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Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13, we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-\u03b2 (TRIF\/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case\u2013control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. \u00a9 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4905","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T02:43:11Z","timestamp":1692672191000},"page":"1700-1717","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development"],"prefix":"10.1093","volume":"38","author":[{"given":"Marjorie","family":"Salga","sequence":"first","affiliation":[{"name":"UPOH (Unit\u00e9 P\u00e9ri Op\u00e9ratoire du Handicap), Physical and Rehabilitation Medicine Department Raymond-Poincar\u00e9 Hospital, Assistance Publique-H\u00f4pitaux de Paris (AP-HP) Garches France"},{"name":"University of Versailles Saint Quentin en Yvelines END:ICAP U1179 INSERM, UFR Simone Veil-Sant\u00e9 Montigny le Bretonneux France"},{"name":"Mater Research Institute\u2014The University of Queensland Translational Research Institute Woolloongabba Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selwin G","family":"Samuel","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology and Microbiology Saveetha Dental College and Hospitals Chennai India"},{"name":"Mater Research Institute\u2014The University of Queensland Translational Research Institute Woolloongabba Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsu-Wen","family":"Tseng","sequence":"additional","affiliation":[{"name":"Mater Research Institute\u2014The University of Queensland Translational Research Institute Woolloongabba Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Gatin","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Raymond Poincar\u00e9 Hospital, AP-HP Garches France"},{"name":"UPOH 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