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Heliyon Mar 2024Contemporary research in the field of microbiota shows that commensal bacteria influence physiological activity of different organs and systems of a human organism, such... (Review)
Review
Contemporary research in the field of microbiota shows that commensal bacteria influence physiological activity of different organs and systems of a human organism, such as brain, lungs, immune and metabolic systems. This influence is realized by various processes. One of them is trough modulation of immune mechanisms. Interactions between microbiota and the human immune system are known to be complex and ambiguous. Dendritic cells (DCs) are unique cells, which initiate the development and polarization of adaptive immune response. These cells also interconnect native and specific immune reactivity. A large set of biochemical signals from microbiota in the form of different microbiota associated molecular patterns (MAMPs) and bacterial metabolites that act locally and distantly in the human organism. As a result, commensal bacteria influence the maturity and activity of dendritic cells and affect the overall immune reactivity of the human organism. It then determines the response to pathogenic microorganisms, inflammation, associated with different pathological conditions and even affects the effectiveness of vaccination.
PubMed: 38444507
DOI: 10.1016/j.heliyon.2024.e27125 -
Parkinson's Disease 2023Parkinson's disease (PD) is a complex multifactorial disease, involving genetic susceptibility, environmental risk factors, and gene-environmental interactions. The...
INTRODUCTION
Parkinson's disease (PD) is a complex multifactorial disease, involving genetic susceptibility, environmental risk factors, and gene-environmental interactions. The microbiota-gut-brain axis is hypothesized to play a role in the pathophysiology of PD, and peptidoglycan recognition proteins (PGLYRPs), which modulate the gut microbiota, are, therefore, relevant candidate genes for PD.
METHODS
Using quantitative real-time PCR, we genotyped three variants (rs892145, rs959117, and rs10888557) and performed an association analysis in 508 PD patients and 585 control individuals. We further conducted a meta-analysis of rs892145 and analyzed gene expression in lymphocytes from patients with PD and controls.
RESULTS
Although initial analysis of the three variants rs892145, rs959117, and rs10888557 and a meta-analysis of rs892145 did not reveal any association between the selected variants and PD, we found an interaction between sex and genotype for rs892145, with a marked difference in the allele distribution of rs892145 between male and female patients. As compared to controls, the T allele was less common in female patients (odds ratio = 0.76, = 0.04) and more common in male patients (odds ratio = 1.29, = 0.04). No difference was found in gene expression between PD patients and controls ( = 0.38), nor between sexes ( = 0.07). . Overall, this genetic screening in Swedish PD patients does not support previous results demonstrating associations of variants with the risk of PD. Meta-analysis of rs892145 revealed pronounced heterogeneity between previously published studies which is likely to have influenced the results. Taken together, the genetic and gene expression analyses suggest a possible link between genetic variants in and sex differences in PD. Because of the limited sample size in our study, these results need to be verified in independent cohorts before concluding.
PubMed: 38106542
DOI: 10.1155/2023/6502727 -
Gut Microbes 2024The majority of cohort-specific studies associating gut microbiota with obesity are often contradictory; thus, the replicability of the signature remains questionable.... (Meta-Analysis)
Meta-Analysis
The majority of cohort-specific studies associating gut microbiota with obesity are often contradictory; thus, the replicability of the signature remains questionable. Moreover, the species that drive obesity-associated functional shifts and their replicability remain unexplored. Thus, we aimed to address these questions by analyzing gut microbial metagenome sequencing data to develop an in-depth understanding of obese host-gut microbiota interactions using 3329 samples (Obese, = 1494; Control, = 1835) from 17 different countries, including both 16S rRNA gene and metagenomic sequence data. Fecal metagenomic data from diverse geographical locations were curated, profiled, and pooled using a machine learning-based approach to identify robust global signatures of obesity. Furthermore, gut microbial species and pathways were systematically integrated through the genomic content of the species to identify contributors to obesity-associated functional shifts. The community structure of the obese gut microbiome was evaluated, and a reproducible depletion of diversity was observed in the obese compared to the lean gut. From this, we infer that the loss of diversity in the obese gut is responsible for perturbations in the healthy microbial functional repertoire. We identified 25 highly predictive species and 37 pathway associations as signatures of obesity, which were validated with remarkably high accuracy (AUC, Species: 0.85, and pathway: 0.80) with an independent validation dataset. We observed a reduction in short-chain fatty acid (SCFA) producers (several species, , etc.) and depletion of promoters of gut barrier integrity ( and ) in obese guts. Our analysis underlines SCFAs and purine/pyrimidine biosynthesis, carbohydrate metabolism pathways in control individuals, and amino acid, enzyme cofactor, and peptidoglycan biosynthesis pathway enrichment in obese individuals. We also mapped the contributors to important obesity-associated functional shifts and observed that these are both dataset-specific and shared across the datasets. In summary, a comprehensive analysis of diverse datasets unveils species specifically contributing to functional shifts and consistent gut microbial patterns associated to obesity.
Topics: Humans; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Amino Acids; Bacteroides; Obesity
PubMed: 38265338
DOI: 10.1080/19490976.2024.2304900 -
Frontiers in Cellular and Infection... 2023Extracellular vesicles (EVs) are nano-sized particles released from cells into the extracellular environment, and are separated from eukaryotic cells, bacteria, and... (Review)
Review
Extracellular vesicles (EVs) are nano-sized particles released from cells into the extracellular environment, and are separated from eukaryotic cells, bacteria, and other organisms with cellular structures. EVs alter cell communication by delivering their contents and performing various functions depending on their cargo and release into certain environments or other cells. The cell walls of Gram-positive bacteria have a thick peptidoglycan layer and were previously thought to be unable to produce EVs. However, recent studies have demonstrated that Gram-positive bacterial EVs are crucial for health and disease. In this review, we have summarized the formation, composition, and characteristics of the contents, resistance to external stress, participation in immune regulation, and other functions of Gram-positive bacterial EVs, as well as their application in clinical diagnosis and treatment, to provide a new perspective to further our understanding of Gram-positive bacterial EVs.
Topics: Gram-Positive Bacteria; Bacteria; Membranes; Extracellular Vesicles
PubMed: 37860067
DOI: 10.3389/fcimb.2023.1273813 -
Gut May 2024Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies.
DESIGN
We used the KPC mouse model () and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent coculture assays, mouse and zebrafish tumorigenesis studies, and database approaches were performed.
RESULTS
Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC.
CONCLUSIONS
This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
PubMed: 38754953
DOI: 10.1136/gutjnl-2023-330995 -
Communications Biology Sep 2023Cell shape is genetically inherited by all forms of life. Some unicellular microbes increase niche adaptation altering shape whereas most show invariant morphology. A...
Cell shape is genetically inherited by all forms of life. Some unicellular microbes increase niche adaptation altering shape whereas most show invariant morphology. A universal system of peptidoglycan synthases guided by cytoskeletal scaffolds defines bacterial shape. In rod-shaped bacteria, this system consists of two supramolecular complexes, the elongasome and divisome, which insert cell wall material along major and minor axes. Microbes with invariant shape are thought to use a single morphogenetic system irrespective of the occupied niche. Here, we provide evidence for two elongasomes that generate (rod) shape in the same bacterium. This phenomenon was unveiled in Salmonella, a pathogen that switches between extra- and intracellular lifestyles. The two elongasomes can be purified independently, respond to different environmental cues, and are directed by distinct peptidoglycan synthases: the canonical PBP2 and the pathogen-specific homologue PBP2. The PBP2-elongasome responds to neutral pH whereas that directed by PBP2 assembles in acidic conditions. Moreover, the PBP2-elongasome moves at a lower speed. Besides Salmonella, other human, animal, and plant pathogens encode alternative PBPs with predicted morphogenetic functions. Therefore, contrasting the view of morphological plasticity facilitating niche adaptation, some pathogens may have acquired alternative systems to preserve their shape in the host.
Topics: Animals; Humans; Peptidoglycan; Salmonella; Acclimatization; Cell Shape; Cell Wall
PubMed: 37689828
DOI: 10.1038/s42003-023-05308-w -
Biotechnology Advances Dec 2023Endolysins are bacteriophage-encoded enzymes that can specifically degrade the peptidoglycan layer of bacterial cell wall, making them an attractive tool for the... (Review)
Review
Endolysins are bacteriophage-encoded enzymes that can specifically degrade the peptidoglycan layer of bacterial cell wall, making them an attractive tool for the development of novel antibacterial agents. The use of genetic engineering techniques for the production and modification of endolysins offers the opportunity to customize their properties and activity against specific bacterial targets, paving the way for the development of personalized therapies for bacterial infections. Gram-negative bacteria possess an outer membrane that can hinder the action of recombinantly produced endolysins. However, certain endolysins are capable of crossing the outer membrane by virtue of segments that share properties resembling those of cationic peptides. These regions increase the affinity of the endolysin towards the bacterial surface and assist in the permeabilization of the membrane. In order to improve the bactericidal effectiveness of endolysins, approaches have been implemented to increase their net charge, including the development of Artilysins containing positively charged amino acids at one end. At present, there are no specific guidelines outlining the steps for implementing these modifications. There is an ongoing debate surrounding the optimal location of positive charge, the need for a linker region, and the specific amino acid composition of peptides for modifying endolysins. The aim of this study is to provide clarity on these topics by analyzing and comparing the most effective modifications found in previous literature.
Topics: Endopeptidases; Anti-Bacterial Agents; Bacteria; Bacteriophages; Peptides
PubMed: 37678419
DOI: 10.1016/j.biotechadv.2023.108250 -
BioRxiv : the Preprint Server For... Aug 2023Active nutrient uptake is fundamental for survival and pathogenicity of Gram-negative bacteria, which operate a multi-protein Ton system to transport essential nutrients...
Active nutrient uptake is fundamental for survival and pathogenicity of Gram-negative bacteria, which operate a multi-protein Ton system to transport essential nutrients like metals and vitamins. This system harnesses the proton motive force at the inner membrane to energize the import through the outer membrane, but the mechanism of energy transfer remains enigmatic. Here, we study the periplasmic domain of ExbD, a crucial component of the proton channel of the Ton system. We show that this domain is a dynamic dimer switching between two conformations representing the proton channel's open and closed states. By phenotypic assays we demonstrate that this conformational switch is essential for the nutrient uptake by bacteria. The open state of ExbD triggers a disorder to order transition of TonB, enabling TonB to supply energy to the nutrient transporter. We also reveal the anchoring role of the peptidoglycan layer in this mechanism. Herein, we propose a mechanistic model for the Ton system, emphasizing ExbD duality and the pivotal catalytic role of peptidoglycan. Sequence analysis suggests that this mechanism is conserved in other systems energizing gliding motility and membrane integrity. Our study fills important gaps in understanding bacterial motor mechanism and proposes novel antibacterial strategies.
PubMed: 37609138
DOI: 10.1101/2023.08.11.552980 -
Protein & Cell Oct 2023Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis. At the host-gut microbiome... (Review)
Review
Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis. At the host-gut microbiome interface, cell wall-derived molecules from gut commensal bacteria have been reported to play a pivotal role in training and remodeling host immune responses. In this article, we review gut bacterial cell wall-derived molecules with characterized chemical structures, including peptidoglycan and lipid-related molecules that impact host health and disease processes via regulating innate and adaptive immunity. Also, we aim to discuss the structures, immune responses, and underlying mechanisms of these immunogenic molecules. Based on current advances, we propose cell wall-derived components as important sources of medicinal agents for the treatment of infection and immune diseases.
Topics: Gastrointestinal Microbiome; Intestinal Mucosa; Bacteria; Immune System; Symbiosis; Immunity, Mucosal; Immunity, Innate
PubMed: 37013853
DOI: 10.1093/procel/pwad016 -
Food Science & Nutrition Aug 2023Functional foods are gaining significant research attention of researchers due to their health-endorsing properties due to their bioactive components either living cells... (Review)
Review
Functional foods are gaining significant research attention of researchers due to their health-endorsing properties due to their bioactive components either living cells (probiotics) or nonviable cells (prebiotics). The term "postbiotic" specifies the soluble substances, such as enzymes, peptides, teichoic acids, muropeptides derived from peptidoglycans, polysaccharides, cell surface proteins, and organic acids, that are secreted by living bacteria or released after bacterial lysis. Due to various signaling molecules which may have antioxidant, immunomodulatory, antiinflammatory, antihypertensive, and antiproliferative activities, postbiotics offer great potential to be used in pharmaceutical, food, and nutraceutical industries, to promote health and ailment prevention. This recent review is a landmark of information relevant to the production of postbiotics along with salient features to use in various fields ranging from food to immunomodulation and selective and effective therapy. It also puts forward the concept that postbiotics are way more effective than probiotics in the veterinary, food as well as medical field which ultimately helps in reducing the disease burden along with human health.
PubMed: 37576043
DOI: 10.1002/fsn3.3465