Gut-lung microbiota dynamics in mice exposed to Nanoplastics.

Concern has grown over potential health effects of micro- and nanoplastics (M/NPs) exposure. There is significant interest in understanding their impact on animal and human microbiota due to its crucial role in preserving health, as research in this area is rapidly advancing. We conducted a sub-chronic exposure study involving 12 male mice, divided into two groups: a control group (n = 6) and a PET-NPs exposure group (n = 6). PET-NPs, administered by oral gavage at a dose of 0.5 mg/day in 0.1 ml/mice, were given daily for 28 days. Microbiota analyses were performed on lung, colon, oral cavity, and stool samples using 16S rRNA sequencing. Additionally, fecal short and medium-chain fatty acids were analyzed by GC/MS. No significant changes were observed in the fecal and oral microbiome of the treated mice, nor in the fecal fatty acid levels. However, there were prominent alterations in the colon, characterized by increased abundance of Gram-negative bacteria belonging to Veillonella and Prevotella genera, and of amino acid metabolism pathways, coupled with a decrease in Lactobacillus. PET-NPs ingestion caused unexpected alterations in the lung microbiome with an increase in the Pseudomonas and changes in microbial energy metabolism and nitrogen utilization. This study provides insights into the differential impact of PET-NPs exposure on various microbiome niches.

Immune Modulation by Epstein-Barr Virus Lytic Cycle: Relevance and Implication in Oncogenesis.

EBV infects more than 90% of people globally, causing lifelong infection. The phases of the EBV life cycle encompass primary infection, latency, and subsequent reactivation or lytic phase. The primary infection usually happens without noticeable symptoms, commonly in early life stages. If it manifests after childhood, it could culminate in infectious mononucleosis. Regarding potential late consequences, EBV is associated with multiple sclerosis, rheumatoid arthritis, chronic active EBV infection, lymphomas, and carcinomas. Previous reports that the lytic phase plays a negligible or merely secondary role in the oncogenesis of EBV-related tumors are steadily losing credibility. The right mechanisms through which the lytic cycle contributes to carcinogenesis are still unclear, but it is now recognized that lytic genes are expressed to some degree in different cancer-type cells, implicating their role here. The lytic infection is a persistent aspect of virus activity, continuously stimulating the immune system. EBV shows different strategies to modulate and avoid the immune system, which is thought to be a key factor in its ability to cause cancer. So, the principal goal of our review is to explore the EBV's lytic phase contribution to oncogenesis.

Probiotics as adjuvants to mitigate adverse reactions and enhance effectiveness in Food Allergy Immunotherapy.

In the past decades, food allergies became increasingly dominant since early childhood, leading to a lower quality of life and to increasing costs addressed by the health care system. Beside standard avoidance of specific allergens and drug treatments following allergen exposure, a great deal of research has lately focused on Food Allergy Allergen Immunotherapy (FA-AIT). SCIT and EPIT (Subcutaneous and Epicutaneous Immunotherapy), OIT (Oral Immunotherapy), and SLIT (Sublingual Immunotherapy) consist in gradual exposure to allergens to desensitize and achieve tolerance once therapy has ended. Although promising, FA-AIT may bring acute local and systemic adverse reactions. To enhance efficacy, safety and convenience of AIT, the quest of potential adjuvants to mitigate the adverse reactions becomes crucial. Immunomodulatory activities, such as that of increasing the regulatory T cells and decreasing the IgE, have been observed in specific probiotics' strains and multiple studies elucidated the role of gut microbiota as a major interplayer among the host and its immune system. In this review, the microbiome modulation is shown as potential AIT adjuvant, nevertheless the need of more clinical studies in the near future is pivotal to assess the efficacy of targeted bacterial therapies and faecal microbiota transplantation.

High-Dimensional Bayesian Semiparametric Models for Small Samples: A Principled Approach to the Analysis of Cytokine Expression Data.

In laboratory medicine, due to the lack of sample availability and resources, measurements of many quantities of interest are commonly collected over a few samples, making statistical inference particularly challenging. In this context, several hypotheses can be tested, and studies are not often powered accordingly. We present a semiparametric Bayesian approach to effectively test multiple hypotheses applied to an experiment that aims to identify cytokines involved in Crohn's disease (CD) infection that may be ongoing in multiple tissues. We assume that the positive correlation commonly observed between cytokines is caused by latent groups of effects, which in turn result from a common cause. These clusters are effectively modeled through a Dirichlet Process (DP) that is one of the most popular choices as nonparametric prior in Bayesian statistics and has been proven to be a powerful tool for model-based clustering. We use a spike-slab distribution as the base measure of the DP. The nonparametric part has been included in an additive model whose parametric component is a Bayesian hierarchical model. We include simulations that empirically demonstrate the effectiveness of the proposed testing procedure in settings that mimic our application's sample size and data structure. Our CD data analysis shows strong evidence of a cytokine gradient in the external intestinal tissue.

Oxidative stress-induced fibrinogen modifications in liver transplant recipients: unraveling a novel potential mechanism for cardiovascular risk.

Background: Cardiovascular events represent a major cause of non-graft-related death after liver transplant. Evidence suggest that chronic inflammation associated with a remarkable oxidative stress in the presence of endothelial dysfunction and procoagulant environment plays a major role in the promotion of thrombosis. However, the underlying molecular mechanisms are not completely understood. Objectives: In order to elucidate the mechanisms of posttransplant thrombosis, the aim of the present study was to investigate the role of oxidation-induced structural and functional fibrinogen modifications in liver transplant recipients. Methods: A case-control study was conducted on 40 clinically stable liver transplant recipients and 40 age-matched, sex-matched, and risk factor-matched controls. Leukocyte reactive oxygen species (ROS) production, lipid peroxidation, glutathione content, plasma antioxidant capacity, fibrinogen oxidation, and fibrinogen structural and functional features were compared between patients and controls. Results: Patients displayed enhanced leukocyte ROS production and an increased plasma lipid peroxidation with a reduced total antioxidant capacity compared with controls. This systemic oxidative stress was associated with fibrinogen oxidation with fibrinogen structural alterations. Thrombin-catalyzed fibrin polymerization and fibrin resistance to plasmin-induced lysis were significantly altered in patients compared with controls. Moreover, steatotic graft and smoking habit were associated with high fibrin degradation rate. Conclusion: ROS-induced fibrinogen structural changes might increase the risk of thrombosis in liver transplant recipients.

Health-promoting worms? Prospects and pitfalls of helminth therapy.

In this manuscript, we explore the potential therapeutic use of helminths. After analyzing helminths' role in connection with human health from the perspective of their symbiotic and evolutionary relationship, we critically examine some studies on their therapeutic applications. In doing so, we focus on some prominent mechanisms of action and potential benefits, but also on the exaggerations and theoretical and methodological difficulties of such proposals. We conclude that further studies are needed to fully explore the potential benefits of this perspective, and we encourage the scientific community in doing so.

Polyethylene Micro/Nanoplastics Exposure Induces Epithelial-Mesenchymal Transition in Human Bronchial and Alveolar Epithelial Cells.

Micro/nanoplastics (MNPs), which are widely spread in the environment, have gained attention because of their ability to enter the human body mainly through ingestion, inhalation, and skin contact, thus representing a serious health threat. Several studies have reported the presence of MNPs in lung tissue and the potential role of MNP inhalation in triggering lung fibrosis and tumorigenesis. However, there is a paucity of knowledge regarding the cellular response to MNPs composed of polyethylene (PE), one of the most common plastic pollutants in the biosphere. In this study, we investigated the effects of low/high concentrations of PE MNPs on respiratory epithelial cell viability and migration/invasion abilities, using MTT, scratch, and transwell assays. Morphological and molecular changes were assessed via immunofluorescence, Western blot, and qRT-PCR. We demonstrated that acute exposure to PE MNPs does not induce cellular toxicity. Instead, cells displayed visible morphological changes also involving actin cytoskeleton reorganization. Our data underlined the role of epithelial-mesenchymal transition (EMT) in triggering this process. Moreover, a remarkable increase in migration potential was noticed, in absence of a significant alteration of the cell's invasive capacity. The present study highlights the potential impact of PE MNPs inhalation on the human respiratory epithelium, suggesting a possible role in carcinogenesis.

The Future Exploring of Gut Microbiome-Immunity Interactions: From In Vivo/Vitro Models to In Silico Innovations.

Investigating the complex interactions between microbiota and immunity is crucial for a fruitful understanding progress of human health and disease. This review assesses animal models, next-generation in vitro models, and in silico approaches that are used to decipher the microbiome-immunity axis, evaluating their strengths and limitations. While animal models provide a comprehensive biological context, they also raise ethical and practical concerns. Conversely, modern in vitro models reduce animal involvement but require specific costs and materials. When considering the environmental impact of these models, in silico approaches emerge as promising for resource reduction, but they require robust experimental validation and ongoing refinement. Their potential is significant, paving the way for a more sustainable and ethical future in microbiome-immunity research.

Gut-Liver-Pancreas Axis Crosstalk in Health and Disease: From the Role of Microbial Metabolites to Innovative Microbiota Manipulating Strategies.

The functions of the gut are closely related to those of many other organs in the human body. Indeed, the gut microbiota (GM) metabolize several nutrients and compounds that, once released in the bloodstream, can reach distant organs, thus influencing the metabolic and inflammatory tone of the host. The main microbiota-derived metabolites responsible for the modulation of endocrine responses are short-chain fatty acids (SCFAs), bile acids and glucagon-like peptide 1 (GLP-1). These molecules can (i) regulate the pancreatic hormones (insulin and glucagon), (ii) increase glycogen synthesis in the liver, and (iii) boost energy expenditure, especially in skeletal muscles and brown adipose tissue. In other words, they are critical in maintaining glucose and lipid homeostasis. In GM dysbiosis, the imbalance of microbiota-related products can affect the proper endocrine and metabolic functions, including those related to the gut-liver-pancreas axis (GLPA). In addition, the dysbiosis can contribute to the onset of some diseases such as non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and type 2 diabetes (T2D). In this review, we explored the roles of the gut microbiota-derived metabolites and their involvement in onset and progression of these diseases. In addition, we detailed the main microbiota-modulating strategies that could improve the diseases' development by restoring the healthy balance of the GLPA.

Changes in cytokine and sequestosome-1 levels during twin pregnancy progression: Association with outcome.

BACKGROUND: Twin pregnancies are associated with complications and adverse outcomes. The number of twin pregnancies has increased in the last decades, due to the use of assisted reproductive techniques and delayed childbearing. Analysis of changes that occur during twin pregnancy progression and their association with outcome will lead to improved clinical interventions. OBJECTIVE: We evaluated if the plasma concentration of select cytokines and the level of sequestosome-1 (p62) in peripheral blood mononuclear cells (PBMCs) during each trimester of twin gestations was predictive of pregnancy outcome. STUDY DESIGN: This prospective, observational study was conducted at Careggi University Hospital, Florence, Italy. Plasma from 82 women with twin pregnancies was collected in each trimester for measurement of interleukin (IL)-1ß, IL-6, IL-10, IL-12 and tumor necrosis factor (TNF)-α. The intracellular PBMC concentration of p62, a protein involved in autophagy, kinase activity and cell differentiation, was also determined. RESULTS: IL-1ß (p < 0.001), IL-6 (p < 0.001), TNF-α (p < 0.001) and p62 (p < 0.05) increased from the 1st to the 2nd to the 3rd trimester. The TNF-α level was correlated with the IL-1ß concentration in the 1st and 3rd trimesters p < 0.01) and with the IL-6 concentration in each of the three trimesters (p < 0.01). The intracellular p62 level in PBMCs was negatively correlated with the concentration of IL-1ß in the 2nd trimester (p < 0.05) and negatively correlated with the IL-6 level in the 3rd trimester (p < 0.05). The TNF-α level was significantly higher in the 2nd (p < 0.05) and 3rd (p < 0.001) trimester in women with a spontaneous preterm delivery. The TNF-α concentrations in the 2nd (p < 0.05) and 3rd (p < 0.01) trimester, respectively, and 3rd trimester IL-6 (p < 0.01), were negatively associated with gestational age at delivery. The concentration of IL-6 was highest in the 2nd (p < 0.05) and 3rd (p < 0.05) trimesters in women who utilized assisted reproductive technologies. An elevated IL-1ß level in the 3rd trimester was associated with gestational diabetes mellitus (p < 0.05). CONCLUSION: Variations in cytokine levels between individual women during the three trimesters of twin gestations are predictive of spontaneous preterm delivery and the onset of gestational diabetes.

Endometriosis, Pain, and Related Psychological Disorders: Unveiling the Interplay among the Microbiome, Inflammation, and Oxidative Stress as a Common Thread.

Endometriosis (EM), a chronic condition in endometrial tissue outside the uterus, affects around 10% of reproductive-age women, significantly affecting fertility. Its prevalence remains elusive due to the surgical confirmation needed for diagnosis. Manifesting with a range of symptoms, including dysmenorrhea, dyschezia, dysuria, dyspareunia, fatigue, and gastrointestinal discomfort, EM significantly impairs quality of life due to severe chronic pelvic pain (CPP). Psychological manifestations, notably depression and anxiety, frequently accompany the physical symptoms, with CPP serving as a key mediator. Pain stems from endometrial lesions, involving oxidative stress, neuroinflammation, angiogenesis, and sensitization processes. Microbial dysbiosis appears to be crucial in the inflammatory mechanisms underlying EM and associated CPP, as well as psychological symptoms. In this scenario, dietary interventions and nutritional supplements could help manage EM symptoms by targeting inflammation, oxidative stress, and the microbiome. Our manuscript starts by delving into the complex relationship between EM pain and psychological comorbidities. It subsequently addresses the emerging roles of the microbiome, inflammation, and oxidative stress as common links among these abovementioned conditions. Furthermore, the review explores how dietary and nutritional interventions may influence the composition and function of the microbiome, reduce inflammation and oxidative stress, alleviate pain, and potentially affect EM-associated psychological disorders.

Metadherin-driven promotion of cancer stem cell phenotypes and its effect on immunity in hepatocellular carcinoma.

In this editorial we provide commentary on the article published by Wang et al, featured in the recent issue of the World Journal of Gastroenterology in 2024. We focus on the metadherin (MTDH), also known as astrocyte elevated gene-1 or lysine rich CEACAM1, and its effects on cancer stem cells (CSCs) and immunity in hepatocellular carcinoma (HCC). HCC is the most common primary liver cancer and one of the leading causes of cancer-related deaths worldwide. Most HCC cases develop in the context of liver cirrhosis. Among the pivotal mechanisms of carcinogenesis are gene mutations, dysregulation of diverse signaling pathways, epigenetic alterations, hepatitis B virus-induced hepatocarcinogenesis, chronic inflammation, impact of tumor microenvironment, oxidative stress. Over the years, extensive research has been conducted on the MTDH role in various tumor pathologies, such as lung, breast, ovarian, gastric, hepatocellular, colorectal, renal carcinoma, neuroblastoma, melanoma, and leukemias. Specifically, its involvement in tumor development processes including transformation, apoptosis evasion, angiogenesis, invasion, and metastasis via multiple signaling pathways. It has been demonstrated that knockdown or knockout of MTDH disrupt tumor development and metastasis. In addition, numerous reports have been carried out regarding the MTDH influence on HCC, demonstrating its role as a predictor of poor prognosis, aggressive tumor phenotypes prone to metastasis and recurrence, and exhibiting significant potential for therapy resistance. Finally, more studies finely investigated the influence of MTDH on CSCs. The CSCs are a small subpopulation of tumor cells that sharing traits with normal stem cells like self-renewal and differentiation abilities, alongside a high plasticity that alters their phenotype. Beyond their presumed role in tumor initiation, they can drive also disease relapse, metastasis, and resistance to chemo and radiotherapy.

Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer's-like clinical phenotype.

Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer's disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, "loss-of-function" profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte "loss-of-function" profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.

Amyotrophic lateral sclerosis stratification: unveiling patterns with virome, inflammation, and metabolism molecules.

Amyotrophic lateral sclerosis (ALS) is an untreatable and clinically heterogeneous condition primarily affecting motor neurons. The ongoing quest for reliable biomarkers that mirror the disease status and progression has led to investigations that extend beyond motor neurons' pathology, encompassing broader systemic factors such as metabolism, immunity, and the microbiome. Our study contributes to this effort by examining the potential role of microbiome-related components, including viral elements, such as torque tenovirus (TTV), and various inflammatory factors, in ALS. In our analysis of serum samples from 100 ALS patients and 34 healthy controls (HC), we evaluated 14 cytokines, TTV DNA load, and 18 free fatty acids (FFA). We found that the evaluated variables are effective in differentiating ALS patients from healthy controls. In addition, our research identifies four unique patient clusters, each characterized by distinct biological profiles. Intriguingly, no correlations were found with site of onset, sex, progression rate, phenotype, or C9ORF72 expansion. A remarkable aspect of our findings is the discovery of a gender-specific relationship between levels of 2-ethylhexanoic acid and patient survival. In addition to contributing to the growing body of evidence suggesting altered peripheral immune responses in ALS, our exploratory research underscores metabolic diversity challenging conventional clinical classifications. If our exploratory findings are validated by further research, they could significantly impact disease understanding and patient care customization. Identifying groups based on biological profiles might aid in clustering patients with varying responses to treatments.

Oral microbiota signatures associated with viremia and CD4 recovery in treatment-naïve HIV-1-infected patients.

PURPOSE: Few reports focused on the role of oral microbiome diversity in HIV infection. We characterized the microbiota-immunity axis in a cohort of treatment-naïve HIV-1-infected patients undergoing antiretroviral therapy (ART) focusing on the oral microbiome (OM) and immunological responsivity. METHODS: The sequencing of 16S rRNA V3-V4 hypervariable region was performed on salivary samples of 15 healthy control (HC) and 12 HIV + patients before starting ART and after reaching virological suppression. Then, we correlated the OM composition with serum cytokines and the Short Chain Fatty acids (SCFAs). RESULTS: The comparison between HIV patients and HC oral microbiota showed differences in the bacterial α-diversity and richness. We documented a negative correlation between oral Prevotella and intestinal valeric acid at before starting ART and a positive correlation between oral Veillonella and gut acetic acid after reaching virological suppression. Finally, an increase in the phylum Proteobacteria was observed comparing saliva samples of immunological responders (IRs) patients against immunological non-responders (INRs). CONCLUSIONS: For the first time, we described an increase in the oral pro-inflammatory Proteobacteria phylum in INRs compared to IRs. We provided more evidence that saliva could be a non-invasive and less expensive approach for research involving the oral cavity microbiome in HIV patients.

Comparison of ELISA with automated ECLIA for IL-6 determination in COVID-19 patients: An Italian real-life experience.

Objectives: Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical severity. A cytokine storm is associated with COVID-19 severity. Of these, IL-6 is significantly associated with higher mortality and is also a marker for predicting disease prognosis. IL-6 may act as a target for therapeutics and, a blockade of IL-6 function by Tocilizumab has been described as a treatment of the inflammatory process COVID-19-related. This study aims to describe our experience comparing two different methods, in detail Human IL-6 Instant ELISA and the Elecsys IL-6 based on ECLIA, for the IL-6 assessment. Design and methods: IL-6 levels from serum samples of 104 COVID-19 patients, admitted to the AOU Careggi (Hospital in Florence -Italy), were assessed by using the two above-mentioned methods, and the results were analysed through Passing-Bablok regression fit and Bland-Altman plot. Results: The regression exhibited a linear relation between the methods with a regression equation (y = - 0.13 + 0.63 x; 95 % C.I. intercept = - 0.13 to 4.55; 95 % C.I. slope = 1.03 to 1.26 with R2 = 0.89, p > 0.05), showing a positive slope. The agreement of the two methods reported a bias of -25.0 pg/mL. Thus, the two methods correlate but do not agree in terms of numeric results. Conclusions: The two assays showed good comparability. However, because of the extremely wide linear range of the ECLIA, its throughput and its capacity for immune profiling, it represents an interesting emerging technology in the immunology field.

Women health and microbiota: Different aspects of well-being.

In this editorial, we comment on the article by Marano et al recently published in the World Journal of Gastroenterology 2023; 29 (45): 5945-5952. We focus on the role of gut microbiota (GM) in women's health, highlighting the need to thoroughly comprehend the sex differences in microbiota. Together, the host and GM support the host's health. The microbiota components consist of viruses, bacteria, fungi, and archaea. This complex is an essential part of the host and is involved in neurological development, metabolic control, immune system dynamics, and host dynamic homeostasis. It has been shown that differences in the GM of males and females can contribute to chronic diseases, such as gastrointestinal, metabolic, neurological, cardiovascular, and respiratory illnesses. These differences can also result in some sex-specific changes in immunity. Every day, research on GM reveals new and more expansive frontiers, offering a wealth of innovative opportunities for preventive and precision medicine.

Comparison of microbial communities and the profile of sulfate-reducing bacteria in patients with ulcerative colitis and their association with bowel diseases: a pilot study.

Considerable evidence has accumulated regarding the molecular relationship between gut microbiota (GM) composition and the onset (clinical presentation and prognosis of ulcerative colitis (UC)). In addition, it is well documented that short-chain fatty acid (SCFA)-producing bacteria may play a fundamental role in maintaining an anti-inflammatory intestinal homeostasis, but sulfate- and sulfite reducing bacteria may be responsible for the production of toxic metabolites, such as hydrogen sulfide and acetate. Hence, the present study aimed to assess the GM composition - focusing on sulfate-reducing bacteria (SRB) - in patients with severe, severe-active and moderate UC. Each one of the six enrolled patients provided two stool samples in the following way: one sample was cultivated in a modified SRB-medium before 16S rRNA sequencing and the other was not cultivated. Comparative phylogenetic analysis was conducted on each sample. Percentage of detected gut microbial genera showed considerable variation based on the patients' disease severity and cultivation in the SRB medium. In detail, samples without cultivation from patients with moderate UC showed a high abundance of the genera Bacteroides, Bifidobacterium and Ruminococcus, but after SRB cultivation, the dominant genera were Bacteroides, Klebsiella and Bilophila. On the other hand, before SRB cultivation, the main represented genera in patients with severe UC were Escherichia-Shigella, Proteus, Methanothermobacter and Methanobacterium. However, after incubation in the SRB medium Bacteroides, Proteus, Alistipes and Lachnoclostridium were predominant. Information regarding GM compositional changes in UC patients may aid the development of novel therapeutic strategies (e.g., probiotic preparations containing specific bacterial strains) to counteract the mechanisms of virulence of harmful bacteria and the subsequent inflammatory response that is closely related to the pathogenesis of inflammatory bowel diseases.