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.
- Colonic diseases
- intestinal microbiology
- inflammation and TNF-α
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TCH and SH share co-first authorship as they have equally contributed to this work.
Funding This work was supported by a pilot and feasibility study grant (#29122) from the UCLA-CURE Center, a Crohn's and Colitis Foundation of America Research Fellowship (#1406) and a Career Development Award (#2691) and NIH K01 DK084256 grant to HWK. Support was also provided by the Blinder Research Foundation for Crohn's Disease, the Eli and Edythe Broad Chair (CP) and United States Public Health Service grant DK072471 (CP) and DK046763 (DQS and SRT).
Competing interests None.
Ethics approval Cedars Sinai IRB and Beth Israel Deaconess Medical Center IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We may share additional unpublished data from the study. Please contact Dr Hon Wai Koon of UCLA.
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