Abstract Background & Aims Cognitive dysfunction is an increasingly recognised manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanistic link remains unclear. The aim of this study was to investigate the hypothesis that experimental MASLD leads to cognitive dysfunction via systemic inflammation and neuroinflammation. Methods Twenty male Sprague Dawley rats were randomised to a high-fat high-cholesterol (HFHC) diet to induce MASLD, or a standard diet (n = 10/group), for 16 weeks. Assessments included: MASLD severity (histology), neurobehaviour, inflammation (liver, plasma and cerebrospinal fluid), brain microglia and astrocyte activation, and synaptic density. Results The HFHC diet induced MASLD with extensive steatosis and lobular inflammation without fibrosis. Several plasma cytokines were elevated (CXCL1, IL-6, IL-17, MIP-1α, MCP-1, IL-10; all p <0.05) and correlated with increases in hepatic chemokine gene expression. Cerebrospinal fluid concentrations of CXCL1 were elevated ( p = 0.04). In the prefrontal brain cortex, we observed a 19% increase in microglial activation confirmed by Iba1 immunohistochemistry ( p = 0.03) and 3 H-PK11195 autoradiography ( p < 0.01). In parallel, synaptic density was reduced to 92%, assessed by 3 H-UCB-J autoradiography ( p < 0.01). MASLD animals exhibited impaired memory to previously encountered objects in the novel object recognition test ( p = 0.047) and showed depression-like behaviour evidenced by increased immobility time ( p < 0.01) and reduced swimming time ( p = 0.03) in the forced swim test. Conclusions Experimental non-fibrotic MASLD, as a model to reflect the early stage of human disease, results in cognitive impairment and depression-like behaviour. This is associated with an inflammatory phenotype not only in the liver but also in the plasma and brain, which together with diminished synaptic density, provides a pathophysiological link between liver disease and cognitive dysfunction in MASLD. Impact and implications Cognitive dysfunction is an increasingly recognised comorbidity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying mechanisms remain unclear. This study provides evidence of impaired memory and depression-like symptoms in early experimental MASLD and indicates that hepatic inflammation may drive a systemic inflammatory response, resulting in neuroinflammation and reduced brain synaptic density. The evidence of impaired memory in MASLD and establishing its underlying pathophysiological link provides insights that could guide the development of potential new treatments for this increasingly common condition in people of working age. The study also emphasises the need to develop better tools for clinical cognitive testing, which will enable physicians to assess and manage brain dysfunction early in MASLD. Keywords: Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver-brain axis, hepatic encephalopathy, neuroscience, cognitive dysfunction, neuroinflammation, systemic inflammation, synaptic density, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis
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Kristoffer Kjærgaard, Anne Catrine Daugaard Mikkelsen, Anne M Landau et al.. Cognitive dysfunction in early experimental metabolic dysfunction-associated steatotic liver disease is associated with systemic inflammation and neuroinflammation. JHEP Reports. (2023). https://doi.org/10.1016/j.jhepr.2023.100992 Kristoffer Kjærgaard, Anne Catrine Daugaard Mikkelsen, Anne M Landau, Peter Lykke Eriksen, Stephen Hamilton-Dutoit, Nils Erik Magnusson, Majken Borup Thomsen, Fenghua Chen, Hendrik Vilstrup, Rajeshwar Prosad Mookerjee, Cecilie Bay-Richter, Karen Louise Thomsen
1Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark 2Department of Emergency Medicine, Horsens Regional Hospital, Denmark 3Department of Nuclear Medicine and PET, Aarhus University Hospital, Denmark 4Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark 5Department of Pathology, Aarhus University Hospital, Denmark 6Medical Research Laboratory, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark 7Institute for Liver and Digestive Health, University College London, United Kingdom 