scholarly journals Lacticaseibacillus casei Strain T21 Attenuates Clostridioides difficile Infection in a Murine Model Through Reduction of Inflammation and Gut Dysbiosis With Decreased Toxin Lethality and Enhanced Mucin Production

2021 ◽  
Vol 12 ◽  
Author(s):  
Wimonrat Panpetch ◽  
Pornpimol Phuengmaung ◽  
Thanya Cheibchalard ◽  
Naraporn Somboonna ◽  
Asada Leelahavanichkul ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Antibiotic Administration ◽  
Colonic Epithelial Cells ◽  
Mucin Production ◽  
Gut Dysbiosis ◽  
Clostridioides Difficile ◽  
Inflammatory Protein ◽  
Clostridioides Difficile Infection

Clostridioides difficile is a major cause of diarrhea in patients with antibiotic administration. Lacticaseibacillus casei T21, isolated from a human gastric biopsy, was tested in a murine C. difficile infection (CDI) model and colonic epithelial cells (Caco-2 and HT-29). Daily administration of L. casei T21 [1 × 108 colony forming units (CFU)/dose] for 4 days starting at 1 day before C. difficile challenge attenuated CDI as demonstrated by a reduction in mortality rate, weight loss, diarrhea, gut leakage, gut dysbiosis, intestinal pathology changes, and levels of pro-inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, macrophage inflammatory protein 2 (MIP-2), and keratinocyte chemoattractant (KC)] in the intestinal tissue and serum. Conditioned media from L. casei T21 exerted biological activities that fight against C. difficile as demonstrated in colonic epithelial cells by the following: (i) suppression of gene expression and production of IL-8, an important chemokine involved in C. difficile pathogenesis, (ii) reduction in the expression of SLC11A1 (solute carrier family 11 member 1) and HuR (human antigen R), important genes for the lethality of C. difficile toxin B, (iii) augmentation of intestinal integrity, and (iv) up-regulation of MUC2, a mucosal protective gene. These results supported the therapeutic potential of L. casei T21 for CDI and the need for further study on the intervention capabilities of CDI.

In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile

2020 ◽  
Author(s):  
Beverly Murray ◽  
Cindy Wolfe ◽  
Andrea Marra ◽  
Chris Pillar ◽  
Dean Shinabarger
Keyword(s):  
Therapeutic Potential ◽  
Oral Treatment ◽  
Clinical Development ◽  
Vitro Activity ◽  
The Novel ◽  
In Vitro Activity ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Time Kill

Abstract Background Ibezapolstat (ACX-362E) is the first DNA polymerase IIIC inhibitor undergoing clinical development for the oral treatment of Clostridioides difficile infection (CDI). Methods In this study, the in vitro activity of ibezapolstat was evaluated against a panel of 104 isolates of C. difficile, including those with characterized ribotypes (e.g. 027 and 078) and those producing toxin A or B and was shown to have similar activity to those of comparators against these strains. Results The overall MIC50/90 (mg/L) for ibezapolstat against evaluated C. difficile was 2/4, compared with 0.5/4 for metronidazole, 1/4 for vancomycin and 0.5/2 for fidaxomicin. In addition, the bactericidal activity of ibezapolstat was evaluated against actively growing C. difficile by determining the MBC against three C. difficile isolates. Time–kill kinetic assays were additionally performed against the three C. difficile isolates, with metronidazole and vancomycin as comparators. Conclusions The killing of C. difficile by ibezapolstat was observed to occur at concentrations similar to its MIC, as demonstrated by MBC:MIC ratios and reflected in time–kill kinetic assays. This activity highlights the therapeutic potential of ibezapolstat for the treatment of CDI.

Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways

2007 ◽  
Vol 293 (1) ◽  
pp. G365-G373 ◽  
Author(s):  
Mahmoud El Homsi ◽  
Robert Ducroc ◽  
Jean Claustre ◽  
Gérard Jourdan ◽  
Arieh Gertler ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mrna Level ◽  
Intestinal Barrier Function ◽  
Rat Colon ◽  
Mrna Levels ◽  
Colonic Epithelial Cells ◽  
Mucin Production ◽  
Leptin Receptors ◽  
Mucin Expression

Mucins play an essential role in the protection and repair of gastrointestinal mucosa. We recently showed that luminal leptin strongly stimulated mucin secretion in vivo in rat colon. In the present study, we challenged the hypothesis that leptin may act directly on goblet cells to induce mucin expression in rat and human intestinal mucin-producing cells (DHE and HT29-MTX). The endoluminal effect of leptin was also studied in vivo in rat perfused colon model. The presence of leptin receptors was demonstrated in the two cell lines by Western blot and RT-PCR. In rat DHE cells, leptin (0.01–10 nmol/l, 60 min) dose dependently increased the secretion of mucins (210 ± 3% of controls) and the expression of Muc2, Muc3, and Muc4 (twofold basal level) but not of Muc1 and Muc5AC. Luminal perfusion of leptin (60 min, 0.1–100 nmol/l) in rat colon also increased the mRNA level of Muc2, Muc3, and Muc4 but not of Muc1. In human HT29-MTX cells, leptin (0.01–10 nmol/l, 60 min) dose dependently enhanced MUC2, MUC5AC, and MUC4 mRNA levels. These effects were prevented by pretreatment of cells with the leptin mutein L39A/D40A/F41A, which acts as a receptor antagonist. Finally, pathway inhibition experiments suggest that leptin increased mucin expression by activating PKC-, phosphatidyl inositol 3-kinase-, and MAPK-dependent pathways but not the JAK/STAT pathway. In conclusion, leptin may contribute significantly to membrane-associated and secreted mucin production via a direct stimulation of colonic epithelial cells and the activation of leptin receptors. These data are consistent with a role for leptin in regulation of the intestinal barrier function.

scholarly journals Entry of spores into intestinal epithelial cells contributes to recurrence of Clostridioides difficile infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pablo Castro-Córdova ◽  
Paola Mora-Uribe ◽  
Rodrigo Reyes-Ramírez ◽  
Glenda Cofré-Araneda ◽  
Josué Orozco-Aguilar ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Intestinal Mucosa ◽  
Intestinal Epithelial Cells ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Spore Surface ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Infection Recurrence

AbstractClostridioides difficile spores produced during infection are important for the recurrence of the disease. Here, we show that C. difficile spores gain entry into the intestinal mucosa via pathways dependent on host fibronectin-α5β1 and vitronectin-αvβ1. The exosporium protein BclA3, on the spore surface, is required for both entry pathways. Deletion of the bclA3 gene in C. difficile, or pharmacological inhibition of endocytosis using nystatin, leads to reduced entry into the intestinal mucosa and reduced recurrence of the disease in a mouse model. Our findings indicate that C. difficile spore entry into the intestinal barrier can contribute to spore persistence and infection recurrence, and suggest potential avenues for new therapies.

scholarly journals Enhanced CXC Chemokine Responses of Human Colonic Epithelial Cells to Locus of Enterocyte Effacement-Negative Shiga-Toxigenic Escherichia coli

2003 ◽  
Vol 71 (10) ◽  
pp. 5623-5632 ◽  
Author(s):  
Trisha J. Rogers ◽  
Adrienne W. Paton ◽  
Shaun R. McColl ◽  
James C. Paton
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Intestinal Epithelial ◽  
Colonic Epithelial Cells ◽  
Inflammatory Protein ◽  
Cxc Chemokine ◽  
Remote Sites ◽  
The Difference ◽  
Enterocyte Effacement ◽  
Culture Supernatants

ABSTRACT There is increasing evidence that by facilitating translocation of Shiga toxin (Stx) across the intestinal epithelium and by transporting bound toxin to remote sites such as the renal endothelium, polymorphonuclear leukocytes (PMNs) play a key role in the pathogenesis of Shiga-toxigenic Escherichia coli (STEC) disease. Plasma levels of PMN-attracting CXC chemokines such as interleukin-8 (IL-8) also appear to correlate in humans with the severity of disease. Thus, the capacity of STEC strains to elicit CXC chemokine responses in intestinal epithelial cells may be a crucial step in pathogenesis. Accordingly, we attempted to determine which STEC factors are responsible for CXC chemokine induction in human colonic epithelial cells. Infection of Hct-8 cells with locus for enterocyte effacement (LEE)-negative STEC strains isolated from patients with severe STEC disease resulted in up-regulation of IL-8, macrophage inflammatory protein 2α (MIP-2α), MIP-2β, and ENA-78 mRNA significantly higher and earlier than that elicited by several LEE-positive STEC strains, including the O157:H7 strain EDL933. Similarly, levels of IL-8 protein in LEE-negative STEC-infected Hct-8 culture supernatants were significantly higher than in LEE-positive STEC-infected culture supernatants. The difference in responses could not be attributed to the expression or nonexpression of LEE genes, the presence or absence of an STEC megaplasmid, or differences in O serogroups or in the type or amount of Stx produced. Interestingly, however, several of the LEE-negative STEC strains eliciting the strongest chemokine responses belonged to flagellar serotype H21. Incubation of Hct-8 cells with isolated H21 flagellin elicited IL-8 and MIP-2α responses similar to those seen in the presence of the most potent LEE-negative STEC strains. Deletion of the fliC gene, but not the stx 2 gene, largely abolished the capacity of O113:H21 LEE-negative STEC strain 98NK2 to elicit IL-8 and MIP-2α responses in Hct-8 cells. Taken together, these data suggest that although Stx is capable of inducing CXC chemokine responses, the elevated responses seen in cells infected with certain STEC strains are largely attributable to the production of flagellin.

scholarly journals Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease

2020 ◽  
Vol 13 ◽  
pp. 175628482094690 ◽  
Author(s):  
Jonathan P. Segal ◽  
Benjamin H. Mullish ◽  
Mohammed N. Quraishi ◽  
Tariq Iqbal ◽  
Julian R. Marchesi ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Gastrointestinal Disease ◽  
Full Potential ◽  
Faecal Microbiota ◽  
Therapeutic Tool ◽  
Faecal Microbiota Transplantation ◽  
Disease States ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Recommended Therapy

Faecal microbiota transplantation (FMT) is currently a recommended therapy for recurrent/refractory Clostridioides difficile infection (CDI). The success of FMT for CDI has led to interest in its therapeutic potential in many other disorders. The mechanisms that underpin the efficacy of FMT are not fully understood. Importantly, FMT remains a crucial treatment in managing CDI and understanding the mechanisms that underpin its success will be critical to improve its clinical efficacy, safety and usability. Furthermore, a deeper understanding of this may allow us to expose FMT’s full potential as a therapeutic tool for other disease states. This review will explore the current understanding of the mechanisms underlying the efficacy of FMT across a variety of diseases.

scholarly journals 96. Surgical Site Infection Prophylaxis Selection and Postoperative Clinical Outcomes in Patients with Reported Penicillin Allergy

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S178-S179
Author(s):  
Ryan K Dare
Keyword(s):  
Surgical Procedures ◽  
Surgical Site Infections ◽  
Antibiotic Administration ◽  
Infection Prophylaxis ◽  
First Line ◽  
Clostridioides Difficile ◽  
Increased Risk ◽  
Hip And Knee Arthroplasty ◽  
Clostridioides Difficile Infection ◽  
To Receive

Abstract Background Administration of preoperative antibiotics are known decrease risk of postoperative surgical site infections (SSI) and deviation from first line prophylaxis increases this risk. Patients who report penicillin (PCN) allergy are less likely to receive cefazolin preoperatively despite being the preferred antibiotic for SSI prevention in the majority of surgical procedures. Methods A single center retrospective descriptive study was performed during the 2018–2019 academic year. Perioperative antimicrobial administration practice was evaluated for all types of surgical procedures. Patient demographics, PCN allergy history, development of Clostridioides difficile infection (CDI) within 90 days of procedure, and total hip and knee arthroplasty SSIs were assessed. Results During the study period, 16,376 procedures were performed with perioperative antibiotic administration. Cefazolin (12,756; 77.9%) was most frequently administered followed by clindamycin (1,396; 8.5%), and vancomycin (735, 4.5%). PCN allergy was reported in 2,051 (12.5%) patients, of which 1,180 (57.5%) had record of previously receiving a cephalosporin. Interestingly, 694 (33.8%) and 11,799 (82%) patients with and without a reported PCN allergy respectively received cefazolin perioperatively (P< 0.001). The incidence of joint replacement SSI was higher in patients with a reported PCN allergy (6 of 97; 6.2%) compared to those without (12 of 671; 1.8%) (P=0.018). CDI occurred in 44 (1.1%) of 3,883 and 70 (0.5%) of 12,493 patients who received a non-cefazolin or cefazolin respectively for prophylaxis (OR 2.1; 95% CI 1.5–2.9). In multivariate analysis controlling for surgery type, age, weight, and renal function, receipt of a non-cefazolin antibiotic was independently associated with developing CDI (OR 1.6; 95% CI 1.1–2.4). Conclusion Patients with a reported PCN allergy were more likely to receive a non-cefazolin antibiotic perioperatively and were more likely to develop a SSI following hip or knee replacement. Administration of a non-cefazolin antibiotic was independently associated with increased risk of CDI. Efforts should be made to minimize inappropriate avoidance of first line perioperative prophylaxis due to reported PCN allergies. Disclosures Ryan K. Dare, MD, MS, Accelerate Diagnostics, Inc (Research Grant or Support)

scholarly journals Faecal microbiota transplantation: a review

2020 ◽  
Vol 41 (2) ◽  
pp. 65
Author(s):  
Holly A Sinclair ◽  
Paul Chapman
Keyword(s):  
Adverse Events ◽  
Healthy Donor ◽  
Donor Selection ◽  
Faecal Microbiota ◽  
Human Faeces ◽  
Faecal Microbiota Transplantation ◽  
Gut Dysbiosis ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Faecal microbiota transplantation (FMT) is the transfer of human faeces from a healthy donor to a recipient with a disease associated with gut dysbiosis. Here we review faecal microbiota transplantation as a treatment for Clostridioides difficile infection (CDI) and other conditions including decolonisation of multiresistant organisms. Donor selection and screening, adverse events, processing, administration and regulation of FMT are discussed.

IFN-γ induces transcription but not secretion of IL-18 in human colonic epithelial cells

2001 ◽  
Vol 120 (5) ◽  
pp. A704-A704
Author(s):  
S KIESSLING ◽  
K SCHIOTTMANN ◽  
W FALK ◽  
T ANDUS ◽  
J SCHOELMERICH ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Colonic Epithelial Cells ◽  
Ifn Γ
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