Toxic Megacolon Due to Fulminant
            <i>Clostridioides difficile</i>
            Infection

Bandaru, Sumanth Kumar

doi:10.1056/nejmicm2202891

Cited by 3 publications

(1 citation statement)

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“…C. difficile is transmitted via the fecal-oral route by which hardy spores traverse the gastrointestinal (GI) tract to germinate in the ileum and colonize the colon as vegetative cells 6 . Infection results in a range of symptoms from mild to severe diarrhea, pseudomembranous colitis, and, in severe cases, toxic megacolon, sepsis, and death 7, 8 . Diarrhea provides a route of spore dispersal onto skin, bedding, clothes, and environmental surfaces that remain contaminated after symptom resolution 9, 10 .…”

Section: Introductionmentioning

confidence: 99%

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated withClostridioides difficileinfection

Peritore-Galve

Kaji

Smith

et al. 2022

Preprint

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Background & Aim:Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis. Two protein toxins, TcdA and TcdB, produced byC. difficileare the major determinants of disease. However, the physiological cause of diarrhea associated with CDI is not well understood. We investigated the effects of CDI on paracellular permeability and apical ion transporters.Methods: We studied intestinal permeability and apical membrane transporters in female C57BL/6J mice. Üssing chambers were used to measure regional differences in paracellular permeability and ion transporter function in intestinal mucosa. Intestinal tissues were collected from mice and analyzed by immunofluorescence microscopy and RNA-sequencing.Results: CDI increased intestinal permeability through the size-selective leak pathway in vivo, but permeability was not increased at the sites of pathological damage. Chloride secretion was reduced in the cecum during infection by decreased CaCC function. Infected mice had decreased SGLT1 (also called SLC5A1) activity in the cecum and colon along with diminished apical abundance and an increase in luminal glucose. SGLT1 and DRA (also called SLC26A3) expression was ablated by either TcdA or TcdB, but NHE3 (also called SLC9A3) was decreased in a TcdB-dependent manner. Finally, expression of these three ion transporters was drastically reduced at the transcriptional level.Conclusions: CDI increases intestinal permeability and decreases apical abundance of NHE3, SGLT1, and DRA. This combination may cause a dysfunction in water and solute absorption in the lower gastrointestinal tract, leading to osmotic diarrhea. These findings may open novel pathways for attenuating CDI-associated diarrhea.

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Section: Introductionmentioning

confidence: 99%

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated withClostridioides difficileinfection

Peritore-Galve

Kaji

Smith

et al. 2022

Preprint

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Metronidazole/vancomycin

2023

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CHAPSAP26-161, A Truncated Protein and Enzymatic Active Domain of Endolysin LysSAP26, as a Potential Therapeutic Agent to Combat Clostridioides difficile Infection

Dahal,

Choi,

Kim

et al. 2024

J Bacteriol Virol.

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Clostridioides difficile is a spore-forming enteric pathogen that causes life-threatening diarrhea and colitis. Notably, C. difficile infection (CDI) is a major healthcare-associated infection with increasing incidence and morbidity rates. Antibiotic-induced microbial disruption has been linked to susceptibility to CDI transmission and relapse. Therefore, alternative therapeutic approaches that effectively prevent C. difficile growth and spore germination are urgently needed. Bacteriophage-derived endolysins and their derivatives have recently shown potential as novel antibacterial agents. Hence, this study aimed to investigate the efficacy of a novel truncated cysteine-histidine-dependent amidohydrolase/peptidase (CHAP) modular endolysin, CHAP SAP26 -161, in combating CDI. In vitro studies demonstrated its potent bactericidal activity against several clinically relevant C. difficile strains, including toxin A-and toxin B-producing and nontoxigenic strains. CHAP SAP26 -161 exhibited rapid and specific killing activity, thereby significantly reducing C. difficile colony-forming units. Furthermore, in a murine CDI model, CHAP SAP26 -161 treatment remarkably reduced C. difficile burden and clinical symptoms, such as diarrhea and weight loss. In histopathological analysis, colonic inflammation and tissue damage decreased in CHAP SAP26 -161-treated mice compared with that in the control group. Moreover, no cytotoxic effects were observed on the A549 cell line, indicating that CHAP SAP26 -161 is safe as a therapeutic agent. These findings highlight that CHAP SAP26 -161 is a promising treatment option for CDI. Importantly, preclinical and clinical studies are warranted to fully evaluate the therapeutic potential of CHAP SAP26 -161 and its possible implementation in clinical practice.

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Toxic Megacolon Due to Fulminant Clostridioides difficile Infection

Cited by 3 publications

References 0 publications

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated withClostridioides difficileinfection

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated withClostridioides difficileinfection

Metronidazole/vancomycin

CHAPSAP26-161, A Truncated Protein and Enzymatic Active Domain of Endolysin LysSAP26, as a Potential Therapeutic Agent to Combat Clostridioides difficile Infection

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