The Association Between Prevotella copri and Advanced Fibrosis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

<b>Background/Objectives</b>: Metabolic dysfunction-associated steatotic liver disease (MASLD), driven by obesity and metabolic syndrome, is increasingly prevalent and a significant contributor to liver fibrosis, cirrhosis, and liver-related mortality. Emerging research implicates the gut microbiome as a critical player in MASLD progression, yet specific microbial drivers remain poorly understood. Here, we explore the role of <i>Prevotella copri</i> (<i>P. copri</i>) in MASLD progression through both human patient cohorts and a mouse model of diet-induced obesity. <b>Methods/Results</b>: Using 16S rRNA sequencing, we identified elevated <i>P. copri</i> abundance in MASLD patients with advanced fibrosis, linked with significant shifts in microbial diversity and bacterial network connectivity. To investigate causality, experimental colonization of <i>P. copri</i> in mice on a high-fat diet worsened MASLD progression, with <i>P. copri</i>-colonized mice showing significant increases in hepatic steatosis, liver triglyceride accumulation, and body weight, independent of caloric intake. At the molecular level, <i>P. copri</i> colonization downregulated key lipid metabolism genes, such as carnitine palmitoyltransferase 1 and adipose triglyceride lipase, and impaired tight intestinal junction integrity through the downregulation of occludin. Collectively, our findings position <i>P. copri</i> as a possible driver of MASLD progression by promoting hepatic steatosis through lipid and triglyceride accumulation and fibrosis through decreased tight junction integrity. These insights suggest a promising therapeutic avenue to target specific microbial signatures like <i>P. copri</i> to curb MASLD progression and mitigate the associated risk of advanced fibrosis.