{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T21:08:05Z","timestamp":1789074485869,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Microbiology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01DK135707"],"award-info":[{"award-number":["R01DK135707"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AI139087"],"award-info":[{"award-number":["R01AI139087"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30DK034854"],"award-info":[{"award-number":["P30DK034854"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HT9425-24-1-0047"],"award-info":[{"award-number":["HT9425-24-1-0047"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Clostridioides difficile<\/jats:italic>\n                  is a major cause of healthcare associated infections.\n                  <jats:italic>C. difficile<\/jats:italic>\n                  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 (\n                  <jats:italic>Mrgprb2<\/jats:italic>\n                  and\n                  <jats:italic>NK2-R)<\/jats:italic>\n                  . Through\n                  <jats:italic>in vivo<\/jats:italic>\n                  mouse infection models, we confirmed the effects of SP in hypervirulent\n                  <jats:italic>C. difficile<\/jats:italic>\n                  are largely mediated by the neurokinin-1 receptor (NK1-R), the high affinity receptor for SP. Through genetic mice that lack mast cells (cKit\n                  <jats:sup>W-sh<\/jats:sup>\n                  ) we determined that mast cells which respond to SP in certain kinds of neurogenic inflammation appear dispensable for inflammation caused by\n                  <jats:italic>C. difficile<\/jats:italic>\n                  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\n                  <jats:italic>C. difficile<\/jats:italic>\n                  infection.\n                <\/jats:p>","DOI":"10.64898\/2026.09.06.749186","type":"posted-content","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:23:28Z","timestamp":1788841408000},"source":"Crossref","is-referenced-by-count":0,"title":["Substance P receptor blockade is associated with increased survival of patients with\n                  <i>C. difficile<\/i>\n                  infection"],"prefix":"10.64898","author":[{"given":"Leo","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh PA"},{"name":"Pittsburgh Center for Pain Research, Center for Vaccine Research, and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh PA"},{"name":"Department of Urology, George Washington University School of Medicine, Washington DC"},{"name":"Department of Urology, Boston Children\u2019s Hospital, Boston MA"},{"name":"Departments of Microbiology and Surgery, Harvard Medical School, Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Boston Children\u2019s Hospital, Boston MA"},{"name":"Departments of Microbiology and Surgery, Harvard Medical School, Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Boston Children\u2019s Hospital, Boston MA"},{"name":"Departments of Microbiology and Surgery, Harvard Medical School, Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Musser","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Pediatrics, Boston Children\u2019s Hospital, Boston MA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Shepherd","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Pediatrics, Boston Children\u2019s Hospital, Boston MA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Boston Children\u2019s Hospital, Boston MA"},{"name":"Departments of Microbiology and Surgery, Harvard Medical School, Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Whalen","sequence":"additional","affiliation":[{"name":"Department of Urology, 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