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Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis.\u00a0Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b\/CXCL1\/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized\u00a0the duration and intensity of mucosal barrier injury and\u00a0accompanying\u00a0clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in\u00a0stem cell\u00a0transplant\u00a0patients with multiple myeloma\u00a0after\u00a0HDM.\u00a0Ramping-up\u00a0anakinra (100\u2013300\u00a0mg administered intravenously for 15\u00a0days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic\u00a0clinical\u00a0consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).<\/jats:p><jats:p><jats:bold>Trial registration<\/jats:bold>: ClinicalTrials.gov identifier: NCT03233776.<\/jats:p>","DOI":"10.1038\/s41598-022-10700-3","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T10:09:32Z","timestamp":1652263772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra"],"prefix":"10.1038","volume":"12","author":[{"given":"H. R.","family":"Wardill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. E. 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