Showing papers in "Frontiers in Cellular and Infection Microbiology in 2019"
TL;DR: The evidence for super-donors in FMT is reviewed and the concept of keystone species as predictors of FMT success is explored, highlighting how super- Donors could provide the basis for dysbiosis-matched FMTs.
Abstract: Fecal microbiota transplantation (FMT) has become a highly effective bacteriotherapy for recurrent Clostridium difficile infection. Meanwhile the efficacy of FMT for treating chronic diseases associated with microbial dysbiosis has so far been modest with a much higher variability in patient response. Notably, a number of studies suggest that FMT success is dependent on the microbial diversity and composition of the stool donor, leading to the proposition of the existence of FMT super-donors. The identification and subsequent characterization of super-donor gut microbiomes will inevitably advance our understanding of the microbial component of chronic diseases and allow for more targeted bacteriotherapy approaches in the future. Here, we review the evidence for super-donors in FMT and explore the concept of keystone species as predictors of FMT success. Possible effects of host-genetics and diet on FMT engraftment and maintenance are also considered. Finally, we discuss the potential long-term applicability of FMT for chronic disease and highlight how super-donors could provide the basis for dysbiosis-matched FMTs.
225 citations
TL;DR: Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure.
Abstract: Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.
205 citations
TL;DR: The anti-inflammatory effects of strain ATCC were stronger than strain 139 in that ATCC significantly reduced spleen weight, colon inflammation index, and fecal lipocalin-2 content in mice with chronic colitis, while strain 139 was not.
Abstract: Akkermansia muciniphila is potential probiotic in that its type strain ATCC BAA-835 has beneficial effects upon obesity and diabetes. However, whether A. muciniphila can improve inflammatory bowel diseases (IBD), which is a form of chronic intestinal dysbiosis, is unknown. Hence, we used an isolated murine A. muciniphila strain (designated 139) and A. muciniphila type strain ATCC, to investigate their anti-inflammatory properties in cell models and in Dextran Sulfate Sodium (DSS)-induced chronic colitis of mice. In vitro, the two A. muciniphila strains exerted similar anti-inflammatory properties as they both reduced IL-8 production by TNF-α-stimulated HT-29 cells. However, neither of the strains showed capacity to increase the differentiation of regulatory T (Treg)-cells from CD4+ T cell populations significantly. In vivo, both A. muciniphila strains exerted anti-inflammatory effects on chronic colitis as they improved clinical parameters including spleen weight, colon inflammation index, and colon histological score. They also down-regulated the expression of the pro-inflammatory cytokines including TNF-α and IFN-γ in the colon of mice. However, the anti-inflammatory effects of strain ATCC were stronger than strain 139 in that ATCC significantly reduced spleen weight, colon inflammation index, and fecal lipocalin-2 content in mice with chronic colitis, while strain 139 was not. Dysbiosis of the gut microbiota was observed in mice with chronic colitis. Both A. muciniphila strains facilitated the normalization of the gut microbiota. The specific capacity of strain ATCC to modulate the differentiation of Tregs as well as increase production of short chain fatty acids, demonstrated strain-specific characteristics for these two A. muciniphila strains. This study suggests the potential beneficial effect of A. muciniphila on IBD and the importance of the future study of the function of A. muciniphila at the strain-level.
205 citations
TL;DR: The developed LF-RPA assay is presented as a new simple, specific, sensitive, rapid and convenient method for the detection of Trichinella infection in domestic animals.
Abstract: Trichinella spp., are amongst the most widespread parasitic nematodes, primarily live in the muscles of a wide range of vertebrate animals and humans. Human infection occurs by ingestion of raw or undercooked meat containing Trichinella larvae. Accurate diagnosis of Trichinella spp. infection in domestic animals is crucial for the effective prevention and control of human trichinellosis. In the present study, a simple, rapid and accurate diagnostic assay was developed combining recombinase polymerase amplification and a lateral flow strip (LF-RPA) to detect Trichinella spp. infection. The LF-RPA assay targets Trichinella spp. mitochondrial small-subunit ribosomal RNA (rrnS) gene and can detect as low as 100 fg DNA of Trichinella strains, which was approximately 10 times more sensitive than a conventional PCR assay. The LF-RPA assay can be performed within 10-25 min, at a wide range of temperatures (25-45°C) and showed no cross-reactivity with DNA of other parasites and related host species of Trichinella. The performance of the LF-RPA assay in the presence of high concentration of PCR inhibitor was better than that of a conventional PCR assay. Results obtained by LF-RPA assay for the detection of experimentally infected mice were comparable to the results obtained by using a conventional PCR, achieving 100% specificity and high sensitivity. These results present the developed LF-RPA assay as a new simple, specific, sensitive, rapid and convenient method for the detection of Trichinella infection in domestic animals.
190 citations
TL;DR: This review gathers and compares the results from most relevant studies and may serve as a framework for directed further experimental approaches to ultimately achieve a resolute challenge of multidrug resistant bacteria based on traditional antibiotics and phages.
Abstract: With the emerging threat of infections caused by multidrug resistant bacteria, phages have been reconsidered as an alternative for treating infections caused by tenacious pathogens. However, instead of replacing antibiotics, the combination of both types of antimicrobials can be superior over the use of single agents. Enhanced bacterial suppression, more efficient penetration into biofilms, and lowered chances for the emergence of phage resistance are the likely advantages of the combined strategy. While a number of studies have provided experimental evidence in support of this concept, negative interference between phages and antibiotics have been reported as well. Neutral effects have also been observed, but in those cases, combined approaches may still be important for at least hampering the development of resistance. In any case, the choice of phage type and antibiotic as well as their mixing ratios must be given careful consideration when deciding for a dual antibacterial approach. The most frequently tested bacterium for a combined antibacterial treatment has been Pseudomonas aeruginosa, but encouraging results have also been reported for Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Enterococcus faecalis, and Burkholderia cepacia. Given the immense play area of conceivable phage-antibiotic combinations and their potential excess value, it is time to recapitulate of what has been achieved so far. This review therefore gathers and compares the results from most relevant studies in order to help researchers and clinicians in their strategies to combat multidrug resistant bacteria. Special attention is given to the selected bacterial model organisms, the phage families and genera employed, and the experimental design and evaluation (e.g., in vitro vs. in vivo models, biofilm vs. planktonic culture experiments, order and frequency of administration etc.). The presented data may serve as a framework for directed further experimental approaches to ultimately achieve a resolute challenge of multidrug resistant bacteria based on traditional antibiotics and phages.
179 citations
TL;DR: The intricate interplay between viruses and the PD-1/PD-L1 axis is discussed, which mediates inflammatory effects in the acute phase of an immune response and modulated by a number of viruses.
Abstract: Programmed cell death protein (PD-1) and its ligands play a fundamental role in the evasion of tumor cells from antitumor immunity. Less well appreciated is the fact that the PD-1/PD-L1 axis also regulates antiviral immune responses and is therefore modulated by a number of viruses. Upregulation of PD-1 and its ligands PD-L1 and PD-L2 is observed during acute virus infection and after infection with persistent viruses including important human pathogens such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). Experimental evidence suggests that insufficient signaling through the PD-1 pathway promotes immunopathology during acute infection by exaggerating primary T cell responses. If chronic infection is established, however, high levels of PD-1 expression can have unfavorable immunological consequences. Exhaustion and suppression of antiviral immune responses can result in viral immune evasion. The role of the PD-1/PD-L1 axis during viral infections is further complicated by evidence that PD-L1 also mediates inflammatory effects in the acute phase of an immune response. In this review, we discuss the intricate interplay between viruses and the PD-1/PD-L1 axis.
172 citations
TL;DR: The ways in which dysbiosis in the supposedly innocuous blood-borne bacterial microbiome may stimulate pathogenesis are explored, and the matter of contamination is addressed, citing the influence of contaminants on the interpretation of blood-derived microbial datasets and urging the routine analysis of laboratory controls to ascertain the taxonomic and metabolic characteristics of environmentally-derived contaminant-taxa.
Abstract: The blood that flows perpetually through our veins and arteries performs numerous functions essential to our survival. Besides distributing oxygen, this vast circulatory system facilitates nutrient transport, deters infection and dispenses heat throughout our bodies. Since human blood has traditionally been considered to be an entirely sterile environment, comprising only blood-cells, platelets and plasma, the detection of microbes in blood was consistently interpreted as an indication of infection. However, although a contentious concept, evidence for the existence of a healthy human blood-microbiome is steadily accumulating. While the origins, identities and functions of these unanticipated micro-organisms remain to be elucidated, information on blood-borne microbial phylogeny is gradually increasing. Given recent advances in microbial-hematology, we review current literature concerning the composition and origin of the human blood-microbiome, focusing on bacteria and their role in the configuration of both the diseased and healthy human blood-microbiomes. Specifically, we explore the ways in which dysbiosis in the supposedly innocuous blood-borne bacterial microbiome may stimulate pathogenesis. In addition to exploring the relationship between blood-borne bacteria and the development of complex disorders, we also address the matter of contamination, citing the influence of contaminants on the interpretation of blood-derived microbial datasets and urging the routine analysis of laboratory controls to ascertain the taxonomic and metabolic characteristics of environmentally-derived contaminant-taxa.
171 citations
TL;DR: This review presents some of the anti-virulence strategies that are currently being developed and will cover strategies focused on quench pathogen quorum sensing (QS) systems, disassemble of bacterial functional membrane microdomains (FMMs), disruption of biofilm formation and bacterial toxin neutralization.
Abstract: Antimicrobial resistance constitutes one of the major challenges facing humanity in the Twenty-First century. The spread of resistant pathogens has been such that the possibility of returning to a pre-antibiotic era is real. In this scenario, innovative therapeutic strategies must be employed to restrict resistance. Among the innovative proposed strategies, anti-virulence therapy has been envisioned as a promising alternative for effective control of the emergence and spread of resistant pathogens. This review presents some of the anti-virulence strategies that are currently being developed, it will cover strategies focused on quench pathogen quorum sensing (QS) systems, disassemble of bacterial functional membrane microdomains (FMMs), disruption of biofilm formation and bacterial toxin neutralization.
170 citations
TL;DR: The function, effectors, and regulation of SPI-1 genes and their contribution to the pathogenicity of Salmonella are reviewed.
Abstract: Salmonella species can infect a diverse range of birds, reptiles, and mammals, including humans. The type III protein secretion system (T3SS) encoded by Salmonella pathogenicity island 1 (SPI-1) delivers effector proteins required for intestinal invasion and the production of enteritis. The T3SS is regarded as the most important virulence factor of Salmonella. SPI-1 encodes transcription factors that regulate the expression of some virulence factors of Salmonella, while other transcription factors encoded outside SPI-1 participate in the expression of SPI-1-encoded genes. SPI-1 genes are responsible for the invasion of host cells, regulation of the host immune response, e.g., the host inflammatory response, immune cell recruitment and apoptosis, and biofilm formation. The regulatory network of SPI-1 is very complex and crucial. Here, we review the function, effectors, and regulation of SPI-1 genes and their contribution to the pathogenicity of Salmonella.
168 citations
TL;DR: The master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3–FADD–caspase-8 cell death complex assembly are reviewed and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis is dubbed here as PAN-optosis.
Abstract: Cell death is central to development, organismal homeostasis, and immune responses. The cell death field has experienced tremendous progress by delineating the molecular programs specific to each of the apoptotic and inflammatory cell death pathways. Moreover, the discovery of the inflammasomes and pyroptosis and necroptosis pathway regulators have provided the genetic basis for the programmed inflammatory cell death pathways. Earlier research highlighted the unique regulation of each of these pathways, but emerging studies discovered co-regulation and crosstalk between these seemingly different cell death complexes. The progress in this area has led to an idea that master regulators play central roles in orchestrating multiple cell death pathways. Here, we provide a brief review of the master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3–FADD–caspase-8 cell death complex assembly and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis, which we dubbed here as PAN-optosis. Furthermore, we discuss the implications and therapeutic potential of targeting these master regulators in health and disease.
One Sentence Summary
ZBP1 and TAK1 regulate PAN-optosis.
167 citations
TL;DR: Examination of a combined action of natural AMPs with different structure and mode of action with varied antibiotic agents found that synergy in antibacterial action mainly occurs between highly membrane-active AMPs and antibiotics with intracellular targets, suggesting bioavailability increase as the main model of such interaction.
Abstract: Rapidly growing resistance of pathogenic bacteria to conventional antibiotics leads to inefficiency of traditional approaches of countering infections and determines the urgent need for a search of fundamentally new anti-infective drugs. Antimicrobial peptides (AMPs) of the innate immune system are promising candidates for a role of such novel antibiotics. However, some cytotoxicity of AMPs toward host cells limits their active implementation in medicine and forces attempts to design numerous structural analogs of the peptides with optimized properties. An alternative route for the successful AMPs introduction may be their usage in combination with conventional antibiotics. Synergistic antibacterial effects have been reported for a number of such combinations, however, the molecular mechanisms of the synergy remain poorly understood and little is known whether AMPs cytotoxicy for the host cells increases upon their application with antibiotics. Our study is directed to examination of a combined action of natural AMPs with different structure and mode of action (porcine protegrin 1, caprine bactenecin ChBac3.4, human alpha- and beta-defensins (HNP-1, HNP-4, hBD-2, hBD-3), human cathelicidin LL-37), and egg white lysozyme with varied antibiotic agents (gentamicin, ofloxacin, oxacillin, rifampicin, polymyxin B, silver nanoparticles) toward selected bacteria, including drug-sensitive and drug-resistant strains, as well as toward some mammalian cells (human erythrocytes, PBMC, neutrophils, murine peritoneal macrophages and Ehrlich ascites carcinoma cells). Using "checkerboard titrations" for fractional inhibitory concentration indexes evaluation, it was found that synergy in antibacterial action mainly occurs between highly membrane-active AMPs (e.g., protegrin 1, hBD-3) and antibiotics with intracellular targets (e.g., gentamicin, rifampcin), suggesting bioavailability increase as the main model of such interaction. In some combinations modulation of dynamics of AMP-bacterial membrane interaction in presence of the antibiotic was also shown. Cytotoxic effects of the same combinations toward normal eukaryotic cells were rarely synergistic. The obtained data approve that combined application of antimicrobial peptides with antibiotics or other antimicrobials is a promising strategy for further development of new approach for combating antibiotic-resistant bacteria by usage of AMP-based therapeutics. Revealing the conventional antibiotics that increase the activity of human endogenous AMPs against particular pathogens is also important for cure strategies elaboration.
TL;DR: The results suggest that microbiota dysbiosis may promote chronic systemic inflammation in CKD and support that modifying the gut microbiota, especially Akkermansia, may be a promising potential therapeutic strategy to attenuate the progression of, and/or systemicinflammatory in, CKD.
Abstract: Alterations to the gut microbiota have been previously suggested to be tightly linked to chronic systemic inflammation, which is a major contributing factor to complications and disease progression in chronic kidney disease (CKD). Nevertheless, the effect of gut dysbiosis on the pathogenesis and/or production of inflammatory factors in CKD has not been extensively studied to date. In the present study, we conducted 16S ribosomal DNA pyrosequencing using fecal microbiota samples and analyzed the production of serum inflammatory factors in 50 patients with CKD and 22 healthy control (HC) subjects. The results revealed that compared to the HC subjects, patients with CKD exhibited a significant reduction in the richness and structure of their fecal microbiota. At the phylum level, compared to the HC group, patients with CKD also presented reduced abundance of Actinobacteria but increased abundance of Verrucomicrobia. Moreover, the genera Lactobacillus, Clostridium IV, Paraprevotella, Clostridium sensu stricto, Desulfovibrio, and Alloprevotella were enriched in the fecal samples of patients with CKD, while Akkermansia and Parasutterella were enriched in those of the HC subjects. The abundance of Akkermansia in the CKD group was significantly lower than that in the HC group (3.08 vs. 0.67%); this decrease in the abundance of Akkermansia, an important probiotic, in patients with CKD is a striking discovery as it has not been previously reported. Finally, we analyzed whether these changes to the fecal microbiota correlated with CKD clinical characteristics and/or the production of known inflammatory factors. Altered levels of the microbiota genera Parasutterella, Lactobacillus, Paraprevotella, Clostridium sensu stricto, and Desulfovibrio were shown to be correlated with CKD disease-severity indicators, including the estimated glomerular filtration rate. Most notably, Akkermansia was significantly negatively correlated with the production of interleukin-10. The results of the present study suggest that microbiota dysbiosis may promote chronic systemic inflammation in CKD. Furthermore, they support that modifying the gut microbiota, especially Akkermansia, may be a promising potential therapeutic strategy to attenuate the progression of, and/or systemic inflammation in, CKD.
TL;DR: This review compares the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections with that oncogenes and tumor suppressors.
Abstract: Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections.
TL;DR: This review summarizes the role of three most widely studied pathogenic factors produced by P. gingivalis (lipopolysaccharide, gingipains, pili) and their interactions with TLRs at the cellular and molecular level in the progress of periodontitis.
Abstract: Periodontitis is a common intraoral infection and is inextricably linked to systemic diseases. Recently, the regulation between host immunologic response and periodontal pathogens has become a hotspot to explain the mechanism of periodontitis and related systemic diseases. Since Porphyromonas gingivalis (P. gingivalis) was proved as critical periodontal pathogen above all, researches focusing on the mechanism of its virulence factors have received extensive attention. Studies have shown that in the development of periodontitis, in addition to the direct release of virulent factors by periodontal pathogens to destroy periodontal tissues, over-low or over-high intrinsic immune and inflammatory response mediated by Toll-like receptors (TLRs) can lead to more lasting destruction of periodontal tissues. It is very necessary to sort out how various cytopathic factors of P. gingivalis mediate inflammation and immune responses between the host through TLRs so as to help precisely prevent, diagnose, and treat periodontitis in clinic. This review summarizes the role of three most widely studied pathogenic factors produced by P. gingivalis (lipopolysaccharide, gingipains, pili) and their interactions with TLRs at the cellular and molecular level in the progress of periodontitis.
TL;DR: The results provide the basic guidance for a systematic, multilayered assessment of the role of the gut microbiome in LC, which has a promising potential for early prevention and targeted intervention.
Abstract: Lung cancer (LC) is one of the most serious malignant tumors, which has the fastest growing morbidity and mortality worldwide. A role of the lung microbiota in LC pathogenesis has been analyzed, but a comparable role of the gut microbiota has not yet been investigated. In this study, the gut microbiota of 30 LC patients and 30 healthy controls were examined via next-generation sequencing of 16S rRNA and analyzed for diversity and biomarkers. We found that there was no decrease in significant microbial diversity (alpha diversity) in LC patients compared to controls (P observed = 0.1422), while the composition (beta diversity) differed significantly between patients and controls (phylum [stress = 0.153], class [stress = 0.16], order [stress = 0.146], family [stress = 0.153]). Controls had a higher abundance of the bacterial phylum Actinobacteria and genus Bifidobacterium, while patients with LC showed elevated levels of Enterococcus. These bacteria were found as possible biomarkers for LC. A decline of normal function of the gut microbiome in LC patients was also observed. These results provide the basic guidance for a systematic, multilayered assessment of the role of the gut microbiome in LC, which has a promising potential for early prevention and targeted intervention.
TL;DR: The rapid progress of CRISPR/Cas9-based HIV-1/AIDS therapy research in recent years is updated and the limitations and future perspectives of its application are discussed.
Abstract: Despite the fact that great efforts have been made in the prevention and therapy of HIV-1 infection, HIV-1/AIDS remains a major threat to global human health. Highly active antiretroviral therapy (HAART) can suppress virus replication, but it cannot eradicate latent viral reservoirs in HIV-1/AIDS patients. Recently, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) system has been engineered as an effective gene-editing technology with the potential to treat HIV-1/AIDS. It can be used to target cellular co-factors or HIV-1 genome to reduce HIV-1 infection and clear the provirus, as well as to induce transcriptional activation of latent virus in latent viral reservoirs for elimination. This versatile gene editing technology has been successfully applied to HIV-1/AIDS prevention and reduction in human cells and animal models. Here, we update the rapid progress of CRISPR/Cas9-based HIV-1/AIDS therapy research in recent years and discuss the limitations and future perspectives of its application.
TL;DR: The correlation between the gut microbiota and stroke risk in people with no prior stroke history is presented and participants at high risk of stroke were characterized by the enrichment of opportunistic pathogens, low abundance of butyrate-producing bacteria, and reduced concentrations of fecalbutyrate.
Abstract: Objective: Gut microbiota is a newly identified risk factor for stroke, and there are no large prospective studies linking the baseline gut microbiome to long-term risk of stroke. We present here the correlation between the gut microbiota and stroke risk in people with no prior stroke history. Methods: A total of 141 participants aged ≥60 years without prior history of stroke were recruited and divided into low-risk, medium-risk, and high-risk groups based on known risk factors and whether they were suffering from chronic diseases. The composition of their gut microbiomes was compared using 16S rRNA gene amplicon next-generation-sequencing and Quantitative Insights into Microbial Ecology (QIIME) analysis. Levels of fecal short-chain fatty acids were measured using gas chromatography. Results: We found that opportunistic pathogens (e.g., Enterobacteriaceae and Veillonellaceae) and lactate-producing bacteria (e.g., Bifidobacterium and Lactobacillus) were enriched, while butyrate-producing bacteria (e.g., Lachnospiraceae and Ruminococcaceae) were depleted, in the high-risk group compared to the low-risk group. Butyrate concentrations were also lower in the fecal samples obtained from the high-risk group than from the low-risk group. The concentrations of other short-chain fatty acids (e.g., acetate, propionate, isobutyrate, isovalerate, and valerate) in the gut were comparable among the three groups. Conclusion: Participants at high risk of stroke were characterized by the enrichment of opportunistic pathogens, low abundance of butyrate-producing bacteria, and reduced concentrations of fecal butyrate. More researches into the gut microbiota as a risk factor in stroke should be carried out in the near future.
TL;DR: This study suggests that the antibiotic-induced changes in gut microbiota might contribute to the inflammation responses through the alternation of metabolic status, providing a novel insight regarding a complex network that integrates the different interactions between gut microbiota, metabolic functions, and immune responses in host.
Abstract: Gut microbiome plays an essential role in modulating host immune responses. However, little is known about the interaction of microbiota, their metabolites and relevant inflammatory responses in the gut. By treating the mice with three different antibiotics (enrofloxacin, vancomycin, and polymixin B sulfate), we aimed to investigate the effects of different antibiotics exposure on gut microbiota, microbial metabolism, inflammation responses in the gut, and most importantly, pinpoint the underlying interactions between them. Although the administration of different antibiotics can lead to different effects on mouse models, the treatment did not affect the average body weight of the mice. A heavier caecum was observed in vancomycin treated mice. Treatment by these three antibiotics significantly up-regulated gene expression of various cytokines in the colon. Enrofloxacin treated mice seemed to have an increased Th1 response in the colon. However, such a difference was not found in mice treated by vancomycin or polymixin B sulfate. Vancomycin treatment induced significant changes in bacterial composition at phylum and family level and decreased richness and diversity at species level. Enrofloxacin treatment only induced changes in composition at family presenting as an increase in Prevotellaceae and Rikenellaceae and a decrease in Bacteroidaceae. However, no significant difference was observed after polymixin B sulfate treatment. When compared with the control group, significant metabolic shift was found in the enrofloxacin and vancomycin treated group. The metabolic changes mainly occurred in Valine, leucine, and isoleucine biosynthesis pathway and beta-Alanine metabolism in enrofloxacin treated group. For vancomycin treatment metabolic changes were mainly found in beta-Alanine metabolism and Alanine, aspartate and glutamate metabolism pathway. Moreover, modifications observed in the microbiota compositions were correlated with the metabolite concentrations. For example, concentration of pentadecanoic acid was positively correlated with richness of Rikenellaceae and Prevotellaceae and negatively correlated with Enterobacteriaceae. This study suggests that the antibiotic-induced changes in gut microbiota might contribute to the inflammation responses through the alternation of metabolic status, providing a novel insight regarding a complex network that integrates the different interactions between gut microbiota, metabolic functions, and immune responses in host.
TL;DR: Spearman correlation analysis of blood physiological measures of RA showed that bacterial genera such as Dorea and Ruminococcus were positively correlated with RF-IgA and anti-CCP antibodies, suggesting that the gut microbiota may contribute to RA development via interactions with the host immune system.
Abstract: Little is known regarding differences in the gut microbiomes of rheumatoid arthritis (RA) patients and healthy cohorts in China. This study aimed to identify differences in the fecal microbiomes of 66 Chinese patients with RA and 60 healthy Chinese controls. The V3-V4 variable regions of bacterial 16S rRNA genes were sequenced with the Illumina system to define the bacterial composition. The alpha-diversity index of the microbiome of the RA patients was significantly lower than that of the control group. The bacterial genera Bacteroides (p = 0.02202) and Escherichia-Shigella (p = 0.03137) were more abundant in RA patients. In contrast, Lactobacillus (p = 0.000014), Alloprevotella (p = 0.0000008615), Enterobacter (p = 0.000005759), and Odoribacter (p = 0.0000166) were less abundant in the RA group than in the control group. Spearman correlation analysis of blood physiological measures of RA showed that bacterial genera such as Dorea and Ruminococcus were positively correlated with RF-IgA and anti-CCP antibodies. Furthermore, Alloprevotella and Parabacteroides were positively correlated with the erythrocyte sedimentation rate, and Prevotella-2 and Alloprevotella were positively correlated with C-reactive protein, both biomarkers of inflammation. These findings suggest that the gut microbiota may contribute to RA development via interactions with the host immune system.
TL;DR: Wang et al. as mentioned in this paper found that children with ASD had a lower relative abundance of Acidaminococcaceae than the healthy controls, and a decrease in the relative abundances of genera Lachnoclostridium, Tyzzerella subgroup 4, Flavonifractor, and unidentified Lchnospiraceae.
Abstract: The link between gut microbes and autism spectrum disorders (ASD) has been already observed in some studies, but some bacterial families/species were found to be inconsistently up or down regulated. This issue has been rarely explored in the Chinese population. In this study, we assessed whether or not gut microbiota dysbiosis was associated with children with ASD in China. We enrolled 45 children with ASD (6-9 years of age; 39 boys and 6 girls) and 45 sex- and age-matched neurotypical children. Dietary and other socio-demographic information was obtained via questionnaires. We characterized the composition of the fecal microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The ASD group showed less diversity and richness of gut microbiota than the neurotypical group, as estimated by the abundance-based coverage estimator index and the phylogenetic diversity index. The analysis of beta diversity showed an altered microbial community structure in the ASD group. After adjustment for confounders and multiple testing corrections, no significant group difference was found in the relative abundance of microbiota on the level of the phylum. At the family level, children with ASD had a lower relative abundance of Acidaminococcaceae than the healthy controls. Moreover, a decrease in the relative abundance of genera Lachnoclostridium, Tyzzerella subgroup 4, Flavonifractor, and unidentified Lachnospiraceae was observed in ASD group. This study provides further evidence of intestinal microbial dysbiosis in ASD and sheds light on the characteristics of the gut microbiome of autistic children in China.
TL;DR: This review concludes with the hypothesis that prematurity of the gut microbiota may be an inconspicuous clinical challenge in achieving optimal feeding besides traditional challenges, such as preterm breast milk composition, high nutritional requirements and immat maturity of the gastrointestinal tract and immune system.
Abstract: The nutritional requirements of preterm infants are unique and challenging to meet in neonatal care, yet crucial for their growth, development and health. Normally, the gut microbiota has distinct metabolic capacities, making their role in metabolism of dietary components indispensable. In preterm infants, variation in microbiota composition is introduced while facing a unique set of environmental conditions. However, the effect of such variation on the microbiota's metabolic capacity and on the preterm infant's growth and development remains unresolved. In this review, we will provide a holistic overview on the development of the preterm gut microbiota and the unique environmental conditions contributing to this, in addition to maturation of the gastrointestinal tract and immune system in preterm infants. The role of prematurity, as well as the role of human milk, in the developmental processes is emphasized. Current research stresses the early life gut microbiota as cornerstone for simultaneous development of the gastrointestinal tract and immune system. Besides that, literature provides clues that prematurity affects growth and development. As such, this review is concluded with our hypothesis that prematurity of the gut microbiota may be an inconspicuous clinical challenge in achieving optimal feeding besides traditional challenges, such as preterm breast milk composition, high nutritional requirements and immaturity of the gastrointestinal tract and immune system. A better understanding of the metabolic capacity of the gut microbiota and its impact on gut and immune maturation in preterm infants could complement current feeding regimens in future neonatal care and thereby facilitate growth, development and health in preterm infants.
TL;DR: This review will discuss the current understanding of the σE- and Cpx-regulated ESRs, with a specific focus on their role in the virulence of a number of model pathogens.
Abstract: The Gram-negative bacterial envelope is an essential interface between the intracellular and harsh extracellular environment. Envelope stress responses (ESRs) are crucial to the maintenance of this barrier and function to detect and respond to perturbations in the envelope, caused by environmental stresses. Pathogenic bacteria are exposed to an array of challenging and stressful conditions during their lifecycle and, in particular, during infection of a host. As such, maintenance of envelope homeostasis is essential to their ability to successfully cause infection. This review will discuss our current understanding of the σE- and Cpx-regulated ESRs, with a specific focus on their role in the virulence of a number of model pathogens.
TL;DR: Recent findings on mechanisms by which T. gondii evades host innate immunity are reviewed, with a focus on parasite evasion of the human innate immune system.
Abstract: Toxoplasma gondii is an intracellular protozoan parasite of global importance that can remarkably infect, survive, and replicate in nearly all mammalian cells. Notably, 110 years after its discovery, Toxoplasmosis is still a neglected parasitic infection. Although most human infections with T. gondii are mild or asymptomatic, T. gondii infection can result in life-threatening disease in immunocompromised individuals and in the developing fetus due to congenital infection, underscoring the role of the host immune system in controlling the parasite. Recent evidence indicates that T. gondii elicits a robust innate immune response during infection. Interestingly, however, T. gondii has evolved strategies to successfully bypass or manipulate the immune system and establish a life-long infection in infected hosts. In particular, T. gondii manipulates host immunity through the control of host gene transcription and dysregulation of signaling pathways that result in modulation of cell adhesion and migration, secretion of immunoregulatory cytokines, production of microbicidal molecules, and apoptosis. Many of these host-pathogen interactions are governed by parasite effector proteins secreted from the apical secretory organelles, including the rhoptries and dense granules. Here, we review recent findings on mechanisms by which T. gondii evades host innate immunity, with a focus on parasite evasion of the human innate immune system.
TL;DR: The current knowledge and new findings regarding the structural features relating to the function of MUC1, its role as a protective barrier against pathogen invasion and mechanisms by which this cs-mucin regulates inflammation are summarized.
Abstract: The family of cell surface (cs-) mucins are constitutively expressed at the cell surface by nearly all epithelial cells, beneath the gel-mucin layer. All cs-mucin family members have structural features that enable them to act as a releasable decoy barrier to mucosal pathogens, by providing ligands for pathogen binding and the ability to shed the bound extracellular domain. Due to the towering structure of cs-mucins at the surface, binding of mucosal pathogens can also sterically block binding to underlying cellular receptors. The cytoplasmic tail domain of cs-mucins are capable of initiating signal transduction cascades and due to their conservation across species, may play an important biological role in cellular signaling. MUC1 is one of the most extensively studied of the cs-mucin family. With respect to its physiological function in the mucosal environment, MUC1 has been demonstrated to play a dynamic role in protection of the host from infection by a wide variety of pathogens and to regulate inflammatory responses to infection. This review briefly summarizes the current knowledge and new findings regarding the structural features relating to the function of MUC1, its role as a protective barrier against pathogen invasion and mechanisms by which this cs-mucin regulates inflammation.
TL;DR: The results reveal distinct and disease-specific patterns of salivary microbial composition between patients with chronic periodontitis and healthy controls, as well as significant correlations between microbiota and host-mediated inflammatory cytokines.
Abstract: Periodontitis is a microbial-induced chronic inflammatory disease, which may not only result in tooth loss, but can also contribute to the development of various systemic diseases. The transition from healthy to diseased periodontium depends on microbial dysbiosis and impaired host immune response. Although periodontitis is a common disease as well as associated with various systemic inflammatory conditions, the taxonomic profiling of the salivary microbiota in periodontitis and its association with host immune and inflammatory mediators has not been reported. Therefore, the aim of this study was to identify key pathogens and their potential interaction with the host's inflammatory mediators in saliva samples for periodontitis risk assessment. The microbial 16S rRNA gene sequencing and the levels of inflammatory mediators were performed in saliva samples from patients with chronic periodontitis and periodontally healthy control subjects. The salivary microbial community composition differed significantly between patients with chronic periodontitis and healthy controls. Our analyses identified a number of microbes, including bacteria assigned to Eubacterium saphenum, Tannerella forsythia, Filifactor alocis, Streptococcus mitis/parasanguinis, Parvimonas micra, Prevotella sp., Phocaeicola sp., and Fretibacterium sp. as more abundant in periodontitis, compared to healthy controls. In samples from healthy individuals, we identified Campylobacter concisus, and Veillonella sp. as more abundant. Integrative analysis of the microbiota and inflammatory mediators/cytokines revealed associations that included positive correlations between the pathogens Treponema sp. and Selenomas sp. and the cytokines chitinase 3-like 1, sIL-6Rα, sTNF-R1, and gp130/sIL-6Rβ. In addition, a negative correlation was identified between IL-10 and Filifactor alocis. Our results reveal distinct and disease-specific patterns of salivary microbial composition between patients with periodontitis and healthy controls, as well as significant correlations between microbiota and host-mediated inflammatory cytokines. The positive correlations between the pathogens Treponema sp. and Selenomas sp. and the cytokines chitinase 3-like 1, sIL-6Rα, sTNF-R1, and gp130/sIL-6Rβ might have the future potential to serve as a combined bacteria-host salivary biomarker panel for diagnosis of the chronic infectious disease periodontitis. However, further studies are required to determine the capacity of these microbes and inflammatory mediators as a salivary biomarker panel for periodontitis.
TL;DR: PE diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with uncomplicated pregnant women, which are associated with maternal clinical features (blood pressure level and liver dysfunction) and newborn birth weight.
Abstract: Background: Imbalances in gut microbiota composition are linked to hypertension, host metabolic abnormalities, systemic inflammation, and other conditions. In the present study, we examined the changes of gut microbiota in women with early-onset preeclampsia (PE) and in normotensive, uncomplicated pregnant women during late pregnancy and at 1 and 6 weeks postpartum. Methods: Gut microbiota profiles of women with PE and healthy pregnant women in the third trimester and at 1 and 6 weeks postpartum were assessed by 16S rRNA gene amplicon sequencing. Plasma levels of interleukin-6 (IL-6), intestinal fatty acid-binding protein (I-FABP), zonulin, and lipopolysaccharide (LPS) were measured in the third trimesters. Results: At the genus level, 8 bacterial genera were significantly enriched in the antepartum samples of PE patients compared to healthy controls, of which Blautia, Ruminococcus2, Bilophila, and Fusobacterium represented the major variances in PE microbiomes. Conversely, 5 genera, including Faecalibacterium, Gemmiger, Akkermansia, Dialister, and Methanobrevibacter, were significantly depleted in antepartum PE samples. Maternal blood pressure and liver enzyme levels were positively correlated to the PE-enriched genera such as Anaerococcus, Ruminococcus2, Oribacterium, and Bilophila, while the fetal features (e.g., Apgar score and newborn birth weight) were positively correlated with PE-depleted genera and negatively correlated with PE-enriched genera. Moreover, maternal blood IL-6 level was positively associated with gut Bilophila and Oribacterium, whereas LPS level was negatively associated with Akkermansia. In terms of postpartum women, both the gut microbial composition and the PE-associated microbial alterations were highly consistent with those of the antepartum women. Conclusion: PE diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with uncomplicated pregnant women, which are associated with maternal clinical features (blood pressure level and liver dysfunction) and newborn birth weight. Moreover, these antepartum alterations in gut microbiota persisted 6 weeks postpartum.
TL;DR: This review explores how viruses mimic, exploit or interfere with host cell metabolic pathways and how, in doing so, they may evade immune responses.
Abstract: Over the last decade, there has been significant advances in the understanding of the cross-talk between metabolism and immune responses. It is now evident that immune cell effector function strongly depends on the metabolic pathway in which cells are engaged in at a particular point in time, the activation conditions, and the cell microenvironment. It is also clear that some metabolic intermediates have signaling as well as effector properties and, hence, topics such as immunometabolism, metabolic reprograming, and metabolic symbiosis (among others) have emerged. Viruses completely rely on their host's cell energy and molecular machinery to enter, multiply, and exit for a new round of infection. This review explores how viruses mimic, exploit or interfere with host cell metabolic pathways and how, in doing so, they may evade immune responses. It offers a brief outline of key metabolic pathways, mitochondrial function and metabolism-related signaling pathways, followed by examples of the mechanisms by which several viral proteins regulate host cell metabolic activity.
TL;DR: A dramatic changes in gut microbiota in tuberculosis patients are observed as reflected by significant decreases in species number and microbial diversity, which will shed light on the design of future diagnoses and treatments for M. tuberculosis infections.
Abstract: Cross talk occurs between the human gut and the lung through a gut-lung axis involving the gut microbiota. However, the signatures of the human gut microbiota after active Mycobacterium tuberculosis infection have not been fully understood. Here, we investigated changes in the gut microbiota in tuberculosis (TB) patients by shotgun sequencing the gut microbiomes of 31 healthy controls and 46 patients. We observed a dramatic changes in gut microbiota in tuberculosis patients as reflected by significant decreases in species number and microbial diversity. The gut microbiota of TB patients were mostly featured by the striking decrease of short-chain fatty acids (SCFAs)-producingbacteria as well as associated metabolic pathways. A classification model based on the abundance of three species, Haemophilus parainfluenzae, Roseburia inulinivorans, and Roseburia hominis, performed well for discriminating between healthy and diseased patients. Additionally, the healthy and diseased states can be distinguished by SNPs in the species of B. vulgatus. We present a comprehensive profile of changes in the microbiota in clinical TB patients. Our findings will shed light on the design of future diagnoses and treatments for M. tuberculosis infections.
TL;DR: PE patients had gut microbiota dysbiosis and increased plasma LPS and TMAO levels, which will lead to a better understanding of the relationship between the gut microbiota and PE.
Abstract: Objective: To characterize the gut microbiota in patients with preeclampsia (PE) compared with healthy controls. Methods: We analyzed and compared the microbiota communities in the feces of 48 PE patients with 48 age-, gestational weeks-, and pre-pregnancy body mass index-matched healthy controls using 16S rRNA gene sequencing, and also we tested fecal and plasma lipopolysaccharide (LPS) and plasma trimethylamine-N-oxide (TMAO) concentration levels in the two groups. Results: Compared with the control group, microbial alpha diversity was lower in the PE group, but there was no statistically significant difference between the two groups. At the phylum level, Firmicutes (51.64% PE vs. 59.62% Control, P < 0.05), Bacteroidetes (40.51% PE vs. 34.81% Control, P< 0.05), Proteobacteria (4.51% PE vs. 2.56% Control, P < 0.05), and Actinobacteria (2.90% PE vs. 1.77% Control, P < 0.05), exhibited significant differences between the PE group and the control group. LEfSe analysis found 17 differentially abundant taxa between the two groups. PICRUSt analysis found that in the KEGG pathways, the microbial gene functions related to LPS biosynthesis were higher in the fecal microbiome of the PE group. The fecal and plasma LPS concentrations and plasma TMAO concentrations of PE patients were higher than those of the healthy controls. Conclusion: PE patients had gut microbiota dysbiosis and increased plasma LPS and TMAO levels, which will lead to a better understanding of the relationship between the gut microbiota and PE.
TL;DR: This review outlines the systems that exist in several Gram-negative pathogens that are associated with heme transport and utilization, beginning with hemolysis and concluding withHeme degradation, showing that co-regulation with other cellular processes is complex and often not completely understood.
Abstract: Iron is a transition metal utilized by nearly all forms of life for essential cellular processes, such as DNA synthesis and cellular respiration During infection by bacterial pathogens, the host utilizes various strategies to sequester iron in a process termed, nutritional immunity To circumvent these defenses, Gram-negative pathogens have evolved numerous mechanisms to obtain iron from heme In this review we outline the systems that exist in several Gram-negative pathogens that are associated with heme transport and utilization, beginning with hemolysis and concluding with heme degradation In addition, Gram-negative pathogens must also closely regulate the intracellular concentrations of iron and heme, since high levels of iron can lead to the generation of toxic reactive oxygen species As such, we also provide several examples of regulatory pathways that control heme utilization, showing that co-regulation with other cellular processes is complex and often not completely understood