{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T05:27:48Z","timestamp":1792819668293,"version":"4.5.0"},"posted":{"date-parts":[[2026,4,6]]},"group-title":"Immunology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH NHLBI","award":["1R01HL146753"],"award-info":[{"award-number":["1R01HL146753"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Lung ischemia\u2013reperfusion (IR) injury drives early morbidity after lung transplantation and cardiothoracic surgery, yet targeted preventive therapies are lacking. The gut\u2013lung axis and microbiota-derived tryptophan metabolites, including indole-3-propionate (IPA), may regulate pulmonary immunity and inflammation. We investigated whether a tryptophan-rich (Trp-Rich) diet attenuates sterile lung IR injury by increasing microbiota-derived indole metabolites and reprogramming alveolar macrophage (AM) inflammatory responses.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    C57BL\/6 mice received isocaloric tryptophan-standard (Trp-Std; 0.18%) or Trp-Rich (0.60%) diets for 14 days, then underwent unilateral left lung IR (60 min ischemia followed by 60 min reperfusion). Oxygen saturation, lung cytokines, and aryl hydrocarbon receptor (AhR) signaling readouts (\n                    <jats:italic>Cyp1a1<\/jats:italic>\n                    \/\n                    <jats:italic>Cyp1b1<\/jats:italic>\n                    ) were evaluated. Gut microbiota was profiled by 16S rRNA sequencing, and targeted metabolomics quantified tryptophan metabolites in feces, portal vein (PV) plasma, and lung tissue. To further assess inflammatory priming\n                    <jats:italic>in vivo<\/jats:italic>\n                    , mice were additionally challenged with intratracheal lipopolysaccharide (LPS). Mechanistic studies compared IPA with related indole metabolites in MH-S cells and primary human AMs, including\n                    <jats:italic>ex vivo<\/jats:italic>\n                    nutritional IR, LPS stimulation, and AhR stimulation and blockade using synthetic agonists and antagonists.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Trp-Rich feeding improved post-IR oxygenation, reduced lung IL-1\u03b2, and increased pulmonary\n                    <jats:italic>Cyp1a1<\/jats:italic>\n                    \/\n                    <jats:italic>Cyp1b1<\/jats:italic>\n                    gene expression. Trp-Rich diet remodeled the gut microbiota, including enrichment of\n                    <jats:italic>Bifidobacterium<\/jats:italic>\n                    and\n                    <jats:italic>Lactobacillus<\/jats:italic>\n                    , and increased IPA levels across feces, PV plasma, and lung tissue, with lower kynurenine\/IPA ratios across matrices. In the LPS intratracheal challenge, Trp-Rich feeding reduced IL-6 levels in lung tissue and systemic plasma. Primary murine AMs isolated from Trp-Rich mice also showed reduced IL-1\u03b2 and IL-6 release in an ex vivo nutritional IR model. Among tested indole metabolites, IPA showed the strongest dose-dependent suppression of LPS-induced cytokines and chemokines in MH-S cells and primary human AMs, remained active in the ex vivo nutritional IR model, and its anti-inflammatory effect was abrogated by AhR blockade and enhanced by co-treatment with other indole metabolites.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A Trp-Rich diet attenuated sterile lung IR injury, coinciding with gut microbiota remodeling, increased systemic and pulmonary IPA, reduced inflammatory priming, and reprogrammed AM responses. These data support diet- or microbiome-directed strategies targeting IPA\u2013AhR signaling to mitigate perioperative lung IR injury.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Caption for graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:caption>\n                      <jats:p>A tryptophan-rich diet remodels the gut microbiota and indole metabolite profiles, including IPA, enhances alveolar macrophage AhR signaling, and attenuates sterile lung ischemia-reperfusion injury.<\/jats:p>\n                    <\/jats:caption>\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"714281v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.02.714281","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T21:35:14Z","timestamp":1775511314000},"source":"Crossref","is-referenced-by-count":2,"title":["Dietary tryptophan mitigates lung ischemia-reperfusion injury via microbiota-derived indole-3-propionate and aryl hydrocarbon receptor signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-3977","authenticated-orcid":false,"given":"Tomohiro","family":"Chaki","sequence":"first","affiliation":[{"name":"Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA"},{"name":"Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5285-9309","authenticated-orcid":false,"given":"Daisuke","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9364-7580","authenticated-orcid":false,"given":"Thien NM","family":"Doan","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0971-9161","authenticated-orcid":false,"given":"Tian","family":"Xiaoli","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1424-0932","authenticated-orcid":false,"given":"Arun","family":"Prakash","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA"},{"name":"Department of Anesthesia and Perioperative Care, San Francisco General Hospital, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"2","key":"2026040805400760000_2026.04.02.714281v1.1","doi-asserted-by":"crossref","first-page":"e652","DOI":"10.1097\/TXD.0000000000001104","article-title":"Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review","volume":"7","year":"2021","journal-title":"Transplant Direct"},{"issue":"10","key":"2026040805400760000_2026.04.02.714281v1.2","doi-asserted-by":"crossref","first-page":"3000605251383318","DOI":"10.1177\/03000605251383318","article-title":"Cardiopulmonary bypass-mediated lung ischemia-reperfusion injury: A protective role of sitaxentan","volume":"53","year":"2025","journal-title":"J Int Med Res"},{"issue":"3","key":"2026040805400760000_2026.04.02.714281v1.3","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/MOT.0000000000000304","article-title":"Mechanisms of lung ischemia-reperfusion injury","volume":"21","year":"2016","journal-title":"Curr Opin Organ Transplant"},{"issue":"1","key":"2026040805400760000_2026.04.02.714281v1.4","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12931-024-02776-4","article-title":"The endothelium: gatekeeper to lung ischemia-reperfusion injury","volume":"25","year":"2024","journal-title":"Respir Res"},{"issue":"A","key":"2026040805400760000_2026.04.02.714281v1.5","first-page":"113051","article-title":"Neutrophil PPIF exacerbates lung ischemia-reperfusion injury after lung transplantation by promoting calcium overload-induced neutrophil extracellular traps formation","volume":"142","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"2026040805400760000_2026.04.02.714281v1.6","doi-asserted-by":"crossref","unstructured":"Nakagiri T , K\u00f6hler NR , Janciauskiene S , Neubert L , Kn\u00f6fel AK , Pradhan P , Ruhparwar A , Ius F , Immenschuh S . 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