Abstract
Background: The intricate interplay between host genes and intrahepatic microbes is vital in shaping the hepatic microenvironment and contributes significantly to our understanding of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms of disease progression mediated by these interactions remain largely elusive.
Methods: We conducted a comprehensive analysis of 570 liver biopsy transcriptomes from five cohorts, including 72 control, 124 nonalcoholic fatty liver (NAFL), 143 borderline and 231 nonalcoholic steatohepatitis (NASH) samples. Least Absolute Shrinkage and Selection Operator penalized regression and Sparse Canonical Correlation Analysis were utilized to identify host-microbiota interactions and their function.
Results: We observed significant upregulations of key genes involved in mitochondrial organization across all disease stages, while genes related to antigen processing showed abnormal activations in advanced stages like NASH. Additionally, the abundances of intrahepatic microbes Methyloversatilis sp. RAC08 and Ralstonia insidiosadecreased significantly across all NAFLD stages. We identified 5537, 1937, 1485, and 2933 host-microbiota interactions in control, NAFL, borderline, and NASH samples, respectively. Notably, interaction strength showed a decreasing trend, especially during the transition from the borderline stage to NASH. In NAFL and borderline stages, bacteria like Bacillales, Ralstonia insidiosa, and Micromonosporaceae played pivotal roles in enhancing host mitophagy by interacting with genes including SQSTM1, OPTN, and BNIP3L. However, such interaction functional clusters were absent in NASH samples.
Conclusion: Disturbed host-microbiota interactions affecting the mitophagy process can lead to a pro-inflammatory hepatic microenvironment through activation of immune reactions, potentially driving disease progression to NASH.