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Microbiota consists of a dynamic organization of bacteria, viruses, archaea, and fungal species involved in a number of vital functions spanning from the digestion of carbohydrates, vitamin synthesis, involvement in immune system to drug metabolism. More than 95 % of microbiota resides within the gut and it is essential for maintaining gut homeostasis. Dysregulation of gut microbiota contributes to the onset of several non-communicable diseases including cancer. Among the latter, pancreatic cancer is catching the attention of scientists around the globe being one of the most aggressive and resistant to therapies positioning the pancreatic cancer as one of the leading causes of death from cancer worldwide. In recent years, several studies have shown that the gut and tumor microbiota play a key role in the development, progression and prognosis of PDAC, mainly due to microbial ability to modulate host immune system and metabolize drugs. This review will focus on the new insights into the role of the microbiota as a new key player in pancreatic cancer PDAC development and prognosis by enlightening the microbial potential to interact with chemo/immunotherapeutic drugs and to modulate tumor microenvironment, thus impacting on cancer therapy success with the aim to pave the way to new integrative and interventional diagnostics or therapeutics approaches to prevent, diagnose and treat pancreatic cancer.
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Antineoplásicos , Carcinoma Ductal Pancreático , Microbiota , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/prevenção & controle , Microambiente Tumoral , Antineoplásicos/uso terapêutico , Neoplasias PancreáticasRESUMO
Cancer cachexia is a complex multifactorial syndrome whose hallmarks are weight loss due to the wasting of muscle tissue with or without the loss of adipose tissue, anorexia, systemic inflammation, and multi-organ metabolic alterations, which negatively impact patients' response to anticancer treatments, quality of life, and overall survival. Despite its clinical relevance, cancer cachexia often remains an underestimated complication due to the lack of rigorous diagnostic and therapeutic pathways. A number of studies have shown alterations in gut microbiota diversity and composition in association with cancer cachexia markers and symptoms, thus supporting a central role for dysbiosis in the pathogenesis of this syndrome. Different tools of microbiota manipulation, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have been investigated, demonstrating encouraging improvements in cachexia outcomes. Albeit pioneering, these studies pave the way for future research with the aim of exploring the role of gut microbiota in cancer cachexia more deeply and setting up effective microbiota-targeting interventions to be translated into clinical practice.
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Microbioma Gastrointestinal , Neoplasias , Probióticos , Humanos , Microbioma Gastrointestinal/fisiologia , Caquexia/terapia , Caquexia/complicações , Qualidade de Vida , Probióticos/uso terapêutico , Prebióticos , Neoplasias/complicações , Neoplasias/terapia , Transplante de Microbiota Fecal , Disbiose/complicações , Disbiose/terapiaRESUMO
Excessive predominance of pathological species in the gut microbiota could increase the production of inflammatory mediators at the gut level and, via modification of the gut-blood barrier, at the systemic level. This pro-inflammatory state could, in turn, increase biological aging that is generally proxied by telomere shortening. In this study, we present findings from a secondary interaction analysis of gut microbiota, aging, and inflammatory marker data from a cohort of patients with different diagnoses of severe mental disorders. We analyzed 15 controls, 35 patients with schizophrenia (SCZ), and 31 patients with major depressive disorder (MDD) recruited among those attending a community mental health center (50 males and 31 females, mean and median age 46.8 and 46.3 years, respectively). We performed 16S rRNA sequencing as well as measurement of telomere length via quantitative fluorescence in situ hybridization and high-sensitivity C-reactive protein. We applied statistical modeling with logistic regression to test for interaction between gut microbiota and these markers. Our results showed statistically significant interactions between telomere length and gut microbiota pointing to the genus Lachnostridium, which remained significantly associated with a reduced likelihood of MDD even after adjustment for a series of covariates. Although exploratory, these findings show that specific gut microbiota signatures overexpressing Lachnoclostridium and interacting with biological aging could modulate the liability for MDD.
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Transtorno Depressivo Maior , Microbioma Gastrointestinal , Masculino , Feminino , Humanos , Microbioma Gastrointestinal/genética , Transtorno Depressivo Maior/metabolismo , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/análise , Hibridização in Situ Fluorescente , Envelhecimento/genética , ClostridialesRESUMO
Lack of specific symptoms and reliable biomarkers, along with aggressive nature and resistance to therapies makes pancreatic cancer (PC) one of the leading causes of death from cancer worldwide. The search for new diagnostic, prognostic, predictive, and therapeutic tools that could improve clinical outcomes of patients has led, in recent years, to the investigation of potential roles for the microbiota in the pathogenesis of this disease. The human microbiota encompasses trillions of microorganisms residing within several body tissues and organs, where they provide beneficial functions for host homeostasis and health. Derangements of the microbial ecology in different anatomic districts have been described in PC, as in many other diseases, both in patients and in animal models. In detail, infection from the gastric pathogen Helicobacter pylori and changes in composition and diversity of oral, intestinal, and pancreatic microbiota have been found to associate with PC. Future research should assess how to potentially exploit such differences in microbiota composition as diagnostic, prognostic, or predictive biomarkers, and as targets for therapeutic interventions, in the hope of improving the dismal prognosis of this insidious cancer.
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Microbiota , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/fisiopatologia , Animais , Microbioma Gastrointestinal , Humanos , Especificidade de ÓrgãosRESUMO
Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use.
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Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Jejum/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Células Hep G2 , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Lipopolissacarídeos/farmacologia , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Sorafenibe , Fatores de TempoRESUMO
Gastrointestinal cancers account for around 40% of cancer-related deaths worldwide, representing a global health burden. There is a growing body of evidence highlighting the link between microbiota and gastrointestinal tumorigenesis and/or resistance to therapy. In the present manuscript, we reviewed the published studies on the relationship between the microbiota and the different gastrointestinal tumors, namely, gastric, colorectal and esophageal, including also the cancer of accessory organs such as liver and pancreas. There is an emergent interest in the manipulation of gastrointestinal microflora in order to understand the gastrointestinal tumorigenesis' processes and the establishment of chemoresistance mechanisms.
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Neoplasias Gastrointestinais/patologia , Microbiota , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/microbiologia , Neoplasias Esofágicas/patologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/microbiologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.
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Antirreumáticos/efeitos adversos , Artrite Reumatoide/microbiologia , Disbiose/etiologia , Etanercepte/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Disbiose/microbiologia , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Identification of cancer biomarkers to allow early diagnosis is an urgent need for many types of tumors, whose prognosis strongly depends on the stage of the disease. Canine olfactory testing for detecting cancer is an emerging field of investigation. As an alternative, here we propose to use GC-Olfactometry (GC/O), which enables the speeding up of targeted biomarker identification and analysis. A pilot study was conducted in order to determine odor-active compounds in urine that discriminate patients with gastrointestinal cancers from control samples (healthy people). METHODS: Headspace solid phase microextraction (HS-SPME)-GC/MS and GC-olfactometry (GC/O) analysis were performed on urine samples obtained from gastrointestinal cancer patients and healthy controls. RESULTS: In total, 91 key odor-active compounds were found in the urine samples. Although no odor-active biomarkers present were found in cancer carrier's urine, significant differences were discovered in the odor activities of 11 compounds in the urine of healthy and diseased people. Seven of above mentioned compounds were identified: thiophene, 2-methoxythiophene, dimethyl disulphide, 3-methyl-2-pentanone, 4-(or 5-)methyl-3-hexanone, 4-ethyl guaiacol and phenylacetic acid. The other four compounds remained unknown. CONCLUSIONS: GC/O has a big potential to identify compounds not detectable using untargeted GC/MS approach. This paves the way for further research aimed at improving and validating the performance of this technique so that the identified cancer-associated compounds may be introduced as biomarkers in clinical practice to support early cancer diagnosis.
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Medicina Clínica , Cães/fisiologia , Neoplasias Gastrointestinais/urina , Olfatometria/métodos , Idoso , Animais , Biomarcadores Tumorais/urina , Estudos de Casos e Controles , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Microextração em Fase SólidaRESUMO
FAD is a redox cofactor ensuring the activity of many flavoenzymes mainly located in mitochondria but also relevant for nuclear redox activities. The last enzyme in the metabolic pathway producing FAD is FAD synthase (EC 2.7.7.2), a protein known to be localized both in cytosol and in mitochondria. FAD degradation to riboflavin occurs via still poorly characterized enzymes, possibly belonging to the NUDIX hydrolase family. By confocal microscopy and immunoblotting experiments, we demonstrate here the existence of FAD synthase in the nucleus of different experimental rat models. HPLC experiments demonstrated that isolated rat liver nuclei contain â¼300 pmol of FAD·mg(-1) protein, which was mainly protein-bound FAD. A mean FAD synthesis rate of 18.1 pmol·min(-1)·mg(-1) protein was estimated by both HPLC and continuous coupled enzymatic spectrophotometric assays. Rat liver nuclei were also shown to be endowed with a FAD pyrophosphatase that hydrolyzes FAD with an optimum at alkaline pH and is significantly inhibited by adenylate-containing nucleotides. The coordinate activity of these FAD forming and degrading enzymes provides a potential mechanism by which a dynamic pool of flavin cofactor is created in the nucleus. These data, which significantly add to the biochemical comprehension of flavin metabolism and its subcellular compartmentation, may also provide the basis for a more detailed comprehension of the role of flavin homeostasis in biologically and clinically relevant epigenetic events.
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Núcleo Celular/metabolismo , Flavina-Adenina Dinucleotídeo/biossíntese , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Homeostase , Humanos , Hidrólise , Immunoblotting , Fígado/citologia , Fígado/metabolismo , Microscopia de Fluorescência , Modelos Biológicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Nucleotidiltransferases/metabolismo , Ratos , Ratos WistarRESUMO
Hepatocellular carcinoma is the fifth most common tumor and the third cause of death for cancer in the world. Among the main causative agents of this tumor is the chronic infection by hepatitis viruses B and C, which establish a context of chronic inflammation degenerating in fibrosis, cirrhosis, and, finally, cancer. Recent findings, however, indicate that hepatitis viruses are not only responsible for cancer onset but also for its progression towards metastasis. Indeed, they are able to promote epithelial-mesenchymal transition, a process of cellular reprogramming underlying tumor spread. In this manuscript, we review the currently known molecular mechanisms by which hepatitis viruses induce epithelial-mesenchymal transition and, thus, hepatocellular carcinoma progression.
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Carcinoma Hepatocelular/etiologia , Transição Epitelial-Mesenquimal , Hepatite Viral Humana/complicações , Neoplasias Hepáticas/etiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Progressão da Doença , Hepatite B/complicações , Hepatite C/complicações , Hepatite D/complicações , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapiaRESUMO
BACKGROUND AND AIMS: Several studies reported the effect of COVID-19 on inducing gut dysbiosis, which is also correlated with disease severity. This study aims to investigate the effect of a nutraceutical formula on the shift of microbiota profiles and, secondly, on the clinical-pathological parameters of acute and post-acute COVID-19 patients. METHODS: In this randomised, double-blind, placebo-controlled trial conducted at National Institute for Infectious diseases (INMI) Lazzaro Spallanzani (Italy), 52 patients were randomly assigned (1:1) to receive a multistrain synbiotic formula (Kebirah®) or placebo orally for 35 days at COVID-19 diagnosis. Health professionals, investigators, and patients were masked to group assignments. The V3-V4 hypervariable region of 16S rRNA gene sequencing was employed to study the gut microbiota composition in the two groups. RESULTS: Supplementation with Kebirah® prevented the decrease in the Shannon diversity index of gut microbiota, which was instead observed in patients receiving the placebo. In addition, decreases in lymphocyte count and haemoglobin levels were observed only in the placebo group and not in the treated group, which was also characterised by an amelioration of the gut microbial profile, with an enrichment in beneficial bacteria and a preservation of species diversity. CONCLUSIONS: Our data suggest that modulating the gut microbiota in acute disease through administration of a specific symbiotic formula could be a useful strategy in the frame of SARS-CoV-2 infections.
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Pancreatic cancer has a dismal prognosis, as it is often diagnosed at stage IV of the disease and is characterized by metastatic spread. Gut microbiota and its metabolites have been suggested to influence the metastatic spread by modulating the host immune system or by promoting angiogenesis. To date, the gut microbial profiles of metastatic and non-metastatic patients need to be explored. Taking advantage of the 16S metagenomic sequencing and the PEnalized LOgistic Regression Analysis (PELORA) we identified clusters of bacteria with differential abundances between metastatic and non-metastatic patients. An overall increase in Gram-negative bacteria in metastatic patients compared to non-metastatic ones was identified using this method. Furthermore, to gain more insight into how gut microbes can predict metastases, a machine learning approach (iterative Random Forest) was performed. Iterative Random Forest analysis revealed which microorganisms were characterized by a different level of relative abundance between metastatic and non-metastatic patients and established a functional relationship between the relative abundance and the probability of having metastases. At the species level, the following bacteria were found to have the highest discriminatory power: Anaerostipes hadrus, Coprobacter secundus, Clostridium sp. 619, Roseburia inulinivorans, Porphyromonas and Odoribacter at the genus level, and Rhodospirillaceae, Clostridiaceae and Peptococcaceae at the family level. Finally, these data were intertwined with those from a metabolomics analysis on fecal samples of patients with or without metastasis to better understand the role of gut microbiota in the metastatic process. Artificial intelligence has been applied in different areas of the medical field. Translating its application in the field of gut microbiota analysis may help fully exploit the potential information contained in such a large amount of data aiming to open up new supportive areas of intervention in the management of cancer.
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Bactérias , Microbioma Gastrointestinal , Aprendizado de Máquina , Metástase Neoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/patologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Masculino , Feminino , RNA Ribossômico 16S/genética , Pessoa de Meia-Idade , Fezes/microbiologia , Idoso , MetagenômicaRESUMO
Introduction: Inflammatory bowel diseases (IBD) are chronic inflammatory conditions that typically involve diarrhea, abdominal pain, fatigue, and weight loss, with a dramatic impact on patients' quality of life. Standard medications are often associated with adverse side effects. Thus, alternative treatments such as probiotics are of great interest. The purpose of the present study was to evaluate the effects of oral administration of Lentilactobacillus kefiri (basonym: Lactobacillus kefiri) SGL 13 and Andrographis paniculata, namely, Paniculin 13™, on dextran sodium sulfate (DSS)- treated C57BL/6J mice. Methods: Colitis was induced by administering 1.5% DSS in drinking water for 9 days. Forty male mice were divided into four groups, receiving PBS (control), 1.5% DSS, Paniculin 13™ and 1.5% DSS + Paniculin 13™. Results: The results showed that body weight loss and Disease Activity Index (DAI) score were improved by Paniculin 13™. Moreover, Paniculin 13™ ameliorated DSS-induced dysbiosis, by modulating the gut microbiota composition. The gene expression of MPO, TNFα and iNOS in colon tissue was reduced and these data matched with the histological results, supporting the efficacy of Paniculin 13™ in reducing the inflammatory response. No adverse effects were associated to Paniculin 13™ administration. Discussion: In conclusion, Paniculin 13™ could be an effective add-on approach to conventional therapies for IBD.
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Pancreatic cancer (PC) has a very low survival rate mainly due to late diagnosis and refractoriness to therapies. The latter also cause adverse effects negatively affecting the patients' quality of life, often requiring dose reduction or discontinuation of scheduled treatments, compromising the chances of cure. We explored the effects of a specific probiotic blend on PC mice xenografted with KRAS wild-type or KRASG12D mutated cell lines alone or together with gemcitabine+nab-paclitaxel treatment to then assess tumor volume and clinical pathological variables. Beside a semi-quantitative histopathological evaluation of murine tumor and large intestine samples, histochemical and immunohistochemical analyses were carried out to evaluate collagen deposition, proliferation index Ki67, immunological microenvironment tumor-associated, DNA damage markers and also mucin production. Blood cellular and biochemical parameters and serum metabolomics were further analyzed. 16S sequencing was performed to analyze the composition of fecal microbiota. Gemcitabine+nab-paclitaxel treatment impaired gut microbial profile in KRAS wild-type and KRASG12D mice. Counteracting gemcitabine+nab-paclitaxel- induced dysbiosis through the administration of probiotics ameliorated chemotherapy side effects and decreased cancer-associated stromatogenesis. Milder intestinal damage and improved blood count were also observed upon probiotics treatment as well as a positive effect on fecal microbiota, yielding an increase in species richness and in short chain fatty acids producing- bacteria. Mice' serum metabolomic profiles revealed significant drops in many amino acids upon probiotics administration in KRAS wild-type mice while in animals transplanted with PANC-1 KRASG12D mutated all treated groups showed a sharp decline in serum levels of bile acids with respect to control mice. These results suggest that counteracting gemcitabine+nab-paclitaxel-induced dysbiosis ameliorates chemotherapy side effects by restoring a favorable microbiota composition. Relieving adverse effects of the chemotherapy through microbiota manipulation could be a desirable strategy in order to improve pancreatic cancer patients' quality of life and to increase the chance of cure.
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Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
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Background: Breast cancer (BC) is the second-leading cause of cancer-related death worldwide. This study aimed to investigate the effects of a 12-week home-based lifestyle intervention (based on nutrition and exercise) on gut microbial composition in twenty BC survivors of the MoviS clinical trial (protocol: NCT04818359). Methods: Gut microbiota analysis through 16S rRNA gene sequencing, anthropometrics, Mediterranean Diet (MD) adherence, and cardiometabolic parameters were evaluated before (Pre) and after (Post) the lifestyle intervention (LI). Results: Beneficial effects of the LI were observed on MD adherence, and cardiometabolic parameters (pre vs post). A robust reduction of Proteobacteria was observed after LI, which is able to reshape the gut microbiota by modulating microorganisms capable of decreasing inflammation and others involved in improving the lipid and glycemic assets of the host. A significant negative correlation between fasting glucose and Clostridia_vadinBB60 (r = -0.62), insulin and homeostatic model assessment (HOMA) index and Butyricicoccus genera (r = -0.72 and -0.66, respectively), and HDL cholesterol and Escherichia/Shigella (r = -0.59) have been reported. Moreover, positive correlations were found between MD adherence and Lachnospiraceae_ND3007 (r = 0.50), Faecalibacterium (r = 0.38) and Butyricimonas (r = 0.39). Conclusion: These data suggest that adopting a healthy lifestyle, may contribute to ameliorate several biological parameters that could be involved in the prevention of cancer relapses through the modulation of gut microbiota.
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer. The characteristic excessive stromatogenesis accompanying the growth of this tumor is believed to contribute to chemoresistance which, together with drug toxicity, results in poor clinical outcome. An increasing number of studies are showing that gut microbiota and their metabolites are implicated in cancer pathogenesis, progression and response to therapies. In this study we tested butyrate, a product of dietary fibers' bacterial fermentation, whose anticancer and anti-inflammatory functions are known. We provided in vitro evidence that, beside slowing proliferation, butyrate enhanced gemcitabine effectiveness against two human pancreatic cancer cell lines, mainly inducing apoptosis. In addition, we observed that, when administered to a PDAC mouse model, alone or combined with gemcitabine treatment, butyrate markedly reduced the cancer-associated stromatogenesis, preserved intestinal mucosa integrity and affected fecal microbiota composition by increasing short chain fatty acids producing bacteria and decreasing some pro-inflammatory microorganisms. Furthermore, a biochemical serum analysis showed butyrate to ameliorate some markers of kidney and liver damage, whereas a metabolomics approach revealed a deep modification of lipid metabolism, which may affect tumor progression or response to therapy. Such results support that butyrate supplementation, in addition to conventional therapies, can interfere with pancreatic cancer biology and response to treatment and can alleviate some damages associated to cancer itself or to chemotherapy.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Bactérias/metabolismo , Butiratos/metabolismo , Butiratos/farmacologia , Butiratos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND AND AIMS: Failure of the embryo to implant causes about three-fourths of lost pregnancies. Female genital tract microbiota has been associated to Assisted Reproductive Technologies (ART) outcomes. The objective of this study was to analyze the microbiota of human cervical swab and to correlate these findings with the ART outcomes. MATERIALS AND METHODS: In this study, 88 cervical swabs were collected from women undergoing ART cycles, with various causes of infertility, at the beginning of the ART protocols. After microbial DNA extraction, V3-V4 variable regions of the 16S rRNA gene were amplified and sequenced on the Illumina MiSeq platform. PEnalized LOgistic Regression Analysis (PELORA) was performed to identify clusters of bacterial populations with differential abundances between patients with unfavorable and favorable pregnancy outcome groups, respectively. RESULTS: We identified a core of microorganisms at lower taxonomic levels that were predictive of women's pregnancy outcomes. Statistically significant differences were identified at species levels with Lactobacillus salivarius, Lactobacillus rhamnosus among others. Moreover the abundance of Lactobacillus crispatus and iners, respectively increased and decreased in favorable group as compared to unfavorable group, resulted within the core of microorganisms associated to positive ART outcome. Although the predominance of lactobacilli is generally considered to be advantageous for ART outcome, we found that also the presence of Bifidobacterium (together with the other lactobacilli) was more abundant in the favorable group. DISCUSSION: Cervix is colonized by microorganisms which can play a role in ART outcomes as seen by an overall decrease in embryo attachment rates and pregnancy rates in both fertile and infertile women. If confirmed in a larger cohort, the abundance of these bacteria can be useful not only as a marker of unfavorable pregnancy outcome but also they may open the way to new interventional strategies based on genital tract microbiota manipulation in order to increase the pregnancy rates in woman undergoing assisted reproductive technologies.
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Chemoresistance is a major problem in the therapeutic management of pancreatic cancer, concurring to poor clinical outcome. A number of mechanisms have been proposed to explain resistance to gemcitabine, a standard of care for this malignancy, among which is included aberrant miRNA expression. In the current study, we investigated the role of miR-217, which is strongly down-regulated in cancerous, compared to normal, pancreatic tissues or cells, in sensitizing human pancreatic cancer cell lines to this drug. The low expression of miR-217 in pancreatic cancer patients was confirmed in two gene expression datasets (GSE41372 and GSE60980), and the prognostic value of two target genes (ANLN and TRPS1), was estimated on clinical data from the Tumor Cancer Genome Atlas (TCGA). Transfecting miR-217 mimic in pancreatic cancer cells reduced viability, enhanced apoptosis, and affected cell cycle by promoting a S phase arrest in gemcitabine-treated cells. Moreover, in drug-exposed cells subjected to miR-217 forced expression, a down-regulation for several genes involved in cancer drug resistance was observed, many of which are cell cycle regulators, such as CCND1, CCNE1, CDK2, CDKN1A, CDKN1B, while others, such as ARNT, BRCA1, BRCA2, ELK1, EGFR, ERBB4, and RARA are involved in proliferation and cell cycle progression. Our results support the notion that miR-217 enhances pancreatic cancer sensitivity to gemcitabine, mainly impairing cell cycle progression.
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Desoxicitidina/análogos & derivados , MicroRNAs/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Bases de Dados Genéticas , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , MicroRNAs/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Gencitabina , Neoplasias PancreáticasRESUMO
The gut microbiota is constituted by more than 40,000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n = 20) presented significant differences when compared to patients treated with atypical antipsychotics (n = 31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS.