# Fecal microbiota transplantation ameliorates radiation-induced lung injury by reshaping gut metabolic homeostasis to activate FAM134B-mediated ER-phagy

## TL;DR

Fecal microbiota transplantation (FMT) helps reduce lung damage from radiation by improving gut health and activating a cellular cleanup process in the lungs.

## Contribution

This study reveals a novel mechanism by which FMT protects against radiation-induced lung injury through metabolic remodeling and activation of PPARγ-FAM134B-mediated ER-phagy.

## Key findings

- FMT alleviates lung injury by restoring gut microbiota and metabolic homeostasis.
- FMT activates FAM134B-mediated ER-phagy via PPARγ, reducing radiation-induced lung damage.
- Arachidonic acid metabolism is a key component of FMT's protective effects.

## Abstract

Radiation-induced lung injury (RILI) is a serious complication of thoracic radiotherapy, with limited effective treatment options. This study demonstrates that fecal microbiota transplantation (FMT) confers protection against RILI through modulation of the gut-lung axis. In a total lung irradiation (TLI) mouse model, FMT significantly alleviated pulmonary histopathological injury, inflammatory responses, oxidative stress, and collagen deposition during fibrogenesis. Concurrently, FMT improved intestinal motility, enhanced mucosal barrier integrity, and restored TLI-induced dysbiosis in gut microbiota diversity and community structure. Metabolomic analysis revealed that TLI significantly disrupted the metabolism of unsaturated fatty acids and arachidonic acid (AA), whereas FMT partially restored these metabolic networks. Transcriptomic and ultrastructural analyses indicated that RILI suppressed endoplasmic reticulum (ER) protein processing and induced ER swelling, while FMT promoted protective ER-phagy and facilitated restoration of ER morphology. Integrated multi-omics analysis further identified the AA metabolism as a key component of FMT-mediated protection, with its alterations closely associated with pulmonary tissue repair. Further in vivo and in vitro experiments demonstrated that AA binds to and activates the nuclear receptor PPARγ, leading to transcriptional upregulation of FAM134B, promoting protective ER-phagy and ameliorating RILI. In summary, this study highlights the bidirectional gut-lung axis as a therapeutic target in RILI progression and intervention, and reveals that FMT confers protection through metabolic remodeling and activation of the PPARγ-FAM134B-mediated ER-phagy pathway, providing a mechanistic basis for potential clinical translation.

RILI is a severe complication of thoracic radiotherapy, yet effective therapies remain limited. We comprehensively delineate the pathogenesis and therapeutic interventions of RILI via the gut-lung axis, emphasizing bidirectional regulation. Thoracic irradiation can compromise intestinal motility and disrupt mucosal barrier integrity via the abscopal effect, whereas FMT restores barrier function and microbial homeostasis, reshapes gut ecology, and enhances pulmonary repair. We define FMT as a systemic intervention that resets metabolic homeostasis and promotes ER adaptation from organismal to organelle levels. Mechanistically, gut‑derived lipid metabiolism, with AA as a key component, activate PPARγ and transcriptionally upregulate FAM134B, thereby enhancing selective ER‑phagy and mitigating RILI. Overall, this study reveals that RILI is not confined to localized pulmonary injury but involves a cross-organ imbalance encompassing metabolic, immune, and organelle adaptive responses. We developed an intervention strategy aimed at restoring gut-lung axis homeostasis to reprogram transcriptional mechanisms governing ER quality control, thereby promoting organ repair and functional reconstruction.