Loratadine is an anti-inflammatory agent against C. difficile toxin B

Ying Xie; Sophie Irwin; Andrea Chupina Estrada; Becca Nelson; Ashlen Bullock; Lindsey Fontenot; Hanping Feng; Mingjun Sun; Hon Wai Koon

doi:10.1093/infdis/jiae021

Loratadine is an anti-inflammatory agent against C. difficile toxin B

J Infect Dis. 2024 Jan 19:jiae021. doi: 10.1093/infdis/jiae021. Online ahead of print.

Authors

Ying Xie^{1

2}, Sophie Irwin¹, Andrea Chupina Estrada¹, Becca Nelson¹, Ashlen Bullock¹, Lindsey Fontenot¹, Hanping Feng³, Mingjun Sun², Hon Wai Koon¹

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, USA.
² Department of Gastroenterology, The First Hospital of China Medical University, Shenyang City, Liaoning Province, China.
³ Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, MD 21201, USA.

PMID: 38243838
DOI: 10.1093/infdis/jiae021

Abstract

Background: Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical non-microbiological therapeutic approach against CDI.

Methods: We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs.

Results: Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein one alpha (MIP-1α) expression in PBMCs. We identified Loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral Loratadine (10 mg/kg/day) maintained survival, inhibited intestinal Ccl3 mRNA expression, and prevented vancomycin-associated recurrence in the VPI10463-infected mice and ribotype 017-infected hamsters. Splenocytes from Loratadine-treated mice conferred anti-inflammatory effects to the VPI10463-infected T/B cell-deficient Rag-/- mice. Oral Loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice.

Conclusions: Loratadine may be repurposed to optimize existing therapies against CDI.

Keywords: cytokine; histamine receptor; splenocytes.

Plain language summary

Loratadine is an FDA-approved antihistamine that inhibits toxin B-mediated pro-inflammatory macrophage inflammatory protein one alpha secretion from immune cells. The anti-inflammatory effect of Loratadine ameliorates intestinal inflammation in C. difficile-infected animals. Loratadine may be repurposed to optimize existing therapies.