Gut Microbiota Colonization in Early Life Influences Susceptibility to Adulthood Hepatic Lipid Accumulation in High‐Fat‐Diet‐Fed Mice

The global prevalence of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) has a rising trend. The Developmental Origins of Health and Disease (DOHaD) theory assumes that MAFLD develops throughout the entire lifecycle but it originates in early life. This study aimed to investigate the influence of early-life gut microbiota colonization on the susceptibility to adulthood hepatic lipid accumulation in high-fat-diet (HFD)-fed mice. The results showed that perinatal AM exposure exacerbated adulthood hepatic lipid accumulation and altered hepatic lipid profile in HFD-fed male but not female offspring. Perinatal AM exposure does not affect hepatic lipid metabolic genes in adult offspring. Instead, perinatal AM exposure inhibited intestinal bile acid (BA) metabolism to reduce secondary BAs production, thereby promoting dietary lipid absorption. Mechanistically, perinatal AM exposure permanently reduces species diversity of the microbial community and impairs its structure and function by disrupting early-life gut microbiota colonization. Supplementing Lactobacillus during lactation improved gut microbiota colonization and intestinal BA metabolism, thereby alleviating HFD-induced hepatic lipid deposition. These results suggest that disruption of early-life gut microbiota colonization elevates susceptibility to adulthood hepatic lipid accumulation by promoting intestinal lipid absorption in HFD-fed mice. Supplementing probiotics during lactation may be an effective strategy for preventing susceptibility to adulthood MAFLD.