{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T08:56:28Z","timestamp":1792745788621,"version":"4.5.0"},"reference-count":98,"publisher":"American Society of Hematology","issue":"17","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,22]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Anemia, the most prevalent hematologic disorder in older adults, imposes a significant burden of cardiovascular events, cognitive decline, and mortality. However, the mechanisms underlying aging-related anemia, especially epigenetic dysregulation in hematopoietic stem and progenitor cells (HSPCs), remain incompletely understood. Although the gut microbiota is critical for hematopoiesis, its specific contribution to aging-related erythropoiesis impairment remains unclear. Here, we reveal that aging markedly activates phenylalanine metabolism and elevates plasma phenylacetic acid (PAA) levels in both humans and mice. We identify Odoribacter splanchnicus as a key gut symbiont whose abundance is significantly increased in aged mice and which directly drives PAA production from phenylalanine via the 2-oxoacid:ferredoxin oxidoreductase superfamily encoded by porA, nifJ, and iorA\/iorB. Rifaximin treatment selectively reduces Osplanchnicus and plasma PAA, thereby alleviating aging-related anemia. Mechanistically, PAA promotes a novel posttranslational modification termed histone lysine phenylacetylation (Kpa) through the acetyltransferase histone acetyltransferase binding to origin recognition complex 1 (HBO1). Elevated histone Kpa increases chromatin accessibility at the GATA2 promoter, disrupts the GATA switch, and blocks erythroid differentiation of HSPCs. In vivo, supplementation with sodium phenylacetate exacerbates anemia in microbiota-depleted mice, whereas the HBO1 inhibitor WM-3835 restores erythropoiesis by reversing histone Kpa and normalizing the GATA switch. Furthermore, dietary phenylalanine restriction lowers circulating PAA and effectively ameliorates aging-related anemia in both naturally aged mice and Osplanchnicus\u2013colonized mice. These findings provide, to our knowledge, the first evidence that gut microbiota\u2013derived PAA plays a critical role in the development of aging-related erythropoiesis impairment and offer multiple translatable strategies for treating this condition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2026033155","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T17:33:33Z","timestamp":1783704813000},"page":"2176-2194","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["The gut microbiota drives aging-related erythropoiesis impairment via phenylacetic acid\u2013induced histone phenylacetylation"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3601-3861","authenticated-orcid":false,"given":"Yifei","family":"Xie","sequence":"first","affiliation":[{"name":"1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"2Key Laboratory of Molecular Cardiology, Xi\u2019an, China"},{"name":"3Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangrui","family":"Qiao","sequence":"additional","affiliation":[{"name":"1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"2Key Laboratory of Molecular Cardiology, Xi\u2019an, China"},{"name":"3Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-6325","authenticated-orcid":false,"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"2Key Laboratory of Molecular Cardiology, Xi\u2019an, China"},{"name":"3Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Hua","sequence":"additional","affiliation":[{"name":"1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"2Key Laboratory of Molecular Cardiology, Xi\u2019an, China"},{"name":"3Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolin","family":"Li","sequence":"additional","affiliation":[{"name":"4Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 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