Gut microbes mediate the synergistic effects of dietary cholesterol and saturated fat in driving fibrosing MASH.
Both dietary cholesterol and saturated fat are necessary for the development of fibrosing MASH in specific pathogen-free mice, highlighting the role of diet in liver health.
Where it sits
this study against the rest of the pnc-27 corpusSummary and findings
This study investigates the effects of dietary cholesterol and saturated fat on the development of fibrosing metabolic dysfunction-associated steatotic liver disease (MASH) using specific pathogen-free (SPF) and germ-free (GF) mice. The findings suggest that both dietary components are necessary for inducing MASH in SPF mice, while GF mice show protection. The study also identifies changes in gut microbial composition associated with these dietary factors.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population and can progress to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, increasing the risk of cirrhosis, hepatocellular carcinoma, and mortality. Gut microbes driven by diets high in saturated fat, simple sugar, and cholesterol contribute to disease progression, yet the underlying mechanisms remain undefined. We explored the independent and synergistic effects of dietary saturated fat and cholesterol on MASH development using specific pathogen-free (SPF) and germ-free (GF) mice. We demonstrate that (1) both dietary cholesterol and saturated fat are required to induce fibrosing MASH in SPF mice, whereas GF mice are protected, (2) saturated fat and cholesterol individually alter gut microbial membership, potentially via altered bile acid metabolism, while their combination promotes a distinct composition, including an increase in <i>Parasutterella</i> spp. which correlates with hepatic fibrosis, and (3) diluted cecal contents from SPF, but not GF, mice fed high-fat, high-cholesterol diets are enriched in deoxycholic acid and activate human hepatic stellate cells <i>in vitro</i>, suggesting a mechanistic link between dietary lipid-induced microbiota and liver fibrogenesis. These findings reveal how specific Western dietary components shape the gut microbiota and contribute to hepatic fibrosis via stellate cell activation, offering potential targets for therapeutic interventions against MASLD/MASH.
Background
The study addresses the relationship between dietary components, specifically cholesterol and saturated fat, and their effects on fibrosing MASH, a condition characterized by liver fibrosis. Prior research has indicated that diet can influence gut microbiota, which may in turn affect liver health. Understanding this relationship is crucial for developing dietary recommendations or interventions.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Key findings
- Not reported in abstract.
Limitations
- Not reported in abstract.