Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome
Beat Moeckli,
Vaihere Delaune,
Benoît Gilbert,
Andrea Peloso,
Graziano Oldani,
Sofia El Hajji,
Florence Slits,
Joana Rodrigues Ribeiro,
Ruben Mercier,
Adrien Gleyzolle,
Laura Rubbia-Brandt,
Quentin Gex,
Stephanie Lacotte,
Christian Toso
Affiliations
Beat Moeckli
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; Department of Surgery, Division of Visceral Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland; Corresponding authors. Addresses: Division of Digestive Surgery, Department of Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; Tel.: +41 22 379 56 61. (C. Toso) or Transplantation & Hepatology Lab, Department of Surgery, University of Geneva, Rue Michel-Servet 1, 1205 Geneva, Switzerland; +41 22 379 56 54. (B. Moeckli).
Vaihere Delaune
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; Department of Surgery, Division of Visceral Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
Benoît Gilbert
Department of Medicine, Division of Rheumatology, Geneva University Hospitals, 1206 Geneva, Switzerland; Geneva Centre for Inflammation Research (GCIR), Faculty of Medicine, University of Geneva, Geneva, Switzerland
Andrea Peloso
Department of Surgery, Division of Visceral Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
Graziano Oldani
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; Department of Surgery, Division of General Surgery, The University of British Columbia, Vancouver, Canada
Sofia El Hajji
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; Department of Surgery, Division of Visceral Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
Florence Slits
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
Joana Rodrigues Ribeiro
Department of Surgery, Division of Visceral Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland
Ruben Mercier
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
Adrien Gleyzolle
Department of Diagnostics, Division of Radiology, Geneva University Hospitals, 1205 Geneva, Switzerland
Laura Rubbia-Brandt
Department of Diagnostics Division of Clinical Pathology, Geneva University Hospitals, 1205 Geneva, Switzerland
Quentin Gex
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
Stephanie Lacotte
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
Christian Toso
Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; Department of Surgery, Division of Visceral Surgery, Geneva University Hospitals, 1205 Geneva, Switzerland; Corresponding authors. Addresses: Division of Digestive Surgery, Department of Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; Tel.: +41 22 379 56 61. (C. Toso) or Transplantation & Hepatology Lab, Department of Surgery, University of Geneva, Rue Michel-Servet 1, 1205 Geneva, Switzerland; +41 22 379 56 54. (B. Moeckli).
Background & Aims: Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms. Methods: Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model. Results: Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 μm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load. Conclusions: Maternal obesity increases female offspring’s susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition. Impact and implications: The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.
