Analysis of gut microbiota-derived extracellular vesicles isolated from newly diagnosed multiple sclerosis patients

Abstract. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. MS is characterized by a gradual loss of neuronal cells, leading to physical and cognitive impairment over time. The gut microbiota has been suggested to be an important environmental factor in MS, but the mechanism of action is vastly unknown. We suggest that production of extracellular vesicles (EVs) is one mechanism how the gut microbiota is able to influence host physiology in health and disease. In this work, EVs were isolated from fecal samples of 16 newly diagnosed MS patients and 18 healthy controls. The object was to determine the protein composition of EVs but the final analysis was hindered due to unfortunate events caused by SARS-CoV-2 pandemic. Nanoparticle tracking analysis of EVs showed that concentration and size distribution of EVs was similar between MS patients and healthy controls. Additionally, this work accomplished to show that as low as 100 mg of fecal material was sufficient for EV isolation, which can be used to improve EV isolation practicalities

Suolistomikrobien vaikutus aivojen toimintaan maha-aivo-akselin välityksellä

Tiivistelmä. Mikrobiomi-maha-aivo-akseli on suolistomikrobien ja aivojen kaksisuuntainen kommunikaatiosysteemi, jonka välityksellä suolistomikrobit kykenevät vaikuttamaan aivojen toimintaan. Suolistomikrobit hyödyntävät signaloinnissa hermostoa, immuunisysteemiä ja verenkiertoa. Suolistomikrobit tuottavat molekyylejä, kuten hermovälittäjäaineita, lyhytketjuisia rasvahappoja ja tryptofaanin johdannaisia, jotka voivat vaikuttaa hermojen toimintaan suoraan tai hermoihin kytköksissä olevien suoliston solujen välityksellä. Suolistomikrobien tuottamat lyhytketjuiset rasvahapot imeytyvät suolistosta vereen ja kulkeutuvat aivoihin. Lyhytketjuiset rasvahapot vaikuttavat veri-aivoesteen läpäisevyyteen ja geenien ilmentymiseen aivoissa, millä voi olla käytökseen ja sairauksiin liittyviä vaikutuksia. Suolistomikrobit vaikuttavat tryptofaanin aineenvaihduntaan, kuten serotoniinin synteesiin sekä kynureniinireittiin. Suolistomikrobien on havaittu olevan osallisina mielenterveyden häiriöissä, autismikirjossa sekä neurodegeneratiivisissa sairauksissa. Probiooteilla eli nautittavilla bakteerivalmistella on havaittu olevan hyötyä näiden sairauksien hoidossa. Probiootteja voidaan tulevaisuudessa käyttää uutena hoitomuotona moniin sairauksiin. Probioottien vaikutusmekanismeista sekä turvallisuudesta tarvitaan kuitenkin lisää tietoa

Bacterial extracellular vesicles in gastrointestinal tract cancer:an unexplored territory

Abstract Bacterial extracellular vesicles are membrane-enclosed, lipid bi-layer nanostructures that carry different classes of biomolecules, such as nucleic acids, lipids, proteins, and diverse types of small molecular metabolites, as their cargo. Almost all of the bacteria in the gut secrete extracellular vesicles to assist them in competition, survival, material exchange, host immune modulation, infection, and invasion. The role of gut microbiota in the development, progression, and pathogenesis of gastrointestinal tract (GIT) cancer has been well documented. However, the possible involvement of bacterial extracellular vesicles (bEVs) in GIT cancer pathophysiology has not been given due attention. Studies have illustrated the ability of bEVs to cross physiological barriers, selectively accumulate near tumor cells, and possibly alter the tumor microenvironment (TME). A systematic search of original published works related to bacterial extracellular vesicles on gastrointestinal cancer was performed for this review. The current systemic review outlines the possible impact of gut microbiota derived bEVs in GIT cancer in light of present-day understanding. The necessity of using advanced sequencing technologies, such as genetic, proteomic, and metabolomic investigation methodologies, to facilitate an understanding of the interrelationship between cancer-associated bacterial vesicles and gastrointestinal cancer is also emphasized. We further discuss the clinical and pharmaceutical potential of bEVs, along with future efforts needed to understand the mechanism of interaction of bEVs in GIT cancer pathogenesis

Microbiota and extracellular vesicles in anti-PD-1/PD-L1 therapy

Abstract Cancer is a deadly disease worldwide. In light of the requisite of convincing therapeutic methods for cancer, immune checkpoint inhibition methods such as anti-PD-1/PD-L1 therapy appear promising. Human microbiota have been exhibited to regulate susceptibility to cancer as well as the response to anti-PD-1/PD-L1 therapy. However, the probable contribution of bacterial extracellular vesicles (bEVs) in cancer pathophysiology and treatment has not been investigated much. bEVs illustrate the ability to cross physiological barriers, assemble around the tumor cells, and likely modify the tumor microenvironment (EVs). This systematic review emphasizes the correlation between cancer-associated extracellular vesicles, particularly bEVs and the efficacy of anti-PD-1/PD-L1 therapy. The clinical and pharmacological prospective of bEVs in revamping the contemporary treatments for cancer has been further discussed

Delivery mode and perinatal antibiotics influence the infant gut bacteriome and mycobiome:a network analysis

Abstract Both exposure to antibiotics at birth and delivery via Caesarean section influence the gut bacteriome’s development in infants. Using 16S rRNA and internal transcribed spacer sequencing on the Ion Torrent platform, we employed network analysis to investigate the bacterial and fungal interkingdom relationships in the gut microbiome from birth to age 18 months in a prospective cohort study of 140 infants. The gut microbiome at ages six and 18 months revealed distinctive microbial interactions, including both positive and negative associations between bacterial and fungal genera in the gut ecosystem. Perinatal factors, delivery mode and intrapartum antibiotic exposure affected the associations between bacterial and fungal species. In infants exposed and unexposed to perinatal antibiotics, the gut microbiome formed distinct networks for the bacteriome and mycobiome. The fungi Saccharomyces, Trichosporon, Pezoloma, Cystofilobasidium, Rigidoporus and Fomitopsis were strongly associated with exposure to antibiotics at birth. Hyaloscypha, Trichosporon, Fomitopsis and Vishniacozyma were strongly associated with the control group that was not exposed to antibiotics. Five distinct networks were formed according to delivery mode. The present study confirms that bacteria and fungi clearly interact in the infant gut ecosystem. Furthermore, perinatal factors appear to influence the relationships between bacteria and fungi in the developing gut microbiome

High adherence of oral streptococcus to polylactic acid might explain implant infections associated with PLA mesh implantation

Abstract The aim of this study was to evaluate and compare the biofilm formation properties of common pathogens associated with implant-related infections on two different implant material types. Bacterial strains tested in this study were Staphylococcus aureus, Streptococcus mutans, Enterococcus faecalis, and Escherichia coli. Implant materials tested and compared were PLA Resorb × polymer of Poly DL-lactide (PDLLA) comprising 50% poly-L-lactic acid and 50% poly-D-lactic acid) and Ti grade 2 (tooled with a Planmeca CAD-CAM milling device). Biofilm assays were done with and without saliva treatment to evaluate the effect of saliva on bacterial adhesion and to mimic the intraoral and extraoral surgical routes of implant placement, respectively. Five specimens of each implant type were tested for each bacterial strain. Autoclaved material specimens were first treated with 1:1 saliva-PBS solution for 30 min, followed by washing of specimens and the addition of bacterial suspension. Specimens with bacterial suspension were incubated for 24 h at 37 °C for biofilm formation. After 24 h, non-adhered bacteria were removed, and specimens were washed, followed by removal and calculation of adhered bacterial biofilm. S. aureus and E. faecalis showed more attachment to Ti grade 2, whereas S. mutans showed higher adherence to PLA in a statistically significant manner. The salivary coating of specimens enhanced the bacterial attachment by all the bacterial strains tested. In conclusion, both implant materials showed significant levels of bacterial adhesion, but saliva treatment played a vital role in bacterial attachment, therefore, saliva contamination of the implant materials should be minimized and considered when placing implant materials inside the body

Bacterial extracellular vesicles – brain invaders?:a systematic review

Abstract Introduction: Knowledge on the human gut microbiota in health and disease continues to rapidly expand. In recent years, changes in the gut microbiota composition have been reported as a part of the pathology in numerous neurodegenerative diseases. Bacterial extracellular vesicles (EVs) have been suggested as a novel mechanism for the crosstalk between the brain and gut microbiota, physiologically connecting the observed changes in the brain to gut microbiota dysbiosis. Methods: Publications reporting findings on bacterial EVs passage through the blood–brain barrier were identified in PubMed and Scopus databases. Results: The literature search yielded 138 non-duplicate publications, from which 113 records were excluded in title and abstract screening step. From 25 publications subjected to full-text screening, 8 were excluded. The resulting 17 publications were considered for the review. Discussion: Bacterial EVs have been described with capability to cross the blood–brain barrier, but the mechanisms behind the crossing remain largely unknown. Importantly, very little data exists in this context on EVs secreted by the human gut microbiota. This systematic review summarizes the present evidence of bacterial EVs crossing the blood–brain barrier and highlights the importance of future research on gut microbiota-derived EVs in the context of gut-brain communication across the blood–brain barrier

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used