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  3. Citrulline inhibits Clostridioides difficile infection with anti-inflammatory effects

Citrulline inhibits Clostridioides difficile infection with anti-inflammatory effects

  • Cell Mol Gastroenterol Hepatol. 2025 Feb 7:101474. doi: 10.1016/j.jcmgh.2025.101474.
Ying Xie 1,  Sophie Irwin 2,  Becca Nelson 3,  Mieke van Daelen 4,  Lindsey Fontenot 5,  Jonathan P Jacobs 6,  Monica Cappelletti 7,  Hanping Feng 8,  Yiling Li 9,  Hon Wai Koon 10
Affiliations

Affiliations

  • 1 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095; Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang City, Liaoning Province, China. Electronic address: yingxie2019@hotmail.com.
  • 2 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. Electronic address: SIrwin@mednet.ucla.edu.
  • 3 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. Electronic address: beccanelson33@ucla.edu.
  • 4 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. Electronic address: miekevandaelen@g.ucla.edu.
  • 5 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. Electronic address: lindsey.fontenot01@gmail.com.
  • 6 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095; Goodman-Luskin Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073. Electronic address: jjacobs@mednet.ucla.edu.
  • 7 Immunogenetics Division, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. Electronic address: mcappelletti@mednet.ucla.edu.
  • 8 Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, MD 21201, USA. Electronic address: hanpingfeng@gmail.com.
  • 9 Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang City, Liaoning Province, China. Electronic address: lyl-72@163.com.
  • 10 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. Electronic address: hkoon@mednet.ucla.edu.
PMID: 39923847 DOI: 10.1016/j.jcmgh.2025.101474
Abstract

Background and aims: Clostridioides difficile Infection (CDI) causes colitis and diarrhea. C. difficile bacterium produces toxins A and B, which cause intestinal inflammation. A metabolomics analysis discovered fecal metabolites with anti-inflammatory effects in CDI. We aimed to identify an anti-CDI metabolite that can inhibit CDI-mediated colitis and prevent recurrence.

Methods: Fresh human colonic tissues and primary human cells were used to determine metabolite effects. Humanized C. difficile-infected HuCD34-NCG mice and antibiotics-treated human gut microbiota-treated (ABX+HGM) hamsters were used to simulate the human environment.

Results: High-throughput screening and fecal metabolomics analysis identified anti-inflammatory metabolites. Compared to Other tested metabolites, citrulline preserved the mucosal integrity of toxin-exposed fresh human colonic tissues with reduced macrophage inflammatory protein 1 alpha (MIP-1α) and increased interleukin-10 (IL-10) expression. Oral citrulline treatment alleviated cecal inflammation in hamsters infected with C. difficile ribotype 027. This was accomplished by the augmented expression of cecal IL-10 and the diminished level of cecal MIP-1α. Citrulline and vancomycin synergistically prevented recurrence in the infected ABX+HGM hamsters. In C57BL/6J mice infected with C. difficile VPI10463, citrulline ameliorated colitis by reducing colonic Ccl3 mRNA expression. In immunologically humanized HuCD34-NCG mice infected with toxin B-expressing C. difficile ribotype 017, citrulline ameliorated colitis with increased human IL-10 expression in colonic macrophages. Citrulline suppressed MIP-1α secretion and GSK3α/β dephosphorylation in the toxin A-exposed human colonic epithelial cells and promoted IL-10 expression in toxin B-exposed human macrophages and heat shock protein 27 phosphorylation.

Conclusion: Citrulline exerts anti-inflammatory effects in the intestines against C. difficile toxins and inhibits CDI recurrence in mice and hamsters.

Keywords

inflammation; metabolite; microbiome.

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