Multi-omic data integration study of immune system alterations in the development of minimal hepatic encephalopathy in patients with liver cirrhosis

Abstract

chain fractures, hospitalizations, and traffic accidents increases 6,7 , making this an important health, social, and economic problem.MHE can progress to a more advanced stage which involves severe cognitive impairment and, in the worst-case scenario, coma and death.Even though MHE is a potentially reversible alteration, most patients currently remain undiagnosed and untreated due the lack of simple diagnostic procedures. The gold standard test used to reveal these less- Factors contributing to minimal hepatic encephalopathyAlthough the etiology of MHE is not completely understood, it is believed that multiple underlying mechanisms induce the functional impairment of the central nervous system observed in this syndorme 10,11 . The appearance of mild cognitive and coordination impairments in patients with MHE is due to the synergistic action of both hyperammonemia and peripheral inflammation arising from liver failure. The proposed general process starts with (1) chronic hyperammonemia and peripheral inflammation which are transmitted to the brain where they induce neuroinflammation; (2) thereafter, the neuroinflammation disrupts neurotransmission and neuronal connectivity which leads to (3), impairment of cognitive and motor function 12 (Figure 1.1). systemic inflammationNeuroinflammation is the immune response of the nervous system and is mainly caused by activation of microglia, the resident innate immune cells in the brain. Analysis of this phenomenon in MHE animal models has shown that neuroinflammation can alter neurotransmission, thereby disturbing neuronal communication and leading to cognitive and motor B lymphocyte activation (CD69), and elevated levels of IL-22 and CXCL13 33 . Inflammation in cases of liver cirrhosisAs discussed in this section, regardless of their level of cognitive impairment, patients with cirrhosis present chronic inflammation of the liver. The general inflammatory process of the immune system is described at molecular level in section 1.2.3. Liver hepatocytes and macrophages (Kupffer cells) recognize toxic agents entering the portal vein circulation. When endotoxin levels 1.1.1.5. Microbiota Over the past decade, microbiota has been added as a new factor contributing to MHE and is now viewed as an important part of the impaired gut-liver-brain axis in cirrhosis. Besides ammonia, other toxic compounds derived from bacterial metabolism are not catabolized due to impaired liver function and are thereby transported to the brain where they exert neurotoxic effects 48 . Some microbial metabolites like endotoxins (lipopolysaccharides [LPS] from bacterial membranes) or bacterial DNA itself, are also able to activate immune cells and therefore may contribute to the inflammatory pathogenesis of MHE. In fact, Jain et al. 49 proved the correlation between serum levels of endotoxins and the grade of encephalopathy in patients with MHE. With the aim of looking for new diagnostic targets, the work of Bajaj et al. 50 determined specific stool and salivary microbial signatures for individual cogni...