Gut microbiota and bile acids changes in MASLD mice model with hepatic PLD1 knockout

Abstract

Hepatocyte phospholipase D1 (PLD1) knockout alleviated metabolic dysfunction-associated steatotic liver disease (MASLD) in mice, but the underlying mechanism is largely unknown. In this study, high-fat diet is fed to wild type (Con) and hepatocyte PLD1 knockout (Con_KO) mice to establish MASLD model (HFHC and HFHC_KO). Intestinal contents of mice are analyzed via metagenomics and metabolomics, the liver bile acids are assessed by mass spectrometry imaging. At phylum level, Bacillota in the intestines of MASLD model mice are significantly increased and Bacteroidota are significantly decreased. However, after the deletion of hepatocyte PLD1, Pseudomonadota and Candidatus Bathyarchaeota are significantly decreased in the MASLD model mice. Then at species level, compared with Con group, the Faecalibaculum rodentium is significantly increased in HFHC group, in which hepatocyte PLD1 knockout causes Desulfovibrionaceae bacterium LT0009 and Lachnospiraceae bacterium 10-1 to significantly decrease. As for intestinal bile acids, two bile acids (Hyodeoxycholic acid and Glycolithocholic acid) are found to be different between the HFHC_KO group and the HFHC group. Association analysis shows the Faecalibaculum co-occurs with DCA, {beta}MCA, {Omega}MCA and MCA, while probiotic Bacteroides uniformis is significantly correlated with UDCA, 12-KetoLCA, 7-KetoLCA. Finally, mass spectrometry imaging reveals that TCA and TDCA in liver are significantly decreased after hepatocyte PLD1 knockout. These findings demonstrate that hepatocyte PLD1 knockout alters gut microbiota and bile acids profiles, suggesting PLD1 deficiency may modulate MASLD progression by changing intestinal microbiota-bile acid homeostasis. HighlightsHere, we show that hepatocyte PLD1 knockout alters gut microbiota and bile acid profiles in metabolic fatty liver disease mouse by high-fat diet. O_LIWild type (Con) and hepatocyte PLD1 knockout (Con_KO) mice were used to establish HFHC and HFHC_KO models, respectively. C_LIO_LIIntestinal contents were collected for metagenomic and metabolomics analysis, and liver tissues were taken for mass spectrometry imaging to investigate gut microbiota-bile acid relationships. C_LIO_LIIn HFHC_KO mice, Desulfovibrionaceae bacterium LT0009 and Lachnospiraceae bacterium 10-1 were significantly reduced, accompanied by altered HDCA and GLCA. C_LIO_LIAssociation analysis revealed Faecalibaculum co-occurred with DCA, {beta}MCA, {Omega}MCA, and MCA, while Bacteroides uniformis was significantly associated with UDCA, 12-KetoLCA, and 7-KetoLCA. C_LIO_LIMass spectrometry imaging showed hepatocyte PLD1 knockout significantly decreased liver TCA and TDCA, suggesting PLD1 deficiency may modulates MASLD progression via microbiota-bile acid homeostasis. C_LI O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/663496v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1b5bfa8org.highwire.dtl.DTLVardef@139ed05org.highwire.dtl.DTLVardef@1f7e905org.highwire.dtl.DTLVardef@e34b59_HPS_FORMAT_FIGEXP M_FIG C_FIG