Neurokinin 1 receptor blockade is associated with increased survival of patients with C. difficile infection

Abstract

Clostridioides difficile is a major cause of healthcare associated infections. C. difficile infection (CDI) is a toxin-mediated disease driven by the secretion of two large protein toxins, Toxin A (TcdA) and Toxin B (TcdB). TcdA and TcdB cause neurogenic inflammation that can contribute to intestinal inflammation in rat and mouse models. Substance P (SP), a potent vasoactive neuropeptide, is a major contributor to C. difficile toxin induced inflammation in animal models. SP acts on multiple receptors including the high affinity receptor NK1-R, and lower affinity receptors (Mrgprb2 and NK2-R). Through in vivo mouse infection models, we confirmed the effects of SP in hypervirulent C. difficile are largely mediated by the neurokinin-1 receptor (NK1-R), the high affinity receptor for SP. Through genetic mice that lack mast cells (cKitW-sh) we determined that mast cells which respond to SP in certain kinds of neurogenic inflammation appear dispensable for inflammation caused by C. difficile infection. We explored the role of NK1-R antagonists in a retrospective study of a large clinical cohort. We determined that, after propensity matching, NK1-R antagonists were associated with a significant survival benefit and that patients treated with NK1-R antagonists showed evidence of reduced vascular inflammation (increased serum albumin). Together these data suggest blocking SP activity through antagonism of NK1-R with small molecule inhibitors may be a useful strategy for adjunctive treatment during C. difficile infection.

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BibTeX RIS

BibTeX

@misc{zhao2026neurokinin,
  title = {{Neurokinin 1 receptor blockade is associated with increased survival of patients with C. difficile infection}},
  author = {L. Zhao and M. Liu and S. Wang and M. A. Musser and A. Shepherd and J. Zhang and M. Whalen and D. Binion and M. Rao and M. Dong and J. Manion},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.06.749186},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.06.749186v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Neurokinin 1 receptor blockade is associated with increased survival of patients with C. difficile infection
AU  - L. Zhao
AU  - M. Liu
AU  - S. Wang
AU  - M. A. Musser
AU  - A. Shepherd
AU  - J. Zhang
AU  - M. Whalen
AU  - D. Binion
AU  - M. Rao
AU  - M. Dong
AU  - J. Manion
PY  - 2026
DA  - 2026/09/06
PB  - bioRxiv
DO  - 10.64898/2026.09.06.749186
UR  - https://www.biorxiv.org/content/10.64898/2026.09.06.749186v1
AB  - Clostridioides difficile is a major cause of healthcare associated infections. C. difficile infection (CDI) is a toxin-mediated disease driven by the secretion of two large protein toxins, Toxin A (TcdA) and Toxin B (TcdB). TcdA and TcdB cause neurogenic inflammation that can contribute to intestinal inflammation in rat and mouse models. Substance P (SP), a potent vasoactive neuropeptide, is a major contributor to C. difficile toxin induced inflammation in animal models. SP acts on multiple receptors including the high affinity receptor NK1-R, and lower affinity receptors (Mrgprb2 and NK2-R). Through in vivo mouse infection models, we confirmed the effects of SP in hypervirulent C. difficile are largely mediated by the neurokinin-1 receptor (NK1-R), the high affinity receptor for SP. Through genetic mice that lack mast cells (cKitW-sh) we determined that mast cells which respond to SP in certain kinds of neurogenic inflammation appear dispensable for inflammation caused by C. difficile infection. We explored the role of NK1-R antagonists in a retrospective study of a large clinical cohort. We determined that, after propensity matching, NK1-R antagonists were associated with a significant survival benefit and that patients treated with NK1-R antagonists showed evidence of reduced vascular inflammation (increased serum albumin). Together these data suggest blocking SP activity through antagonism of NK1-R with small molecule inhibitors may be a useful strategy for adjunctive treatment during C. difficile infection.
ER  -

Abstract

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