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These treatments have long been known to lack antigen specificity. Despite empirically selected long-term immunosuppression regimens, most allografts succumb to alloimmune responses that result in chronic inflammation and scarring. Additionally, immunosuppressive medications themselves contribute to unintended intestinal dysbiosis and metabolic disorders. This review focuses on the effect of immunosuppressant treatments on alloimmunity, gut microbiome, and metabolism, with a particular emphasis on the effects on metabolic disorders. We also outline the shared and unique microbial and metabolic signatures produced by each immunosuppressant class, underlining their distinct impacts on immunity and metabolic homeostasis. These observations underscore the need for a holistic understanding of these drugs\u2019 on- and off-target effects to refine therapeutic strategies, enhance immunosuppression efficacy, and ultimately enhance graft and patient survival. By characterizing these complex interactions, strategies informed by the gut microbiome and host metabolism may offer a promising adjunctive approach to optimizing immunosuppressive regimens and promoting sustained graft acceptance.<\/jats:p>","DOI":"10.1128\/cmr.00178-24","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T09:00:36Z","timestamp":1741165236000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Immunosuppressant imprecision: multidirectional effects on metabolism and microbiome"],"prefix":"10.1128","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-8917","authenticated-orcid":false,"given":"Allison","family":"Kensiski","sequence":"first","affiliation":[{"name":"Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Gavzy","sequence":"additional","affiliation":[{"name":"Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine","place":["Baltimore, USA"]},{"name":"Department of Surgery, University of Maryland School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Mas","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Maryland School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3488-2393","authenticated-orcid":true,"given":"Bing","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute for Genome Sciences, University of Maryland School of Medicine","place":["Baltimore, USA"]},{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-8795","authenticated-orcid":false,"given":"Jonathan S.","family":"Bromberg","sequence":"additional","affiliation":[{"name":"Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine","place":["Baltimore, USA"]},{"name":"Department of Surgery, University of Maryland School of Medicine","place":["Baltimore, USA"]},{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2023.02.003"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.14208"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009101043"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1159\/000209208"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v26.i38.5797"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1053\/jlts.2001.27475"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa030"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12604"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1390055"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199512000-00007"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.18.1.309"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1053\/tr.2000.5377"},{"key":"e_1_3_1_14_2","first-page":"15","article-title":"mTOR inhibitors at a glance","volume":"7","author":"Zheng Y","year":"2015","unstructured":"Zheng Y, Jiang Y. 2015. mTOR inhibitors at a glance. 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