The influence of perilipin 5 deficiency on gut microbiome profiles in murine metabolic dysfunction-associated fatty liver disease (MAFLD) and MAFLD-hepatocellular carcinoma

Front Cell Infect Microbiol. 2024 Oct 14:14:1443654. doi: 10.3389/fcimb.2024.1443654. eCollection 2024.

Abstract

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as the leading cause of hepatocellular carcinoma (HCC) worldwide. Over the years, Perilipin 5 (PLIN5) has been recognized as a key regulator of both MAFLD and HCC development. In our previous studies we demonstrated that deficiency in Plin5 reduces the severity of MAFLD and HCC in mice. Interestingly, it has been established that patients with MAFLD and HCC exhibit various changes in their gut microbiome profiles. The gut microbiome itself has been shown to play a role in modulating carcinogenesis and the immune response against cancer.

Methods: Therefore, we conducted a study to investigate the alterations in fecal microbiome composition in wild type (WT) and Plin5-deficient (Plin5 -/-) mice models of MAFLD and MAFLD-induced HCC (MAFLD-HCC). We utilized 16S rRNA gene sequencing analysis to profile the composition of gut bacteria in fecal samples.

Results: Notably, we discovered that the absence of Plin5 alone is already associated with changes in gut microbiota composition. Moreover, feeding the mice a Western diet (WD) resulted in additional microbial alterations. Interestingly, Plin5 -/- animals exhibited an enrichment of the beneficial taxa Lactobacillus in both animal models.

Discussion: Our findings identify Plin5 as a major regulator of gut microbiota during the development of MAFLD and MAFLD-HCC.

Keywords: animal models; fatty liver disease; hepatocellular carcinoma; metabolic dysfunction; metabolic syndrome; microbial diversity; microbiome.

MeSH terms

  • Animals
  • Bacteria / classification
  • Bacteria / genetics
  • Bacteria / isolation & purification
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / microbiology
  • Disease Models, Animal*
  • Fatty Liver / metabolism
  • Fatty Liver / microbiology
  • Feces* / microbiology
  • Gastrointestinal Microbiome*
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / microbiology
  • Liver Neoplasms* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Perilipin-5* / metabolism
  • RNA, Ribosomal, 16S / genetics

Substances

  • Perilipin-5
  • RNA, Ribosomal, 16S

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. AA received funding from the Wilhelm Sander Stiftung (project 2020.002.1) and the START program (project 102/20). RW is supported by grants from the German Research Foundation (projects WE2554/13-1, WE2554/15-1, and WE2554/17-1), the Deutsche Krebshilfe (grant 70115581), and the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (grant PTD 1-5). PŠ and RK were funded by grants from the Croatian National Science Foundation Project PREDI-COO (Project number: IP-2019-04-9308). The funders had no role in the design of this article or in the decision to publish it.