Gut microbiota and bile acids changes in MASLD mice model with hepatic <italic>PLD1</italic> knockout

Hepatocyte phospholipase D1 ( <i>PLD1</i>) knockout alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) in mice, but the underlying mechanism is largely unknown. In this study, the mice were divided into four groups: Con (wild-type mice with normal control diet), HFHC (wild-type mice with high-fat diet), Con_KO (hepatocyte <i>PLD1</i>-knockout mice with normal control diet), and HFHC_KO (hepatocyte <i>PLD1</i>-knockout mice with high-fat diet). Intestinal contents of mice are analyzed via metagenomics and metabolomics, and the liver bile acids are assessed by mass spectrometry imaging. The results show that at the phylum level the abundance of Bacillota in the intestines of MASLD model mice is significantly increased, whereas that of Bacteroidota significantly is decreased. However, after the deletion of hepatocyte <i>PLD1</i>, Pseudomonadota and Candidatus Bathyarchaeota are significantly decreased in the MASLD model mice. At the species level, compared with that in the Con group, the abundance of <i>Faecalibaculum rodentium</i> is significantly increased in the HFHC group, whereas hepatocyte <i>PLD1</i> knockout causes the abundances of <i>Desulfovibrionaceae bacterium</i> LT0009 and <i>Lachnospiraceae bacterium</i> 10-1 to be significantly decreased. In terms of intestinal bile acids, the levels of two bile acids (hyodeoxycholic acid and glycolithocholic acid) differ between the HFHC_KO group and the HFHC group. Association analysis shows that <i>Faecalibaculum</i> co-occurs with DCA, βMCA, ΩMCA and αMCA, while probiotic <i>Bacteroides uniformis</i> is significantly correlated with UDCA, 12-KetoLCA, and 7-KetoLCA. Finally, mass spectrometry imaging reveals that the TCA and TDCA contents in the liver are significantly decreased after <i>PLD1</i> knockout in hepatocytes. These findings demonstrate that hepatocyte <i>PLD1</i> knockout alters the gut microbiota and bile acids profiles, suggesting that PLD1 deficiency may modulate MASLD progression by changing intestinal microbiota-bile acid homeostasis.