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European Journal of Gastroenterology &... Sep 2023Many colorectal diseases depend on complex interactions between several pathophysiological factors, including the intestinal microbiota. In recent years, the widespread...
Many colorectal diseases depend on complex interactions between several pathophysiological factors, including the intestinal microbiota. In recent years, the widespread use of antibiotics has been recognized as a main cause of intestinal dysbiosis and a favouring factor for Clostridioides difficile infection. The latter, in addition, causes infectious diarrhoea, pseudomembranous colitis, and toxic megacolon by means of its toxins (A and, especially, B), is characterized by frequent relapses; thus, its persistence in a host may be long-lasting. Based on recent experimental evidence, here we analyse the possibility that, similarly to other bacteria, Clostridioides difficile may be considered a potential carcinogen for colorectal cancer.
Topics: Humans; Clostridioides difficile; Clostridioides; Enterocolitis, Pseudomembranous; Anti-Bacterial Agents; Clostridium Infections; Colorectal Neoplasms
PubMed: 37505976
DOI: 10.1097/MEG.0000000000002615 -
Journal of Molecular Medicine (Berlin,... Sep 2023Hirschsprung disease (HSCR) is a congenital disorder caused by the failure of enteric neural crest cells (ENCCs) to colonize the distal bowel, resulting in absence of...
Hirschsprung disease (HSCR) is a congenital disorder caused by the failure of enteric neural crest cells (ENCCs) to colonize the distal bowel, resulting in absence of enteric nervous system. While a range of molecules and signaling pathways have been found to contribute to HSCR development, the risk factors and pathogenesis of this disease in many patients remain unknown. We previously demonstrated that increased activity of the prostaglandin E2 (PGE2)/PGE2 receptor subtype EP2 pathway can be a risk factor for HSCR. In this study, an Ednrb-deficient mouse model of HSCR was generated and used to investigate if PGE2/EP2 pathway could be a potential therapeutic target for HSCR. We found that downregulation of PGE2/EP2 signaling by siRNA-mediated ablation of a PGE2 synthase or pharmacologic blockage of EP2 enhanced ENCC colonization in the distal bowel of Ednrb mice and alleviated their HSCR-like symptoms. Furthermore, blockage of EP2 was shown to promote ENCC migration through upregulating p38 mitogen-activated protein kinase activity, which was downregulated in the colon of Ednrb mice and in the distal aganglionic bowel of HSCR patients. These data provide evidence that maternal exposure during embryonic development to an environment with dysregulated activation of the PGE2/EP2 pathway may predispose genetically susceptible offspring to HSCR, and avoidance or early disruption of maternal events (e.g. inflammation) that possibly enhance PGE2/EP2 signaling during pregnancy would reduce the occurrence and severity of this disease. KEY MESSAGES : Knockdown of PTGES alleviates HSCR severity in Ednrb mice. Blockage of EP2-mediated PGE2 signaling alleviates HSCR severity in Ednrb mice. Blockage of EP2-mediated PGE2 signaling promotes ENCC migration via enhancing p38 activity.
Topics: Female; Mice; Animals; Hirschsprung Disease; Dinoprostone; p38 Mitogen-Activated Protein Kinases; Enteric Nervous System
PubMed: 37522903
DOI: 10.1007/s00109-023-02353-0 -
IDCases 2023
PubMed: 37577052
DOI: 10.1016/j.idcr.2023.e01858 -
Pediatric Surgery International Mar 2024This study aims to compare the fecal metabolome in post pull-through HD with and without HAEC patients and healthy young children using nuclear magnetic resonance (NMR)...
PURPOSE
This study aims to compare the fecal metabolome in post pull-through HD with and without HAEC patients and healthy young children using nuclear magnetic resonance (NMR) spectroscopy.
METHODS
Fresh fecal samples were collected from children under 5 years of age in both post-pull-through HD patients and healthy Thai children. A total of 20 fecal samples were then analyzed using NMR spectroscopy.
RESULTS
Thirty-four metabolites identified among HD and healthy children younger than 5 years were compared. HD samples demonstrated a significant decrease in acetoin, phenylacetylglutamine, and N-acetylornithine (corrected p value = 0.01, 0.04, and 0.004, respectively). Succinate and xylose significantly decreased in HD with HAEC group compared to HD without HAEC group (corrected p value = 0.04 and 0.02, respectively). Moreover, glutamine and glutamate metabolism, and alanine, aspartate, and glutamate metabolism were the significant pathways involved, with pathway impact 0.42 and 0.50, respectively (corrected p value = 0.02 and 0.04, respectively).
CONCLUSION
Differences in class, quantity, and metabolism of protein and other metabolites in young children with HD after pull-through operation were identified. Most of the associated metabolic pathways were correlated with the amino acids metabolism, which is required to maintain intestinal integrity and function.
Topics: Child; Humans; Infant; Child, Preschool; Hirschsprung Disease; Enterocolitis; Intestines; Feces; Glutamates; Postoperative Complications; Retrospective Studies
PubMed: 38512700
DOI: 10.1007/s00383-024-05667-3 -
Biomolecules Jan 2024Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance,...
Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, we applied a computational approach based on multi-omics network characterization and clustering analysis for HSCR-related gene/miRNA identification and biomarker discovery. Protein-protein interaction (PPI) and miRNA-target interaction (MTI) networks were analyzed by DPClusO and BiClusO, respectively, and finally, the biomarker potential of miRNAs was computationally screened by miRNA-BD. In this study, a total of 55 significant gene-disease modules were identified, allowing us to propose 178 new HSCR candidate genes and two biological pathways. Moreover, we identified 12 key miRNAs with biomarker potential among 137 predicted HSCR-associated miRNAs. Functional analysis of new candidates showed that enrichment terms related to gene ontology (GO) and pathways were associated with HSCR. In conclusion, this approach has allowed us to decipher new clues of the etiopathogenesis of HSCR, although molecular experiments are further needed for clinical validations.
Topics: Humans; Hirschsprung Disease; Multiomics; MicroRNAs; Computational Biology; Biomarkers
PubMed: 38397401
DOI: 10.3390/biom14020164 -
Biomedical Journal Dec 2023Clostridioides difficile, the etiological agent of C. difficile infection (CDI), elicits a spectrum of diarrheal symptoms with varying severity and the potential to...
Clostridioides difficile, the etiological agent of C. difficile infection (CDI), elicits a spectrum of diarrheal symptoms with varying severity and the potential to result in severe complications such as colonic perforation, pseudomembranous colitis, and toxic megacolon. The perturbation of gut microbiome, often triggered by antibiotic usage, represents the primary factor augmenting the risk of CDI. This underscores the significance of interactions between C. difficile and the microbiome in determining pathogen adaptability. In recent years, researchers have increasingly recognized the pivotal role played by intestinal microbiota in host health and its therapeutic potential as a target for medical interventions. While extensive evidence has been established regarding the involvement of gut bacteria in CDI, our understanding of symbiotic interactions between hosts and fungi within intestinal microbiota remains limited. Herein, we aim to comprehensively elucidate both composition and key characteristics of gut fungal communities that significantly contribute to CDI, thereby enhancing our comprehension from pharmacological and biomarker perspectives while exploring their prospective therapeutic applications for CDI.
PubMed: 38086471
DOI: 10.1016/j.bj.2023.100686 -
Nature Communications Mar 2024Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric...
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric neural stem cells (ENSCs) to rescue the enteric nervous system (ENS) in a model of colonic aganglionosis. ENSCs are isolated from a segment of small intestine from Wnt1::Cre;R26iDTR mice in which focal colonic aganglionosis is simultaneously created by diphtheria toxin injection. Autologous ENSCs are isolated, expanded, labeled with lentiviral-GFP, and transplanted into the aganglionic segment in vivo. ENSCs differentiate into neurons and glia, cluster to form neo-ganglia, and restore colonic contractile activity as shown by electrical field stimulation and optogenetics. Using a non-lethal model of colonic aganglionosis, our results demonstrate the potential of autologous ENSC therapy to improve functional outcomes in neurointestinal disease, laying the groundwork for clinical application of this regenerative cell-based approach.
Topics: Mice; Animals; Hirschsprung Disease; Stem Cell Transplantation; Neural Stem Cells; Neurons; Enteric Nervous System; Colorectal Neoplasms
PubMed: 38509106
DOI: 10.1038/s41467-024-46793-9 -
Journal of Clinical Pathology May 2024Paired-like homeobox 2B () is a gene essential in the development of the autonomic nervous system. mutations are associated with neurocristopathies-Hirschsprung disease... (Review)
Review
Paired-like homeobox 2B () is a gene essential in the development of the autonomic nervous system. mutations are associated with neurocristopathies-Hirschsprung disease (HSCR) and congenital central hypoventilation syndrome (CCHS)-and peripheral neuroblastic tumours. PHOXB2 plays an important role in the diagnostics of these conditions.Genotyping of a pathogenic variant is required to establish a diagnosis of CCHS. In HSCR patients, PHOX2B immunohistochemical staining has proven to be a valuable tool in identifying this disease. Furthermore, is a predisposition gene for neuroblastoma, in which PHOX2B immunohistochemical staining can be used as a highly sensitive and specific diagnostic marker. The utility of PHOX2B immunohistochemistry in pheochromocytoma and paraganglioma has also been studied but yields conflicting results.In this review, an overview is given of , its associated diseases and the usefulness of PHOX2B immunohistochemistry as a diagnostic tool.
Topics: Humans; Homeodomain Proteins; Transcription Factors; Hypoventilation; Neuroblastoma; Immunohistochemistry; Sleep Apnea, Central; Biomarkers, Tumor; Hirschsprung Disease; Mutation; Adrenal Gland Neoplasms; Genetic Predisposition to Disease
PubMed: 38458747
DOI: 10.1136/jcp-2023-209047 -
Visceral Medicine Apr 2024(. ) is a spore-forming bacterial species that ubiquitously exists in the environment. Colonization by is highly prevalent in infants, while fewer than 5% of adults... (Review)
Review
BACKGROUND
(. ) is a spore-forming bacterial species that ubiquitously exists in the environment. Colonization by is highly prevalent in infants, while fewer than 5% of adults are asymptomatic carriers. Disruption of the microbiome, such as through antibiotic treatment, triggers the germination of bacterial spores into numerous vegetative cells. These cells then produce enterotoxins that result in watery diarrhea and colonic inflammation. If left untreated, infection (CDI) can lead to pseudomembranous colitis with the potentially life-threatening complication of toxic megacolon.
SUMMARY
Over the past few decades, the incidence, morbidity, and mortality associated with CDIs have increased. They have emerged as the primary cause of nosocomial gastrointestinal infections in industrialized countries, posing a significant burden on healthcare systems. Despite antibiotics often being the cause of CDIs, they remain the standard treatment. However, a considerable number of patients treated with antibiotics will experience recurrent CDI (rCDI). Microbiota-based therapies targeting the core issue of CDI - antibiotic-induced dysbiosis - hold promise for rCDI treatment. While data for probiotics are insufficient, numerous studies have highlighted the effectiveness of fecal microbiota transplantation (FMT) as a safe and viable therapeutic option for rCDI. This approach is now endorsed by multiple guidelines. Nonetheless, regulatory prerequisites, such as comprehensive stool donor screening, restrict the widespread adoption of FMT beyond specialized centers. Recently, the US Food and Drug Administration has approved two commercial microbiota-based therapeutics to prevent CDI recurrence. These therapeutics are available by prescription in the USA. RBX2660 (REBYOTA™) comprises a diverse consortium of live microbes derived from human stool and is administered via enema. On the other hand, SER-109 (VOWST™) is an orally administered spore-based medication. In this review, we discuss the potential of microbiota-based treatments for rCDI against the background of medico-legal challenges associated with classical FMT.
KEY MESSAGES
FMT has emerged as a highly effective cure for rCDI. Nonetheless, regulatory prerequisites and laborious preparation procedures impede its widespread use. The establishment of ready-to-use microbiota-based therapeutics in clinical practice is necessary. In the USA, the recent approval of the first two commercial medications, including a spore-based oral preparation, marks a significant step forward.
PubMed: 38584858
DOI: 10.1159/000535851 -
Cureus Apr 2024infection (CDI) is a clinical and laboratory diagnosis. Populations at higher risk of developing disease require a high clinical index of suspicion for laboratory... (Review)
Review
INTRODUCTION
infection (CDI) is a clinical and laboratory diagnosis. Populations at higher risk of developing disease require a high clinical index of suspicion for laboratory testing to avoid incorrect assumptions of colonization. Common risk factors include recent antibiotic use, elderly (>65 years old), and immunocompromised patients. ssays should be ordered in an algorithm approach to diagnose an infection rather than colonization. Screening tests are widely available in hospital systems, but novel molecular testing may aid in diagnosis in patients with inconclusive or discordant antigen and toxin test results. Methods: Data was extracted from PubMed, Scopus, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases based on the keywords "", "toxin assay", and "toxic megacolon". The data extracted is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A total of 27 reports were included in this systematic review.
RESULTS
Testing patients with a significant gastrointestinal surgical history, hypogammaglobulinemia, inflammatory bowel disease, intensive care unit, and immunocompromised patients for CDI is highly recommended. Diarrhea in these subsets of patients requires correlation of clinical context and an understanding of assay results to avoid over- and under-treating.
CONCLUSION
CDI should be considered in all patients with traditional risk factors. Heightened clinical suspicion of CDI is required in patients with hypogammaglobulinemia, transplant recipients, patients with gastrointestinal surgical history, and inflammatory bowel disease. Testing should be limited to patients with clinical manifestations of CDI to ensure a high pretest probability for test interpretation. Healthcare workers should adhere to testing algorithms to optimize yield in the appropriate clinical context. Diagnostic assays should follow a sequential, stepwise approach to categorize the toxin expression status of the bacteria accurately.
PubMed: 38800338
DOI: 10.7759/cureus.59016