Distinguishing feature of gut microbiota in Tibetan highland coronary artery disease patients and its link with diet.

The prevalence of coronary artery disease (CAD) in Tibetan Highlanders is lower than that in plain-living individuals, but the mechanism still unclear. Gut microbiota (GM) disorder is considered one of the potential factors involved in the pathogenesis of CAD, but the GM characteristics of Tibetan Highlanders suffering from CAD are unknown. We sequenced the V3-V4 region of the 16S ribosomal RNA of gut bacteria from fecal samples from Tibetan and Han CAD patients and healthy individuals inhabiting the Qinghai-Tibet Plateau, as well as from Han CAD patients and healthy individuals living at sea level, and we analyzed the GM characteristics of these subjects by bioinformatics analysis. The results showed that Tibetan Highlanders suffering from CAD had higher GM α-diversity, with differently distributed cluster compared with healthy Tibetan Highlanders and Han CAD patients living at high and low altitudes. Genera Catenibacterium, Clostridium_sensu_stricto, Holdemanella, and Ruminococcus 2 were enriched in Tibetan Highlanders suffering from CAD compared with healthy Tibetan Highlanders and Han CAD patients living at high- and low-altitudes. Prevotella was enriched in Tibetan Highlanders suffering from CAD compared with Han CAD patients living at high- and low-altitudes. Moreover, Catenibacterium was positively correlated with Prevotella. Additionally, Catenibacterium, Holdemanella, and Prevotella were positively correlated with fermented dairy product, carbohydrate and fiber intake by the subjects, while Clostridium_sensu_stricto was negatively correlated with protein intake by the subjects. In conclusion, our study indicated that Tibetan Highlanders suffering from CAD showed distinct GM, which was linked to their unique dietary characteristics and might associated with CAD.

Bile acid toxicity in Paneth cells contributes to gut dysbiosis induced by high-fat feeding.

High-fat feeding (HFF) leads to gut dysbiosis through unclear mechanisms. We hypothesize that bile acids secreted in response to high-fat diets (HFDs) may act on intestinal Paneth cells, leading to gut dysbiosis. We found that HFF resulted in widespread taxonomic shifts in the bacteria of the ileal mucosa, characterized by depletion of Lactobacillus and enrichment of Akkermansia muciniphila, Clostridium XIVa, Ruminococcaceae, and Lachnospiraceae, which were prevented by the bile acid binder cholestyramine. Immunohistochemistry and in situ hybridization studies showed that G protein-coupled bile acid receptor (TGR5) expressed in Paneth cells was upregulated in the rats fed HFD or normal chow supplemented with cholic acid. This was accompanied by decreased lysozyme+ Paneth cells and α-defensin 5 and 6 and increased expression of XBP-1. Pretreatment with ER stress inhibitor 4PBA or with cholestyramine prevented these changes. Ileal explants incubated with deoxycholic acid or cholic acid caused a decrease in α-defensin 5 and 6 and an increase in XBP-1, which was prevented by TGR5 antibody or 4PBA. In conclusion, this is the first demonstration to our knowledge that TGR5 is expressed in Paneth cells. HFF resulted in increased bile acid secretion and upregulation of TGR5 expression in Paneth cells. Bile acid toxicity in Paneth cells contributes to gut dysbiosis induced by HFF.

Diversity of the Genomes and Neurotoxins of Strains of Clostridium botulinum Group I and Clostridium sporogenes Associated with Foodborne, Infant and Wound Botulism.

Clostridium botulinum Group I and Clostridium sporogenes are closely related bacteria responsible for foodborne, infant and wound botulism. A comparative genomic study with 556 highly diverse strains of C. botulinum Group I and C. sporogenes (including 417 newly sequenced strains) has been carried out to characterise the genetic diversity and spread of these bacteria and their neurotoxin genes. Core genome single-nucleotide polymorphism (SNP) analysis revealed two major lineages; C. botulinum Group I (most strains possessed botulinum neurotoxin gene(s) of types A, B and/or F) and C. sporogenes (some strains possessed a type B botulinum neurotoxin gene). Both lineages contained strains responsible for foodborne, infant and wound botulism. A new C. sporogenes cluster was identified that included five strains with a gene encoding botulinum neurotoxin sub-type B1. There was significant evidence of horizontal transfer of botulinum neurotoxin genes between distantly related bacteria. Population structure/diversity have been characterised, and novel associations discovered between whole genome lineage, botulinum neurotoxin sub-type variant, epidemiological links to foodborne, infant and wound botulism, and geographic origin. The impact of genomic and physiological variability on the botulism risk has been assessed. The genome sequences are a valuable resource for future research (e.g., pathogen biology, evolution of C. botulinum and its neurotoxin genes, improved pathogen detection and discrimination), and support enhanced risk assessments and the prevention of botulism.

Herpes simplex virus infection, Acyclovir and IVIG treatment all independently cause gut dysbiosis.

Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) treatment to suppress infection and deleterious inflammatory responses. As many diverse medications have recently been shown to change composition of the gut microbiome, we used Illumina 16S rRNA gene sequencing to determine the effects of ACV and IVIG on the gut bacterial community. We found that HSV, ACV and IVIG can all independently disrupt the gut bacterial community in a sex biased manner when given to uninfected C57BL/6 mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed complex interactions between these drugs and infection that caused pronounced sex biased dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant as these taxa are associated with protection against the development of graft versus host disease (GVHD) in hematopoietic stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT patients and ACV also decreased Akkermansia muciniphila, which is important for maintaining gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment of HSCT patients may contribute to GVHD and also potentially impact immune reconstitution. These data have important implications for other clinical settings, including HSV eye disease and genital infections, where ACV is given long-term.

The Gut Microbiota Profile in Children with Prader-Willi Syndrome.

Although gut microbiota has been suggested to play a role in disease phenotypes of Prader-Willi syndrome (PWS), little is known about its composition in affected children and how it relates to hyperphagia. This cross-sectional study aimed to characterize the gut bacterial and fungal communities of children with PWS, and to determine associations with hyperphagia. Fecal samples were collected from 25 children with PWS and 25 age-, sex-, and body mass index-matched controls. Dietary intake data, hyperphagia scores, and relevant clinical information were also obtained. Fecal bacterial and fungal communities were characterized by 16S rRNA and ITS2 sequencing, respectively. Overall bacterial α-diversity and compositions of PWS were not different from those of the controls, but 13 bacterial genera were identified to be differentially abundant. Interestingly, the fungal community, as well as specific genera, were different between PWS and controls. The majority of the variation in the gut microbiota was not attributed to differences in dietary intake or the impact of genotype. Hyperphagia scores were associated with fungal α-diversity and relative abundance of several taxa, such as Staphylococcus, Clostridium, SMB53, and Candida. Further longitudinal studies correlating changes in the microbiome with the degree of hyperphagia and studies integrating multi-omics data are warranted.

Osteomielitis postraumática difícil de tratar: papel del Clostridium celerecrescens / A review of difficult-to-treat post-traumatic osteomyelitis: Role of Clostridium celerecrescens

OBJETIVO: Se ha realizado una revisión sobre las infecciones producidas por Clostridium celerecrescens que aparecen recogidas en la literatura. C. celerecrescens es un patógeno emergente relacionado con infecciones de heridas traumáticas que progresan a infecciones profundas y osteomielitis. MÉTODOS: En la literatura solo se han encontrado 4 casos con suficientes datos para ser analizados; nosotros añadimos un nuevo caso y experiencia en el manejo de la infección. La identificación se realizó mediante espectrometría desorción/ionización láser asistida por matriz acoplada a un detector de tiempo de vuelo (MALDI-TOF) o mediante galería API. Se realizó secuenciación del ARNr 16S en todos los casos. RESULTADOS: La identificación de la bacteria fue discrepante según el método utilizado debido a las similitud fenotípica y genética con otras especies del mismo género. La identificación mediante MALDI-TOF y galerías API no resulta adecuada para la determinación a nivel de especie, siendo necesaria la secuenciación del ARNr 16S. El tratamiento de la infección incluye combinaciones de antibióticos complejas y tratamiento quirúrgico junto con curas de piel y partes blandas debido a la persistencia de la bacteria a lo largo del tiempo. CONCLUSIÓN: El presente estudio manifiesta el potencial patogénico de C. celerecrescens en infecciones postraumáticas y la necesidad de mejorar el tratamiento de estas infecciones

PURPOSE: We reviewed the clinical features of post-traumatic infections produced by Clostridium celerecrescens reported in the literature. C. celerecrescens is an emerging pathogen involved in traumatic wound infection that progresses to deep infection and osteomyelitis. METHODS: We found only 4 cases reported in the literature with enough data to be analysed and we added our own case and experience with this type of infection. The identification was performed by matrix-assisted desorption ionization-time of flight mass spectrometry (MALDI TOF) or API gallery, and 16S rRNA gene sequencing were performed to confirm identification in all cases. RESULTS: Identification of the bacteria is discrepant according to the method used due to the genetic and phenotypic similarities of other species of the genus. Identification through MALDI-TOF and API gallery is not suitable for determining the specie, confirmation by 16S rRNA sequencing being necessary. Treatment of the infection included complex antibiotic combinations and surgical treatment together with skin and soft tissue dressings due to the persistence of the pathogen over time. CONCLUSION: This report supports the pathogenic role of C. celerecrescens in post-traumatic infections and the need to improve the management of these difficult-to-treat infections

In-Vitro Growth Inhibition of Bacterial Pathogens by Probiotics and a Synbiotic: Product Composition Matters.

A variety of activities potentially contribute to the beneficial effects of probiotic bacteria observed in humans. Among these is a direct inhibition of the growth of pathogenic bacteria in the gut. The present study characterizes head-to-head the in-vitro pathogen growth inhibition of clinically relevant infectious bacterial strains by different types of probiotics and a synbiotic. In-vitro growth inhibition of Escherichia (E.) coli EPEC, Shigella (Sh.) sonnei, Salmonella (S.) typhimurium, Klebsiella (K.) pneumoniae and Clostridioides (C.) difficile were determined. Investigated products were a yeast mono strain probiotic containing Saccharomyces (Sac.) boulardii, bacterial mono strain probiotics containing either Lactobacillus (L.) rhamnosus GG or L. reuteri DSM 17938, a multi strain probiotic containing three L. rhamnosus strains (E/N, Oxy, Pen), and a multi strain synbiotic containing nine different probiotic bacterial strains and the prebiotic fructooligosaccharides (FOS). Inhibition of pathogens was moderate by Sac. boulardii and L. rhamnosus GG, medium by L. reuteri DSM 17938 and the L. rhamnosus E/N, Oxy, Pen mixture and strong by the multi strain synbiotic. Head-to-head in-vitro pathogen growth inhibition experiments can be used to differentiate products from different categories containing probiotic microorganisms and can support the selection process of products for further clinical evaluation.

Impact of Clostridium Bacteria in Children with Autism Spectrum Disorder and Their Anthropometric Measurements.

Current research has shown that gut microbiota may play a fundamental role in neurological activity, behavior, mood, cognition, and possibly for the onset as well as the severity of autism spectrum disorder (ASD). Previous studies emphasized the possible correlation between Clostridium spp., gut colonization, and possible development or exacerbating of ASD in affected children. The aim of the present study was to investigate how Clostridia gut colonization can have an impact on the neurological outcome and anthropometric values in ASD children. The present study included 60 children (30 ASD and 30 neurotypical controls) of both sexes aged from 2 to 8 years. Children with ASD were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), Autism Diagnostic Interview-Revised (ADI-R), as well as the Childhood Autism Rating Scale (CARS). Quantitative real-time polymerase chain reaction (real-time PCR) was used to determine Clostridium presence in the stools of the enrolled subjects. The number of Clostridium spp. (Clostridium paraputri, Clostridium bolteae, and Clostridium perfringens) found in the stools of ASD children was greater than neurotypical children. Children with ASD had two types of Clostridium (Clostridium diffiicile and Clostridium clostridiioforme) not found in neurotypical children, whereas neurotypical children yielded only one species (Clostridium tertium) not found in the ASD children. The present study emphasizes the potential correlation between gut colonization of Clostridia and the probability of developing or exacerbating ASD among Egyptian children. If Clostridium bacteria play a potential role in the etiology of ASD, this may open the possibility for effective treatment of these patients.

Clostridium ventriculi Infection in a Child with Phenylketonuria.

Disabled individuals may be at risk for common and rare infections. We report on a 13-year-old female who had a diagnosis of phenylketonuria (PKU). The child received a percutaneous endoscopic gastrostomy (PEG) feeding tube at five years of age for the supplementation of her specialized formula. After eight years, she no longer required the gastrostomy tube for formula supplementation, and she presented for the closure of the gastrocutaneous fistula tract. The histological examination revealed acute and chronic inflammation and colonization by gram-positive bacteria with a characteristic tetrad packet arrangement known as Clostridium ventriculi (formerly Sarcina ventriculi). A review of the literature evidenced the rarity of this infection in children. This patient is the 11th case of such infection in literature, and the first patient affected with PKU. Physically and mentally disabled children are particularly vulnerable to infection because of their different feeding abilities, toilet needs, and sanitary arrangements.

Sporulation and Germination in Clostridial Pathogens.

As obligate anaerobes, clostridial pathogens depend on their metabolically dormant, oxygen-tolerant spore form to transmit disease. However, the molecular mechanisms by which those spores germinate to initiate infection and then form new spores to transmit infection remain poorly understood. While sporulation and germination have been well characterized in Bacillus subtilis and Bacillus anthracis, striking differences in the regulation of these processes have been observed between the bacilli and the clostridia, with even some conserved proteins exhibiting differences in their requirements and functions. Here, we review our current understanding of how clostridial pathogens, specifically Clostridium perfringens, Clostridium botulinum, and Clostridioides difficile, induce sporulation in response to environmental cues, assemble resistant spores, and germinate metabolically dormant spores in response to environmental cues. We also discuss the direct relationship between toxin production and spore formation in these pathogens.

Genomics of the Pathogenic Clostridia.

Whole-genome sequences are now available for all the clinically important clostridia and many of the lesser or opportunistically pathogenic clostridia. The complex clade structures of C. difficile, C. perfringens, and the species that produce botulinum toxins have been delineated by whole-genome sequence analysis. The true clostridia of cluster I show relatively low levels of gross genomic rearrangements within species, in contrast to the species of cluster XI, notably C. difficile, which have been found to have very plastic genomes with significant levels of chromosomal rearrangement. Throughout the clostridial phylotypes, a large proportion of the strain diversity is driven by the acquisition and loss of mobile elements, including phages, plasmids, insertion sequences, and transposons. Genomic analysis has been used to investigate the diversity and spread of C. difficile within hospital settings, the zoonotic transfer of isolates, and the emergence, origins, and geographic spread of epidemic ribotypes. In C. perfringens the clades defined by chromosomal sequence analysis show no indications of clustering based on host species or geographical location. Whole-genome sequence analysis helps to define the different survival and pathogenesis strategies that the clostridia use. Some, such as C. botulinum, produce toxins which rapidly act to kill the host, whereas others, such as C. perfringens and C. difficile, produce less lethal toxins which can damage tissue but do not rapidly kill the host. The genomes provide a resource that can be mined to identify potential vaccine antigens and targets for other forms of therapeutic intervention.

Enterotoxic Clostridia: Clostridioides difficile Infections.

Clostridioides difficile is a Gram-positive, anaerobic, spore forming pathogen of both humans and animals and is the most common identifiable infectious agent of nosocomial antibiotic-associated diarrhea. Infection can occur following the ingestion and germination of spores, often concurrently with a disruption to the gastrointestinal microbiota, with the resulting disease presenting as a spectrum, ranging from mild and self-limiting diarrhea to severe diarrhea that may progress to life-threating syndromes that include toxic megacolon and pseudomembranous colitis. Disease is induced through the activity of the C. difficile toxins TcdA and TcdB, both of which disrupt the Rho family of GTPases in host cells, causing cell rounding and death and leading to fluid loss and diarrhea. These toxins, despite their functional and structural similarity, do not contribute to disease equally. C. difficile infection (CDI) is made more complex by a high level of strain diversity and the emergence of epidemic strains, including ribotype 027-strains which induce more severe disease in patients. With the changing epidemiology of CDI, our understanding of C. difficile disease, diagnosis, and pathogenesis continues to evolve. This article provides an overview of the current diagnostic tests available for CDI, strain typing, the major toxins C. difficile produces and their mode of action, the host immune response to each toxin and during infection, animal models of disease, and the current treatment and prevention strategies for CDI.

Iron-Oxide Nanocluster Labeling of Clostridium novyi-NT Spores for MR Imaging-Monitored Locoregional Delivery to Liver Tumors in Rat and Rabbit Models.

PURPOSE: To label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion. MATERIALS AND METHODS: Vegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA. RESULTS: Both fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery. CONCLUSIONS: C. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion.

Clostridia and necrotizing enterocolitis in preterm neonates.

Necrotizing enterocolitis (NEC) is the most severe life threatening gastrointestinal disease among preterm neonates. NEC continues to account for substantial morbidity and mortality in neonatal intensive care units worldwide. Although its pathogenesis remains incompletely elucidated, NEC is recognized as a multifactorial disease involving intestinal unbalanced inflammatory response, feeding strategies, and bacterial colonization. Epidemiological studies, clinical signs, and animal models support the participation of anaerobic bacteria, particularly clostridia species, in NEC development. Colonization by clostridia seems particularly deleterious. The present review is the opportunity to propose an update on the role of clostridia and NEC.

Peritonitis por Clostridium innocuum asociada a diálisis peritoneal / Peritonitis by Clostridium innocuum associated to peritoneal dialysis

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Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species.

The botulinum neurotoxin (BoNT) has been extensively researched over the years in regard to its structure, mode of action, and applications. Nevertheless, the biological roles of four proteins encoded from a number of BoNT gene clusters, i.e., OrfX1-3 and P47, are unknown. Here, we investigated the diversity of orfX-p47 gene clusters using in silico analytical tools. We show that the orfX-p47 cluster was not only present in the genomes of BoNT-producing bacteria but also in a substantially wider range of bacterial species across the bacterial phylogenetic tree. Remarkably, the orfX-p47 cluster was consistently located in proximity to genes coding for various toxins, suggesting that OrfX1-3 and P47 may have a conserved function related to toxinogenesis and/or pathogenesis, regardless of the toxin produced by the bacterium. Our work also led to the identification of a putative novel BoNT-like toxin gene cluster in a Bacillus isolate. This gene cluster shares striking similarities to the BoNT cluster, encoding a bont/ntnh-like gene and orfX-p47, but also differs from it markedly, displaying additional genes putatively encoding the components of a polymorphic ABC toxin complex. These findings provide novel insights into the biological roles of OrfX1, OrfX2, OrfX3, and P47 in toxinogenesis and pathogenesis of BoNT-producing and non-producing bacteria.