(P18-015-25) Diet, Metabolism and Innate Immune Training in individuals With MAFLD

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) involves complex interplay between metabolic and innate immune dysfunction. However the impact of metabolic dysregulation in MAFLD on the functionality of innate immune cells is unclear. Therefore, we investigated how metabolic and inflammatory phenotypes in response to dietary fat and fructose challenges influenced innate immune responses in individuals with MASLD and MASH.

Methods: People with MASLD (n=20) and MASH (n=16) and age-matched controls (n=10) completed postprandial high-fat and fructose challenges. Metabolic, whole blood cytokine responses to bacterial (TLR2/4) and viral (TLR7/8) agonists and monocyte innate immune training (IIT) profiles were determined.

Fecal samples from individuals with MASLD (n=6) and MASH (n=6) were transplanted into antibiotic-cleansed mice fed a high/standard fat diet (HFD/SFD).

Results: Whole blood cytokine responses (IL-6, IL-1β, CCL3) to bacterial and viral ligands were higher in patients with MASL, but not MASH, versus healthy controls (p < 0.001). The whole blood IL-1β response to viral ligands was greater in individuals with MASLD vs MASH (p < 0.01). On-going metabolomics is defining the immuno-metabolic nature of the whole blood responses. The IIT response, as in an increased TNF-α response to BG+LPS in comparison to LPS only, was compromised in MAFLD and MASH subjects. The IIT response was quite heterogenous, on-going analysis defining the precents to training in MAFLD versus healthy controls.

Despite differences in the immuno-phenotype, plasma glucose, insulin and lipid responses to dietary fat and fructose challenges were similar between individuals with MASLD and MASH.

Fecal matter transplantation (FMT) of MAFLD v MASH microbiome into high-fat fed mice showed greater fasting insulin, HOMA-IR and glucose intolerance following the MASH FMT. Immuno-phenotyping is on-going.

Conclusions: Innate immune responses were compromised in individuals with MASLD. Despite similar metabolic impairment following high-fat and fructose challenges, inflammatory responses were higher in MASLD than MASH, suggesting that MASLD may influence innate immune plasticity. The heterogenous innate immune functionality in progression of MASLD, underscores the need for precision medicine approaches.

Funding Sources: Research Ireland