Gut Microbiota Drives Aging-related Erythropoiesis Impairment via Phenylacetic Acid-induced Histone Phenylacetylation.

Yifei Xie, Xiangrui Qiao, Hao Wu, Yiming Hua, Bolin Li, Ning Ding, Jinglong Pang, Mingmin Zhang, Wen Xi, Kai Deng, Yu Xu, Peining Liu, Xue Shi, Lele Cheng, Xiaozhen Zhuo, Ting Li, Zuyi Yuan, Yue Wu

Key Laboratory of Molecular Cardiology, Shaanxi Province, Xi'an, China.Key Laboratory of Molecular Cardiology, Shaanxi Province, Xi'an, China. · pubmed

Paper

Abstract

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 oxoacid:ferredoxin oxidoreductase (OFOR) 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 post-translational modification (PTMs) termed histone lysine phenylacetylation (Kpa) through the acetyltransferases 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 (NaPA) 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 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.

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Research summary

The study identifies gut microbiota-derived phenylacetic acid as a mechanistic driver of aging-related erythropoiesis impairment via histone phenylacetylation, offering a potential therapeutic target for age-associated anemia. This work is relevant because it elucidates a specific molecular pathway linking microbial metabolism to epigenetic dysregulation in hematopoietic stem cells, a fundamental process in aging, although the direct impact on overall lifespan extension remains unproven and the condition (anemia) is often viewed as a symptom rather than a root cause of aging itself.

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