Dyslipidemia, a driver of atherosclerosis and fatty liver disease, burdens society and is associated with gut microbiota responses to dietary patterns. This study aimed to identify key intestinal metabolites involved in regulating lipid metabolism in dyslipidemia and to explore the underlying mechanisms. We performed a metabolome analysis of a humanized dyslipidemia mouse model. Then we screened out hyodeoxycholic acid (HDCA) and cholesterol sulfate (CSS) that potentially interact with farnesoid X receptor (FXR) based on molecular docking and cell culture. Oral administration demonstrated that the HDCA and CSS may ameliorate dyslipidemia via regulating bile acid metabolism, potentially mediated by activation of hepatic or intestinal FXR. Additionally, HDCA promoted the proliferation of g_Roseburia and g_norank_Muribaculaceae, and CSS enhanced the multiplication of g_Alloprevotella. These findings underscored that the intestinal steroid metabolites HDCA and CSS may be promising functional substances for regulating lipid metabolism.

The Bama diet (BD), Mediterranean diet (MD), and Japanese diet (JD) are three typical dietary patterns from distinct geographical regions. The aim of this study was to compare the efficacy of three diets in preventing colitis through gut microbe-metabolite-mediated regulatory mechanisms. This was achieved by integrating gut microbiome and metabolomics analyses. Results showed that BD could significantly increase the level of interleukin 10 (IL-10), which has the potential to modulate the intestinal immune response. This was achieved by modulating the α-linoleic acid metabolism and promoting Akkermansia proliferation. MD elevated IL-10 level and increased the expression of tight junction proteins such as occludin, claudin-1, and zonula occludens-1. This effect might be attributed to the increased abundance of bifidobacteria, which impacted the primary bile acid biosynthesis pathway. JD decreased tumor necrosis factor α level and increased IL-10 level. This could be due to JD promoting the enrichment of Faecalibacterium, which affected the metabolism of arachidonic acid. Furthermore, the anti-inflammatory effects of the different metabolites, namely α-linoleic acid, cholic acid, and arachidonic acid, were confirmed using the RAW264.7 cellular inflammation model.