The knowledge accumulated over the past two decades has revealed that the natural history of metabolic dysfunction-associated steatotic liver disease (MASLD) and the drivers of the disease severity are not only complex but also exhibit variation among patients. This intricate clinical scenario entails major therapeutic and management implications. In this review, we provide a comprehensive examination of recent advancements in our understanding of MASLD heterogeneity, drawing insights from multiomics and panomics studies. The discussion herein explores the instrumental role of panomics in MASLD research, elucidating the potential for the identification of molecular subtypes that exhibit divergent survival outcomes or heterogeneous responses to various treatments. Furthermore, we provide insights into the challenges in addressing disease heterogeneity and potential solutions. Finally, the most advanced technological advancements and prospective research directions in the domain of MASLD research are delineated, with the objective of facilitating the implementation of personalized diagnosis and interventions.
Background/Aims Evidence suggests that the gastrointestinal microbiome plays a significant role in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether disparities in the gut microbiome across intestinal tissular compartments between the sexes lead to MASLD pathogenesis.
Methods Sex-specific analyses of microbiome composition in two anatomically distinct regions of the gut, the small intestine and colon, were performed using an experimental model of MASLD. The study involved male and female spontaneously hypertensive rats and the Wistar-Kyoto control rat strain, which were fed either a standard chow diet or a high-fat diet for 12 weeks to induce MASLD (12 rats per group). High-throughput 16S sequencing was used for microbiome analysis.
Result s: There were significant differences in the overall microbiome composition of male and female rats with MASLD, including variations in topographical gut regions. The beta diversity of the jejunal and colon microbiomes was higher in female rats than in male rats (PERMANOVA p-value=0.001). Sex-specific analysis and discriminant features using LEfSe showed considerable variation in bacterial abundance, along with distinct functional properties, in the jejunum and colon of animals with MASLD. Significantly elevated levels of lipopolysaccharide and protein expression of Toll-like receptor 4 were observed in the livers of male rats with MASLD compared with their female counterparts.
Conclusions This study uncovered sexual dimorphism in the gut microbiome of MASLD and identified microbial heterogeneity within intestinal compartments. Insights into sex-specific variations in gut microbiome composition could facilitate customised treatment strategies.
Citations
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