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Multi-kingdom profiling reveals altered gut phage-bacteria-metabolite interactions in MASLD

Xiaofeng Zhou1,2, Da Zhou3,4, Yanni Pu1,2

  • 1Ministry of Education Key Laboratory of Contemporary Anthropology, Human Phenome Institute, Fudan University, Shanghai, China.

Nature Communications
|April 18, 2026
PubMed

Insights

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves gut microbes, viruses, and fungi. This study reveals a disrupted phage-bacteria-metabolite axis in MASLD, offering new diagnostic and therapeutic targets.

Area of Science:

  • Microbiology
  • Gastroenterology
  • Systems Biology

Background:

  • Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to gut dysbiosis.
  • Previous research primarily focused on bacterial communities, neglecting viral and fungal roles and their interactions.

Purpose of the Study:

  • To investigate the coordinated disruption of bacterial, viral, and fungal communities in MASLD.
  • To explore the phage-bacteria-metabolite axis and its association with bile acid changes in MASLD.
  • To identify potential non-invasive biomarkers and therapeutic targets for MASLD.

Main Methods:

  • Integrated shotgun metagenomics, fungal ITS2 sequencing, fecal metabolomics, and clinical profiling in 210 MASLD patients and 210 controls.
  • Analyzed cross-kingdom ecological networks and phage-host interactions.
  • Developed a diagnostic classifier using bacterial, viral, and clinical features.

Main Results:

  • MASLD exhibits reduced microbial diversity and remodeled cross-kingdom ecological networks.
  • Ruminococcus gnavus was enriched, while Faecalibacterium prausnitzii and its bacteriophages were depleted.
  • A disrupted phage-bacteria-metabolite axis, altered bile acids (e.g., isodeoxycholic acid), and impaired F. prausnitzii fitness were observed.
  • A diagnostic classifier achieved high accuracy in distinguishing MASLD patients.

Conclusions:

  • MASLD is characterized by a coordinated, multi-kingdom microbial disruption and a disturbed phage-bacteria-metabolite axis.
  • Findings suggest diminished phage control contributes to R. gnavus expansion and disease progression.
  • The study provides a multi-kingdom framework for MASLD biomarker discovery and microbiome-targeted therapies.

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