Dataset Information

The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.

ABSTRACT:

Background

Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties.

Objectives

To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes.

Design

Wild-type (WT) and mCRAMP-deficient (Camp(-/-)) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP.

Results

Intracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp(-/-) mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice.

Conclusion

Exogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.

SUBMITTER: Hing TC

PROVIDER: S-EPMC3737259 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.

Hing Tressia C TC Ho Samantha S Shih David Q DQ Ichikawa Ryan R Cheng Michelle M Chen Jeremy J Chen Xinhua X Law Ivy I Najarian Robert R Kelly Ciaran P CP Gallo Richard L RL Targan Stephan R SR Pothoulakis Charalabos C Koon Hon Wai HW

Gut 20120703 9

<h4>Background</h4>Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties.<h4>Objectives</h4>To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes.<h4>Design</h4>Wild-type (WT) and mCRAMP- ...[more]

PMID: 22760006

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Project description:Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease of the gastrointestinal tract. This study aimed to determine the effect of cathelicidin-related antimicrobial peptide (Cramp) on dextran sulfate sodium (DSS)-induced acute experimental colitis in mice and to investigate the underlying mechanisms. Acute UC was induced in C57BL/6 mice with 3% DSS for 7 days, 4 mg/kg b.w. synthetic Cramp peptide was administrated once daily starting on day 4 of the experimental period. Mice were evaluated for body weight, colon length, colon histopathology, and inflammatory cytokines in colon tissue. Using 16 s rRNA sequencing, the composition structure of gut microbiota was characterized. Metabolomic profiling of the serum was performed. The results showed that DSS treatment significantly induced intestinal damage as reflected by disease activity index, histopathological features, and colon length, while Cramp treatment significantly prevented these trends. Meanwhile, Cramp treatment decreased the levels of inflammatory cytokines in both serum and colonic tissue on DSS-induced colitis. It was also observed that DSS damaged the integrity of the intestinal epithelial barrier, whereas Cramp also played a protective role by attenuating these deteriorated effects. Furthermore, Cramp treatment reversed the oxidative stress by increasing the antioxidant enzymes of GSH-PX and decreasing the oxidant content of MDA. Notably, compared to the DSS group, Cramp treatment significantly elevated the abundance of Verrucomicrobiota at the phylum level. Furthermore, at the genus level, Parasutterella and Mucispirllum abundance was increased significantly in response to Cramp treatment, although Roseburia and Enterorhabdus reduced remarkably. Metabolic pathway analysis of serum metabolomics showed that Cramp intervention can regulate various metabolic pathways such as α-linolenic acid, taurine and hypotaurine, sphingolipid, and arachidonic acid metabolism. The study concluded that Cramp significantly ameliorated DSS-induced colonic injury, colonic inflammation, and intestinal barrier dysfunction in mice. The underlying mechanism is closely related to the metabolic alterations derived from gut microbiota.

Dataset Information

The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.

Background

Objectives

Design

Results

Conclusion

Publications

The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.

Similar Datasets

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