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Hepatic encephalopathy (HE) reflects a wide spectrum of frequent and complex neurological complications that are associated with advanced liver diseases. It significantly impacts the quality of life and daily activities of those affected. Despite many investigations, the precise pathophysiology of HE is still under discussion. One contributing factor believed to be responsible for HE is the accumulation of neurotoxic substances in the brain such as ammonia, mercaptans, short-chain fatty acids, and lipopolysaccharides, originating from the dysfunctional liver. Strong data, however, suggests that HE is a complex symptom, and inflammation interacts synergistically with ammonia to worsen gliopathy and neuronal destruction. Recent data suggests that HE might come from the intestines. Increased activity of gut innate immune cells, especially macrophages and dendritic cells, can initiate inflammatory signals from the gut to systemic circulation, liver tissue, and finally the central nervous system. In this chapter, all inflammatory mechanisms at the levels of the gut-liver-brain axis following cirrhosis and HE are presented in detail. The chapter highlights the role of intestinal innate immune cells, liver Kupffer cells, and brain microglia in cirrhosis and the progression of HE.
Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Ali Shahbazi*
Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
*Address all correspondence to: sepehrinezhad.a@iums.ac.ir and shahbazi.a@iums.ac.ir
1. Introduction
Hepatic encephalopathy (HE) is a frequent neurological disorder and a serious consequence of advanced liver disease, acute liver failure, or portal-systemic shunting. HE is defined as a wide range of neuropsychiatric disturbances, including changes in personality, a shortened attention span, intellectual disability, cognitive impairment, alterations in sleep patterns, delirium, asterixis, episodic confusion, seizures, decreased level of consciousness, and even coma [1, 2, 3]. Three varieties of HE are distinguished based on the underlying cause. Type A refers to brain dysfunction that arises as a result of acute liver failure. Type B is observed in cases where there is portosystemic shunting without liver insufficiency, and type C as a consequence of liver cirrhosis [3, 4]. According to the West Haven Criteria (WHC), HE is categorized into grades I to IV, ranging from a lack of attention (grade I) to coma (grade IV). Based on the severity of manifestations, the International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) classifies HE into two categories: covert HE (CHE) and overt HE (OHE). CHE refers to minimal HE (MHE) and grade I HE, which are characterized by neuropsychological alterations without clinical evidence of mental changes. On the other hand, OHE displays severe neurological manifestations [3, 5]. The exact mechanism behind brain dysfunction in patients with liver diseases is complex and not yet fully revealed. However, it has been agreed that ammonia plays a key role. It mainly originates from the degradation of nitrogen-containing compounds by the intestinal microbiome, as well as the hydrolysis of glutamine by gut glutaminase, which is then transported into the portal circulation. A large portion of circulating ammonia is metabolized in the urea cycle by intact hepatocytes and subsequently excreted by the kidneys as urea [6]. In patients with liver insufficiency, the injured hepatocytes are no longer able to effectively detoxify ammonia from the blood. Subsequently, the level of circulatory ammonia is increased, which can result in a condition called hyperammonemia. Increased levels of ammonia in systemic circulation can cause detrimental effects on the central nervous system (CNS) through various pathways [6, 7]. Findings from numerous animal and clinical studies have indicated that inflammation, synergistically with ammonia, can potentially link to the development of HE [8, 9, 10, 11, 12]. Recently, there has been a growing focus among researchers on finding out the pathogenesis of brain dysfunction that occurs following liver diseases in organs beyond the liver and CNS [13]. Evidence indicates a correlation between alteration of gut microbiota composition (gut dysbiosis) and its associated by-products with conditions such as intestinal and liver inflammation, systemic inflammation, hyperammonemia, and neuroinflammation in liver diseases and HE [14, 15, 16, 17]. The gut, liver, and brain have some strong associations. The portal system allows a considerable part of the blood that passes through the gastrointestinal tract and many gut-active metabolites to reach the liver parenchyma. Similarly, the liver can influence intestine processes by synthesizing and secreting bile acids. Furthermore, both the gut and the liver can control various cerebral processes via their metabolites and immune systems. Moreover, through a cascade of humoral, neuroendocrine, immunological, neural, and metabolic signals, the brain can alter the activities of the liver and intestines [18, 19, 20]. The gut-liver-brain axis is a fascinating concept that involves a complex and multidirectional communication pathway linking the gastrointestinal tract, hepatic system, and CNS. In this axis, the brain influences the activity of gut and hepatic innate immune cells, while the liver and intestine regulate mental processes through gut microbiota and immune interactions [21, 22]. Recent reports indicate that impairment of the gut-liver-brain axis may play a role in the pathophysiology of liver diseases and HE [23, 24, 25]. It has been reported that the components of the innate immune system are considered the main communication route between the gut, liver, and brain. Innate immune cells found in the enteric, hepatic, and central nervous systems may mediate complicated connections between these organs. Researchers would benefit from an accurate understanding of the inflammatory signals emanating from residual innate immune cells and their impact on the gut-liver-brain axis in advanced liver disease and HE.
2. Intestinal macrophages and dendritic cells produce gut inflammatory signals
Gut macrophages (Mϕ), like other tissue Mϕ, originate from pluripotent bone marrow stem cells that develop into circulatory monocytes in the presence of interleukin (IL)-1, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Circulatory monocytes eventually extravasate into the intestinal lamina proparia, submucosal, and myentric plexus, where they come into contact with mucosal epithelium, luminal contents, and the enteric nervous system (ENS) [26, 27]. C-C motif chemokine receptor 2 (CCR2) signaling is totally required for blood monocyte penetration into the gut [28]. In mice, newly recruited monocytes are identified by the expression of profibrotic Ly6C and C-X3-C motif chemokine receptor 1 (CX3CR1), whereas mature resident intestinal Mϕ is identified by the expression of CD14, CD11b, MHCII, CX3CR1, and CD64 markers [28]. Furthermore, mediators, such as colony-stimulating factor 1 (CSF-1), transforming growth factor beta (TGFβ), IL-10, and CX3CR1, aid in the differentiation of monocytes into mature Mϕ [28, 29, 30, 31]. Intestinal Mϕ phagocytize pathogens as they express high levels of phagocytic markers such as Cd36, Gas6, Mertk, Axl, Itgav, Mrc1, Itgb5, Cd81, and C1qa-c [32]. They also express the efferocytosis receptor αvβ5, which facilitates the scavenging of apoptotic epithelial cells, hence maintaining the integrity of the mucosal epithelial barrier [33, 34]. The intestinal barrier and mucosal integrity are safeguarded by mediators produced by gut Mϕ, such as hepatocyte growth factor (HGF), Wnt signaling elements, IL-10, and prostaglandin E2 (PGE2) and their balloon-like protrusions [35, 36, 37, 38]. Additionally, intestinal Mϕ receives components of the luminal side through their projection processes into the mucosal layer. They play an important role in the presentation of antigens to dendritic cells (DCs) in the lamina proparia and the activation of T cells [39]. Gut Mϕ also interacts with both neural cells in ENS and enteric smooth muscle cells through the bone morphogenetic protein 2 (BMP2) and transient receptor potential cation channel subfamily V Member 4 (TRPV4)-PGE2-E-prostanoid receptor 1 or 3 (EP1/3) pathways, respectively [40, 41]. Colony stimulating factor 1 (CSF-1) is also secreted by ENS neurons, and it controls macrophage activity by binding to its membrane-bound CSF-1 receptors [42]. These multidirectional pathways allow Mϕ to regulate intestinal motility.
The homeostasis of the gut environment is maintained by an integrated epithelial mucosal barrier and intact tight junctions. Patients with cirrhosis and HE have been shown to have gut dysbiosis and a change in the composition of their gut microbiome from normal flora to pathogenic species such as Streptococcus salivarius, Proteobacteria, and Enterobacteriaceae [17, 43, 44]. Gut microbiota alteration was also revealed in several experimental animal models of liver disease and HE (Table 1) [63, 64, 65, 66, 67]. In addition, these patients had small bowel bacterial overgrowth, as determined by Qin et al. in a quantitative metagenomics analysis, which found differences in 75,245 genes between healthy people and cirrhotic patients [68]. Cirrhosis-related gut dysbiosis alters intestinal barrier permeability and epithelial tight junctions through the induction of oxidative stress, immune cell infiltration, a decrease in short-chain fatty acids, and a loss in the capacity of epithelial stem cells to self-renew [59, 67, 69, 70]. Portal hypertension also impairs the intestinal barrier via perturbation of intestinal circulation and cellular hypoxia in cirrhosis [71, 72]. In cirrhosis and liver disease, decrease in expression of some intestinal antimicrobial molecules, such as α-defensin5, α-defensin6, RegIII, and β-defensin 1, may exacerbate dysbiosis and bacterial translocation [73, 74, 75, 76]. In both rat models of acute liver failure and cirrhosis, a decrease in the expression of several intestine antimicrobial peptides was shown [77, 78]. In cirrhosis, bacterial translocation and endotoxin products, such as flagellin, peptidoglycan, lipopolysaccharide (LPS), bacterial DNA, and pathogen-associated molecular pattern molecules (PAMPs), were able to enter the lamina proparia and portal circulation due to the compromised intestinal barrier [79, 80]. These endotoxins and false metabolites stimulate Mϕ and DCs in Peyer’s patches of the lamina proparia. Activated Mϕ synthetize and secrete pro-inflammatory cytokines such as IL-1, IL-18, TGF-β, IL-6, interferon gamma (IFNγ), IL-1β, nitric oxide (NO), and tumor necrosis factor alpha (TNFα) (Figure 1). These metabolites also increase the phagocytosis capacity of DCs. Increasing levels of intestinal pro-inflammatory cytokines injure the mucosal epithelial barrier and enhance neutrophil infiltration into the lamina proparia. An electron microscopy analysis of biopsy samples from the duodenum revealed that patients with cirrhosis had an impaired intestinal barrier due to activated gut Mϕ and production of IL-6 and NO [61]. Fecal analysis in patients with acute decompensating cirrhosis indicated an increase in intestinal pro-inflammatory cytokines that were correlated with intestinal barrier disruption [81]. Furthermore, an increase in serum levels of LPS was associated with a decrease in the expression of intestinal tight junction proteins (i.e., occludin and claudin-1) in patients with cirrhosis [82]. IL-6 and TNFα can initiate downstream inflammatory signals by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ) [83, 84, 85, 86, 87]. The number of NO-releasing duodenal CD33+-CD14+-Trem-1+ Mϕ increased in cirrhosis. Additionally, these patients had higher levels of blood pro-inflammatory cytokines and circulatory LPS, as well as overexpressed claudin-2, a permeable tight protein, in the duodenum [61]. Injured epithelial cells and activated Mϕ release damage-associated molecular patterns (DAMPs). These DAMPs, along with PAMPs, have the ability to activate pattern recognition receptors (PRRs), particularly toll-like receptors (TLRs) that are found in intestinal Mϕ and DCs [88, 89]. Among the TLR family, TLR1, TLR2, TLR4, TLR5, and TLR6 are known to localize on the cell membrane and recognize various pathogen membrane elements. On the other hand, intracellular TLR3, TLR7, TLR8, and TLR9 are able to detect nucleic acids [90]. LPS derived from altered microbiota triggers an inflammatory signaling pathway through TLR4 in Mϕ (Figure 1). This pathway involves the activation of signaling proteins, including TRAM, TRIF, RIP1, TRF3, or TRAF6, which subsequently lead to the overexpression of MAPK and NF-kβ proteins [91, 92]. The majority of PAMPs can trigger PRRs, predominantly TLR2 and TLR4, on DCs. This mediates the migration of DCs to mesenteric lymph nodes, where they subsequently differentiate the naïve T cells into Th1, Th2, and inflammatory effector T cells. Activated DCs by PAMPs-TLR also present their antigens to CD4+ T cells through the major histocompatibility complex II and T cell receptor interaction. Additionally, these activated DCs secrete pro-inflammatory cytokines that further activate CD4+ T cells [84, 88, 93]. Increased Th1 cell numbers and an imbalanced Th17/Treg ratio have been shown to worsen intestinal inflammation in cirrhosis and liver disease [67, 94]. Th1 cells produced several pro-inflammatory cytokines, such as IFN-γ, IL-2, and TNFα, that worsened intestinal barrier disruption [95, 96]. Basal secreting levels of IL-17 by Th17 cells maintain the intestinal barrier by increasing the expression of tight junction proteins [97, 98]. However, following gut dysbiosis, activated Mϕ and DCs by PAMPs and DAMPs increase the number of Th17 cells by secreting IL-23, IL-6, and IL-1β. A number of powerful pro-inflammatory cytokines are produced by activated Th17 cells, which aggravate intestinal inflammation [99, 100, 101, 102]. Additionally, Th17-derived cytokines stimulate the production of neutrophil chemotaxis factors such as IL-8, C-X-C motif chemokine ligand 8 (CXCL8), GM-CSF, and C-X-C motif chemokine ligand 10 (CXCL10) by Mϕ, epithelial cells, and DCs [103]. Moreover, cytokines produced by Th17 cells prevent naive T cells from differentiating into Treg cells. Treg cells produce and secrete anti-inflammatory cytokines in response to activated DCs [104].
Main intestinal changes following cirrhosis and HE.
Figure 1.
Gut dysbiosis and intestinal inflammation in pathophysiology of cirrhosis and HE, highlighting the role of intestinal macrophages and dendritic cells. CXCL8, C-X-C motif chemokine ligand 8; CXCL10, C-X-C motif chemokine ligand 10; DAMPs, damage-associated molecular pattern molecules; DC, dendritic cell; IFNγ, interferon gamma; IL-1β, Interleukin-1 beta; IL-6, Interleukin-6; IL-17, Interleukin-17; IL-21, Interleukin-21; IL-22, Interleukin-22; LPS, lipopolysaccharide; Mϕ, macrophages; NH4+, ammonia; NO, nitric oxide; PAMPs, pathogen-associated molecular patterns; PMN, polymorphonuclear; ROS, reactive oxygen species; TLR4, toll-like receptor 4; TNFα, tumor necrosis factor alpha. Created with BioRender.com.
Finally, all pro-inflammatory cytokines, chemokines, PAMPs, DAMPs, and gut microbiome-derived ammonia can reach the portal circulation and result in systemic inflammation and hyperammonemia. Gut dysbiosis, bacterial translocation, and elevated levels of circulating pro-inflammatory cytokines, as well as bacterial metabolites (i.e. methanol and threonine) were also observed in cirrhosis patients with HE [105]. Moreover, gut dysbiosis was associated with levels of circulatory pro-inflammatory cytokines, and circulatory bacterial products were positively associated with HE [105]. Likewise, elevated serum levels of pro-inflammatory cytokines, including ІFN-γ, ІL-1β, and ІL-6, were also correlated with grade of HE in patients with cirrhosis [106]. In cirrhosis patients with HE, the systemic inflammatory response score was also positively correlated with the grade of HE [107]. Furthermore, systemic inflammatory response and hyperammonemia were also reported in acute-on-chronic liver failure (ACLF) and HE patients. Also, in these patients, blood ammonia was correlated with grade of HE and mortality rate [108]. Furthermore, cirrhotic patients with history of previous HE presented higher levels of circulatory IL-6, IL-2, IL-1β, TNFα, and endotoxins [43]. Gut microbiome alteration was also correlated with systemic inflammation in these patients [43]. Increase the number of Th17 cells and reduce the population of Treg, resulting in decrease the Treg/Th17 ratio shown in the blood circulation of cirrhosis patients due to hepatitis C virus [94]. Soluble sCD163 is a good marker that represents monocyte expansion and macrophage activation [109]. The circulatory level of this peptide was significantly raised in cirrhotic patients with ACLF [110]. An increase in serum inflammatory mediators was also revealed in carbon tetrachloride (CCL4)-induced cirrhosis and HE in rats [106]. Furthermore, our group indicated that the levels of pro-inflammatory mediators and ammonia are increased in thioacetamide-induced HE mice [23]. Increased concentrations of pro-inflammatory cytokines, active monocytes, T helper CD34+ cells, and bacterial DNA were seen in circulation of CCL4-induced cirrhosis rats [85]. Moreover, the number of T helper CD34+ cells and monocytes as well as elevated levels of bacterial DNA were demonstrated in the mesenteric lymph nodes of these rats [85].
3. Activated Kupffer cells exacerbate hepatocyte injury and systemic inflammation
Active bacterial metabolites and products, DAMPs, gut-derived pro-inflammatory cytokines, ammonia, and activated immune cells finally reach the liver through the portal vein and are directly exposed to other types of body-resident Mϕ named Kupffer cells (KCs) [111]. They are localized to hepatic sinusoidal endothelial cells and have a great role in scavenging circulatory pathogenic agents (Figure 2). The KCs are amoeboid-shaped cells with several processes, including microvilli, lamellipodia, and pseudopodia, that let them move around and endocytosis pathogens, apoptotic cells, and endotoxins [112]. The liver KCs originate from the embryonic yolk sac and have self-renewing properties [113, 114]. However, it has been shown that bone marrow-derived circulatory monocytes can be differentiated into KCs [115]. The KCs are functionally divided into two distinct types: M1 (pro-inflammatory classically activated KCs) and M2 (anti-inflammatory alternatively activated KCs). M1 KCs are activated in response to LPS, bacterial DNA, and pathogens, as well as pro-inflammatory mediators, resulting in the induction of oxidative stress and the production of pro-inflammatory cytokines. On the other hand, M2 KCs are triggered in response to IL-10, IL-13, and IL4, which lead to the secretion of anti-inflammatory cytokines [116, 117, 118]. KCs express several surface receptors that distinguish them from other cell types in the liver parenchyma. These molecules include CD68, CD14, and TLR4 in humans and CD11b, CD68, F4/80, CD163, CLEC4F, TIM4, TLR4, TLR9, and CRIg in rodents [119].
In liver cirrhosis, hepatocyte injury produces a substantial amount of DAMPs such as apoptotic bodies, ATP, high mobility group protein B1 (HMGB1), ATP, and DNA in the perisinusoidal space (space of Disse), where hepatic stellate cells (HSCs) are located (Figure 2) [120, 121, 122]. These agents, along with PAMPs and other gut-derived metabolites, activate HSCs to secrete monocyte and neutrophil chemotactic agents, such as chemokine (C-C motif) ligand 2, as well as activate KCs [123]. Moreover, KCs, through some mediators such as TGFβ, CCL2, CCL3, and CCL5 activate HSCs [124]. The HSCs progress liver fibrosis through a signaling pathway dependent on TGFβ, NLRP3 inflammasome-Caspase1-IL1β, and WNT/β-catenin [125, 126, 127]. Like intestinal Mϕ, KCs express PRRs on their surface, including TLR, RIG-like receptors, C-type lectin receptors (CLR), and nucleotide-binding oligomerization domain (NOD)-like receptors that recognize DAMPs and PAMPs [128, 129, 130]. For instance, activation of TLR4 in response to circulatory LPS through activation of myeloid differentiation factor 88 and overexpression of NF-kβ induces the production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFα, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [129, 131, 132, 133]. Moreover, activation of intracellular TLR3 in response to viral RNA through activation of TRIF and IRF3 produces IFNα and IFNβ in KCs [134]. In response to elevated levels of sinusoidal DAMPs and PAMPs, KCs are activated and release pro-inflammatory mediators (i.e. IL-12, IL-1β, iNOS, CCL2, and MIP-1) and induce oxidative stress in the liver parenchyma [118, 135]. Activated KCs also secrete Fas ligand (FasL), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and TNFα that trigger hepatocyte apoptosis [136]. Triggered KCs also exacerbate the recruitment of neutrophils and circulatory monocytes through production of several chemoattractant chemokines, such as CXCL1, CXCL2, CXCL8, CCL1, CCL2, and CCL25 in cirrhosis [137]. DCs are also triggered by activated KCs, DAMPs, PAMPs, and liver inflammation. According to function and surface receptors, five subsets of DCs are present in the nonlymphoid tissue of humans and mice. This includes Langerhans DCs (CD207+ and CD14−, human), CD11b+ cells (CD207−, CD14+, BDCA1+ and CD11chigh, human), CD8α+-like conventional cells (CD207−, CD14−, CD1a+, BDCA3+ and CD11chigh, human), monocyte-derived cells (Lyc6C+, MAC3+, CD11b+ and CD11c+, mouse), and plasmacytoid DCs (BDCA3+, CD11c-, human) [138, 139, 140, 141]. Two subtypes, including monocyte-derived and plasmacytoid DCs, are implicated in liver cirrhosis [142, 143]. The monocyte-derived DCs express TLR4, TLR8, and NOD-like receptors, while the plasmacytoid DCs express TLR1, TLR7, and TLR9 in both humans and mice [140, 144, 145]. In response to KCs-derived chemokines and liver inflammation, DCs recruit to the liver parenchyma. Liver DCs also express PRRs that mediate their responses to DAMPs and PAMPs. Activated DCs may trigger HSCs and CD8+ T cells through the secretion of IL-12 and programmed death ligand 1 (PD-L1), respectively [146, 147]. DCs also express MHC I and II peptides, which interact with CD8+ and CD4+ receptors and result in the activation of T cells. Moreover, activated DCs can trigger the differentiation of T cells through the production of IL-12 and IFNγ [148]. Severe infiltration of monocyte-derived and plasmacytoid DCs in the liver parenchyma along with increased production of IFNα have been reported in cirrhotic patients with ACLF [142]. In CCL4-induced cirrhosis and HE mouse models, liver inflammation along with increase in the number of CD11c+-MHCIIhigh-CD11b+ DCs have been shown in liver tissue [149]. Activated KCs and DCs have an impact on T cell activity. An increase in the infiltration of inflammatory Th17 cells in the liver parenchyma of patients with chronic hepatitis C has been shown [150]. Moreover, the recruitment of Th17 cells in liver tissue was correlated with grade of liver inflammation [150]. Likewise, the population of Th17 cells is increased in blood and liver tissue of patients with chronic hepatitis B and cirrhosis. Also, raise in the infiltration of Th17 cells into the liver parenchyma and an elevated level of IL-17 were associated with the severity of the disease and grade of liver fibrosis [151]. Furthermore, an increase in the Th17/Treg ratio along with overexpression of NF-kβ, TNFα, IL-1β, and IL-6 was revealed in patients with hepatitis B and cirrhosis [152]. In cirrhotic rats, an increase in the population of CD3+ T cells, T helper cells (CD4+-CD8−), and CD134+ T cells were observed in hepatic lymph nodes [85]. Moreover, overexpression of IL-17 mRNA and protein was demonstrated in the liver tissue of bile duct ligation (BDL) rats as a model of chronic liver failure-induced HE [153]. In cirrhosis, the detoxification of ammonia, as well as endogenous agents, PAMPs, and DAMPs by injured hepatocytes is compromised, leading to liver inflammation (Table 2) and elevated levels of these compounds in the systemic circulation. Moreover, pro-inflammatory cytokines and chemokines produced by activated KCs, HSCs, DCs, and infiltrating neutrophils can be released into systemic blood flow and eventually make their way to the brain.
Study
Findings (Liver tissue)
References
Luckey et al. (2001)
⇧TNFα mRNA, ⇧IL-6 mRNA, ⇧IL-1β mRNA, ⇧cyclooxygenase 2 mRNA, ⇧CD14 mRNA, ⇧I kappa B alpha transcription (in activated Kupffer cells of CCL4 rats)
One subset of cerebral glial cells, known as brain microglia, makes up approximately 10–15% of the cells in the brain parenchyma. As resident macrophage cells, microglia differentiate from progenitors in the yolk sac and develop through CSF-1 and IL-34 signaling. During the development of the CNS, microglia have a crucial role in programmed cell death, neurogenesis, phagocytosis of neuronal cells, reforming synapses, and survival of neural progenitor cells [175, 176, 177]. Under normal conditions, microglia scavenge brain parenchyma from dead cells, apoptotic neurons, and misfolding proteins (via phagocytosis), maintain the activity of other brain cells (i.e. astrocytes, oligodendrocytes, and neurons) through extracellular signaling molecules, remodeling false synapses and presenting antigens in the CNS [178, 179, 180, 181]. Basically, the central nervous system is protected from circulatory neurotoxic substances through a well-organized and intact blood-brain barrier (BBB). The BBB is a multilayer semipermeable structure that consists of capillary single-layer endothelial cells, the basement membrane, pericytes, and the astrocyte end-feet [182, 183]. This barrier is restricted, and only lipophilic molecules (MW 500 Da) are permitted to passively cross through this structure. Moreover, carrier-mediated transport facilitates the transportation of glucose and amino acids. Other limit transport systems (i.e. restricted paracellular pathway, transcytosis transport) mediated the entry of hydrated ions, low-density lipoprotein, iron, and insulin-like growth factor into the brain tissue [17, 183]. Transport across the BBB is constrained by several proteins, such as claudin-5 and occludin, zonula occludens-1 (ZO-1), and junctional adhesion molecules between endothelial cells (paracellular pathway). Systemic inflammation and injuries negatively affect tight junction structure and functions, resulting in disruption of the integrity of the BBB and penetration of harmful substances into the brain tissue [17]. These agents activate microglia and astrocytes to produce pro-inflammatory cytokines, which cause neuroinflammation. While neuroinflammation is a normal physiological process that protects the brain environment from infection, toxic agents, and misfolding proteins, chronic cerebral inflammation exerts detrimental consequences in the CNS [184]. Microglia are identified by several surface receptors (CD11b, CD45, CX3CR1, CD16, CD40, CD80, CD68, CD115, and others) and intracellular proteins (IBA1, Pu.1, HexB, vimentin, and Sall1) in the CNS [185, 186, 187, 188, 189, 190, 191, 192]. Functionally, there are two distinct states of microglia. The resting or ramified microglia represent round cell bodies and vigorous branching processes, which constitute a large part of cerebral microglia in physiological conditions. Under pathological conditions (PAMPs, DAMPs, and toxic substances in the brain), amoeboid form or activated microglia are the dominant state. Microglia in this form are less branched and have round cell bodies with thick processes that make it easier to move toward injury sites [193, 194, 195, 196]. Just like liver KCs, microglia can be classified phenotypically into two types: M1 (pro-inflammatory phenotype) and M2 (anti-inflammatory). The M1 microglia (CD14+, CD16+, CD40+, CD32+, CD86+, and MHCII+) often triggered by pro-inflammatory factors such as TNFα, IFNγ, and LPS, which cause the production of pro-inflammatory mediators. M2 microglia (CD163+ and CD206+) in response to IL-13, TGFβ, IL-4, and IL-10 secrete anti-inflammatory mediators and neurotropic factors, including IL-13, CCL22, CCL17, IL-10, brain-derived neurotrophic factor (BDNF), CSF-1, glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and TGFβ [197, 198].
Following cirrhosis, hyperammonemia, and systemic inflammation may interrupt the function of tight junction proteins and impair the integrity of the BBB (Table 3) [229, 230, 231]. Hyperammonemia, systemic inflammation, and enhanced BBB permeability were found in mice with BDL as a model for chronic liver disease-induced HE [8]. Similar findings were also revealed in CCL4-induced cirrhosis in rats [232]. Likewise, disruption of the BBB and decreased mRNA and protein expression of tight junction proteins (i.e. claudin-5, occludin, and ZO-1) were demonstrated in a BDL-rat model of HE [205]. Furthermore, systemic inflammation, hyperammonemia, and a decrease in the expression of thigh junction proteins were revealed in mice after the injection of CCL4 [233, 234]. Quinn et al. demonstrated elevated circulating bile acids increase the permeability of the BBB through a detrimental impact on tight junction proteins in BDL rats [235]. Elevated circulatory ammonia (unprotonated form; NH3) can passively diffuse into the brain parenchyma. Moreover, several transporting systems (i.e., aquaporins, Na+/H+ exchangers, Na+/K+-ATPase, and potassium channels) mediated ammonia transportation (ionic form; NH4+) across the BBB [236, 237, 238, 239, 240]. Disrupted integrity of the BBB and tight junction proteins leads to exposure of brain tissue to high levels of harmful circulatory substances, including LPS, pro-inflammatory cytokines, chemokines, ammonia, bacterial DNA, DAMPs, and bile acids (Figure 3). In addition to impaired BBB, several reported pathways were identified for the entry of systemic cytokines into the brain parenchyma: peripheral vagus nerve, circumventricular organs, recruitment of activated circulatory immune cells, and activated capillary endothelial cells that produce pro-inflammatory cytokines in the brain parenchyma [241, 242, 243, 244]. Elevated levels of DAMPs (i.e., HMGB1, ATP, bacterial DNA segments, and apoptotic bodies), pro-inflammatory cytokines, ammonia, LPS, bacterial metabolites, and their components in the brain parenchyma trigger microglia through activation of their TLR2, TLR4, TLR9, NOD2, RAGE, and purinergic receptors, resulting in change in their phenotypes from resting-branched to active-amoeboid state (Figure 3). The activated microglia produce and secrete pro-inflammatory mediators, including IL-1β, TNFα, IL-6, IL-12, CCL2, iNOS, IL-23, CXCL10, and PGE2, which progress the induction of oxidative stress and neuroinflammation (Figure 3). Chronic neuroinflammation in response to elevated cerebral levels of PAMPS, DAMPs, and ammonia induces neuronal loss and impairs neurogenesis, resulting in neurodegeneration and encephalopathy [199, 223, 224, 245, 246, 247, 248, 249, 250, 251, 252]. Interestingly, postmortem brain examinations of cirrhotic individuals with HE showed up-regulation of genes related to oxidative stress, inflammatory pathways, and microglial activation [224]. Hyperammonemia in BDL rats triggered microglial activation, increased cerebral levels of iNOS, PGE2, and IL-1β, and progressed motor dysfunction, as well as impaired cognitive functions [199]. Microglia activation and increased population of CD11+ cells, as well as an increase in the number of degenerative neurons demonstrated in the hippocampus and cerebellum of BDL rats [207]. Moreover, increased expression of microglia marker Iba1 and cerebral ammonia were seen in the prefrontal cortex of BDL mice [8]. Increased lipid peroxidation, decreased total antioxidant capacity, infiltrated leukocytes, and injured neuronal cells were observed in the brain tissues of CCL4-induced cirrhosis rats [253]. In addition, mouse models of liver fibrosis by CCL4 showed increased mRNA expression of IL-1β, TGF-β1, and matrix metalloproteinase-9 (MMP9) in the brain parenchyma [234]. Likewise, mRNA and protein levels of MMP9 and VCAM-1 were up-regulated in different brain regions of BDL rats [205]. Activated microglia also stimulate the recruitment of circulatory monocytes and neutrophils into brain tissue through their secretory chemoattractant agents, CCL2, MCP-1, CXCL3, and MMPs (Figure 3) [254, 255, 256]. In a mouse model of chronic liver failure due to bile duct resection, activated brain microglia with a mechanism dependent on TNFα-TNF receptor 1 (TNFR1)-produced CCL2 and MCP-1 stimulate monocyte chemotaxis into the brain [256]. Cerebral astrocytes (glial fibrillary acidic protein; GFAP) are directly exposed to ammonia and circulatory PAMPs and DAMPs. These agents changed the astrocyte state from resting to a reactive form that produced pro-inflammatory mediators and induced oxidative stress. Afterward, reactive astrocytes activate microglia through secretion of G-CSF and CCL11 [257, 258, 259, 260]. Moreover, activated microglia, via production of GM-CSF, TNFα, and IL-1β trigger astrocytes to produce pro-inflammatory cytokines that exacerbate neuroinflammation [231]. Hyperammonemic cerebral conditions induce astrocyte swelling and brain edema through mislocalization of aquaporin four water channels, inflammation, TLR4 activation, mitochondrial dysfunction, glutamine accumulation, and induction of oxidative stress [7, 257, 261]. Although cerebral edema often progresses in acute forms of HE, patients with cirrhosis were found to have minimal levels of brain edema using 1H-magnetic resonance (MR) spectroscopy [262]. Systemic inflammation, hyperammonemia, an abnormal phenotype of astrocytes (thin chromatin and enlarged nuclei), and increased brain water content (an indicator of cerebral edema) were demonstrated in BDL rats [263]. Moreover, in other experimental models of cirrhosis-induced HE, astrogliosis, gliopathy, neuroinflammation, and raise in brain water content were observed [8, 207, 233, 234, 248, 264].
⇧BBB permeabilization, ⇧brain water content, ⇧aquaporin-4 mRNA and protein, ⇧MMP-9 mRNA and protein, ⇩mRNA and protein occludin, ⇩mRNA and protein claudin-5, ⇩mRNA and protein ZO-1 (BDL rats)
Change in the expression patterns of genes related to oxidative stress, microglia activation, inflammatory signaling, cell proliferation, and apoptosis (postmortem; cirrhosis patients with HE)
While the pathophysiology of cirrhosis-induced HE remains to be elucidated, the progression of cirrhosis and HE is associated with innate immune disturbances at different levels of the gut-liver-brain axis. In cirrhosis, gut dysbiosis and bacterial overgrowth cause intestinal barrier disruption, leading to bacterial translocation and activation of intestinal Mϕ and DCs that initiate tissue inflammation. Bacterial metabolites, ammonia, and gut-derived inflammatory cytokines reach the hepatic sinusoids and activate HSCs and KCs, resulting in the production of liver inflammation and the induction of oxidative stress and exacerbate systemic inflammation. Also, injured hepatocytes cannot detoxify ammonia, resulting in hyperammonemia. Systemic inflammation, hyperammonemia, and endotoxemia induce the BBB injury and allow brain tissue to be exposed to all circulatory neurotoxic substances. These agents stimulate brain microglia to produce pro-inflammatory cytokines and induce oxidative stress in the CNS. Neuroinflammation and oxidative stress decrease neurogenesis and induce neuronal degeneration, resulting in neurological and psychological manifestations seen in HE. Due to the implication of Mϕ, immune cells and inflammation in different levels of gut-liver-brain axis, they can be potent therapeutic targets for future experimental and clinical research to find an all-encompassing treatment option that targets restoration of the immune system in multiple organs following cirrhosis and HE.
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Written By
Ali Sepehrinezhad and Ali Shahbazi
Submitted: 16 October 2023Reviewed: 15 November 2023Published: 15 January 2024
Open access peer-reviewed chapter
