Abstract The integrated stress response (ISR) plays a pivotal role in the cellular stress response, primarily through global translational arrest and the upregulation of cellular adaptation-linked molecules. Growth differentiation factor 15 (Gdf15) is a potent stress-responsive biomarker of clinical inflammatory and metabolic distress in various types of diseases. Herein, we assess whether ISR-driven cellular stress contributes to pathophysiological outcomes by modulating Gdf15. Clinical transcriptome analysis demonstrates that PKR is positively associated with Gdf15 expression in patients with renal injury. Gdf15 expression is dependent on protein kinase R (PKR)-linked ISR during acute renointestinal distress in mice and genetic ablation of Gdf15 aggravates chemical-induced lesions in renal tissues and the gut barrier. An in-depth evaluation of the gut microbiota indicates that Gdf15 is associated with the abundance of mucin metabolism-linked bacteria and their enzymes. Moreover, stress-responsive Gdf15 facilitates mucin production and cellular survival via the reorganization of the autophagy regulatory network. Collectively, ISR-activated Gdf15 counteracts pathological processes via the protective reprogramming of the autophagic network and microbial community, thereby providing robust predictive biomarkers and interventions against renointestinal distress.

Navin Ray

Seung Jun Park

Hoyung Jung

Juil Kim

Tamas Korcsmaros

Yuseok Moon

Communications Biology

COMMUNICATIONS BIOLOGY 是 NATURE RESEARCH 的开放获取期刊，出版生物科学所有领域的高质量研究、评论和评论。该杂志发表的研究论文代表了重大进展，为专业研究领域带来了新的生物学见解。

Communications Biology is an open-access journal published by NATURE RESEARCH, covering all areas of biological sciences. It publishes high-quality research articles, reviews, and commentaries. The research papers published in this journal represent significant advancements and provide new insights into the field of biology.

《Communications Biology》是NATURE RESEARCH旗下的开放获取期刊，涵盖生物科学各个领域，发表高质量的研究论文、评论和综述。该期刊所刊登的研究成果代表了生物学领域的重要进展，为专业研究提供了新的见解。

Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming

Stress-responsive Growth Differentiation Factor 15 controls acute renointestinal distress by facilitating mucin production and cellular protection via reorganization of cell-protective autophagic signalling and muco-regulatory microbiota in mice.

Category	Quartile
生物学	1
生物学, 生物学	1

Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming

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