TY - JOUR
T1 - The gut microbiota drives aging-related erythropoiesis impairment via phenylacetic acid–induced histone phenylacetylation
AU - Xie, Yifei
AU - Qiao, Xiangrui
AU - Wu, Hao
AU - Hua, Yiming
AU - Li, Bolin
AU - Ding, Ning
AU - Pang, Jinglong
AU - Zhang, Mingmin
AU - Xi, Wen
AU - Deng, Kai
AU - Xu, Yu
AU - Liu, Peining
AU - Shi, Xue
AU - Cheng, Lele
AU - Zhuo, Xiaozhen
AU - Li, Ting
AU - Yuan, Zuyi
AU - Wu, Yue
N1 - Publisher Copyright:
© 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/
PY - 2026
Y1 - 2026
N2 - 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 (O 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 O splanchnicus 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 O splanchnicus–colonized mice. These findings provide, to our knowledge, the first evidence that gut microbiota–derived PAA plays a critical role in the development of aging-related erythropoiesis impairment and offer multiple translatable strategies for treating this condition.
AB - 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 (O 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 O splanchnicus 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 O splanchnicus–colonized mice. These findings provide, to our knowledge, the first evidence that gut microbiota–derived PAA plays a critical role in the development of aging-related erythropoiesis impairment and offer multiple translatable strategies for treating this condition.
UR - https://www.scopus.com/pages/publications/105050428990
U2 - 10.1182/blood.2026033155
DO - 10.1182/blood.2026033155
M3 - 文章
C2 - 42430365
AN - SCOPUS:105050428990
SN - 0006-4971
JO - Blood
JF - Blood
ER -