growth factor 2 (Igf2) gene hypomethylation) were only associated with a lack of maternal-derived gal-3. Paternal gal-3 deficiency caused compromised vascularization in the placental labyrinth without affecting fetal growth trajectory. Thus, maternal-derived gal-3 may play a key role in fetal-placental development through the gut-placenta axis.

Association of gut microbiota with depression post-myocardial infarction: A systematic evaluation and meta-analysis protocol.

BACKGROUND: Depression post-myocardial infarction (MI) is becoming more prevalent. The gut-brain axis (GBA), influenced by the gut microbiota, is a critical component in understanding depression post-MI. Despite the well-established connection between gut microbiota and depression post-MI, this relationship remains incompletely understood. METHODS AND ANALYSIS: This protocol will follow the Preferred Reporting Items for Systematic Review and Meta-analysis Protocol (PRISMA-P) 2020 statement. Beginning from inception to October 2023, a systematic search will be conducted across eight electronic databases, including PubMed, MEDLINE, Scopus, Embase, Cochrane Clinical Trials Database, Web of Science, China National Knowledge Infrastructure, and China Biomedical Literature Database. Pre-selected studies will be independently assessed by two researchers following a standard inclusion, data extraction and quality assessment protocol. The primary outcome measures are differences in the profile of gut microbiota and rating scale scores for depression. Fixed-effects models will be used when both clinical heterogeneity and statistical heterogeneity are low, otherwise random-effects models will be used. Furthermore, subgroup analyses will be conducted on the depression severity of the participants using the same psychiatric scales employed, study type and geographic region. Random forest plot runs and research-related statistical analyses will be carried out using Rev Man V.5.3 software. EXPECTED RESULTS: This study will identify the association between the gut microbiota and the onset of depression post-MI, and provide evidence for the use of probiotics as an adjunctive treatment for depression post-MI. TRIAL REGISTRATION: Prospero registration number: CRD42023444026.

Gut microbe-generated phenylacetylglutamine is an endogenous allosteric modulator of ß2-adrenergic receptors.

Allosteric modulation is a central mechanism for metabolic regulation but has yet to be described for a gut microbiota-host interaction. Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, has previously been clinically associated with and mechanistically linked to cardiovascular disease (CVD) and heart failure (HF). Here, using cells expressing ß1- versus ß2-adrenergic receptors (ß1AR and ß2AR), PAGln is shown to act as a negative allosteric modulator (NAM) of ß2AR, but not ß1AR. In functional studies, PAGln is further shown to promote NAM effects in both isolated male mouse cardiomyocytes and failing human heart left ventricle muscle (contracting trabeculae). Finally, using in silico docking studies coupled with site-directed mutagenesis and functional analyses, we identified sites on ß2AR (residues E122 and V206) that when mutated still confer responsiveness to canonical ß2AR agonists but no longer show PAGln-elicited NAM activity. The present studies reveal the gut microbiota-obligate metabolite PAGln as an endogenous NAM of a host GPCR.