Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome

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 mothers developed steatosis (9.43 vs 3.09%, p=0.0023), fibrosis (3.75 vs 2.70%, p=0.039), an increased number of inflammatory infiltrates (4.8 vs 1.0, p=0.018) and a higher expression of genes involved in fibrosis and inflammation compared to ND offspring. A higher proportion of female 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). Offspring of HFD mothers 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 the susceptibility to develop HCC in female offspring. The transmission of an altered gut microbiome plays an important role in this increased predisposition.