Clostridium innocuum, an emerging pathogen that induces lipid raft-mediated cytotoxicity

ABSTRACT

Clostridium innocuum is an emerging spore-forming anaerobe that is often observed in Clostridioides difficile-associated inflammatory bowel disease (IBD) exacerbations. Unlike C. difficile, C. innocuum neither produces toxins nor possesses toxin-encoding genetic loci, but is commonly found in both intestinal and extra-intestinal infections. Membrane lipid rafts are composed of dynamic assemblies of cholesterol and sphingolipids, allowing bacteria to gain access to cells. However, the direct interaction between C. innocuum and lipid rafts that confers bacteria the ability to disrupt the intestinal barrier and induce pathogenesis remains unclear. In this study, we investigated the associations among nucleotide-binding oligomerization domain containing 2 (NOD2), lipid rafts, and cytotoxicity in C. innocuum-infected gut epithelial cells. Our results revealed that lipid rafts were involved in C. innocuum-induced NOD2 expression and nuclear factor (NF)-κB activation, triggering an inflammatory response. Reducing cholesterol by simvastatin significantly dampened C. innocuum-induced cell death, indicating that the C. innocuum-induced pathogenicity of cells was lipid raft-dependent. These results demonstrate that NOD2 mobilization into membrane rafts in response to C. innocuum-induced cytotoxicity results in aggravated pathogenicity.

KEYWORDS:

• Clostridium innocuum
• cholesterol
• lipid rafts
• cytotoxicity
• inflammation

Acknowledgements

The authors would like to thank the editor and reviewers for the editorial assistance and their valuable comments. The authors sincerely thank the Microscopy Center at Chang Gung University for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author’s contributions

Conception and design of this work: CCN, YMC, CHC, CHL

Experimental study: HYW, CJK, CHC, MWH, CLC, TSH, YCC

Data analysis and interpretation: HYW, CJK, CHC, MWH, CLC

Writing the manuscript: CHC, CHL

Final approval: all authors.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Additional information

Funding

This work was supported by the National Science and Technology Council, Taiwan [112-2320-B-182-036-MY3, 112-2320-B-182-042-MY3], Chang Gung Memorial Hospital at Linkou [CMRPD1K0361, CMRPD1L0321, CMRPD1M0491-2, CORPD1M0021-3], and Tomorrow Medical Foundation.