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Address for correspondence: Mark G. Swain, Professor of Medicine, Cal Wenzel Family Foundation Chair in Hepatology, Head, Division of Gastroenterology and Hepatology, University of Calgary, 6th Floor, TRW Building, Rm 6D31, Calgary, Alberta T2N 4N1, Canada. Tel.: +1 403 592 5010; fax: +1 403 592 5080.
A growing body of evidence now highlights a key role for systemic inflammation in altering behavior and mood in patients with liver disease. How inflammation occurring in the periphery in the context of liver disease, communicates with the brain to mediate changes in neurotransmission and thereby behavior is incompletely understood. Traditional routes of communication between the periphery and the brain involve neural (i.e. vagal afferent nerves) and humoral (blood-borne) pathways, with increased circulating levels of endotoxin and cytokines (especially Tumor Necrosis Factor α, TNFα) that occur during systemic inflammatory responses, as being primarily implicated in mediating signaling via these pathways. However, in recent years communication via peripheral immune-cell-to-brain and the gut-microbiota-to-brain routes have received increasing attention in the context of liver disease for their ability to modulate brain function, and generate a spectrum of symptoms ranging from fatigue and altered mood to overt Hepatic Encephalopathy (HE). In this review, we discuss periphery-to-brain communication pathways and their potential role in mediating systemic inflammation-associated alterations in behavior, that are in turn ultimately part of a spectrum of brain changes linked to the development of clinically apparent HE.
Hepatic Encephalopathy (HE) is a serious complication of acute or chronic liver failure and includes a spectrum of neuropsychiatric disturbances. The pathogenesis of HE remains a topic of discussion in the scientific community with several theories proposed, including the central concept that hyperammonemia is a key driving factor.
However, serum concentrations of ammonia often correlate poorly with the severity of HE in cirrhotic patients. Other proposed mechanisms involve disruption of the blood–brain barrier, changes in neurotransmission, neuroinflammation, oxidative stress, Small Intestinal Bacterial Overgrowth (SIBO), and brain blood flow abnormalities.
How liver disease-related systemic inflammation and immune activation leads to remote changes in brain function remains unclear. A number of general signaling pathways have been described that link systemic inflammation to changes occurring in the brain, which in turn give rise to altered behavior.
Neural pathway: Vagal afferent nerves innervate the liver and can be activated through cytokine receptors expressed on vagal nerve endings by proinflammatory cytokines released during peripheral immune responses. After activation, vagal afferents carry stimuli to the brain which in turn activate primary and secondary cerebral projection areas, leading to changes in brain function and behavior.
Humoral pathway: Circulating proinflammatory cytokine levels (e.g. Tumor Necrosis Factor α, TNFα, Interleukin-6, IL-6) are often increased in the setting of peripheral immune activation, and in patients with liver disease.
Proinflammatory cytokines, including TNFα, can induce the production of secondary messengers (such as prostaglandins and nitric oxide) in CECs, which can be released into the brain and subsequently lead to changes within the brain.
Adherence of immune cells to CECs can lead to stimulation of secondary messenger production by CECs, which in turn are released within the brain parenchyma and activate resident immune cells in the brain (e.g. astrocytes, microglia).
Immune system-to-brain signaling in liver disease in the absence of liver failure and HE
Changes in behavior, including decreased cognition (“brain fog”), fatigue, anorexia and altered mood (depression, anxiety) are commonly experienced by patients with liver disease, regardless of liver disease severity.
suggesting that the peripheral and central drivers of these two symptom complexes are intimately related and therefore must share similarities in their pathogenesis. Systemic inflammation and associated immune system activation occur in both cirrhotic and non-cirrhotic liver disease.
Therefore, a spectrum of differential activation of peripheral signaling pathways that drive central changes in neurotransmission and behavior, may underlie differences in the clinical expression of symptoms in liver disease patients, ranging from common-liver disease associated symptoms to those more typical of HE. An improved understanding of the link between peripheral inflammation-driven changes in the three main signaling pathways, and changes in brain function, may provide novel therapeutic approaches to improve symptoms, QoL, and reduce the severity of HE.
In the setting of liver disease, the importance of neural pathways linking the liver and the brain, resulting in altered brain function, is likely of lesser importance compared to the other signaling pathways. Specifically, liver transplantation which denervates the liver, does not typically improve fatigue severity or neurological dysfunction in patients with primary biliary cirrhosis.
An active role for a humoral liver-to-brain communication pathway in the setting of liver disease is possible, as increased circulating proinflammatory cytokine levels have been documented in patients with chronic liver disease.
Through this mechanism high concentrations of cytokines can be delivered in close proximity to endothelium, driving the subsequent generation of secondary signaling molecules such as nitric oxide from the endothelium.
The secondary signaling molecules generated in this fashion, can in turn be released within the brain parenchyma where they activate microglia and facilitate changes in neurotransmission that alter behavior.
Importantly, we have previously shown in an experimental model of liver disease that this process occurs, is regulated by TNFα produced by monocytes adherent to cerebral endothelium, and critically drives microglia activation within the brain and the subsequent generation of adverse liver disease-related behaviors.
Although activation of monocytes within the circulation can be associated with liver injury, the mechanism linking liver damage and monocyte activation to produce TNFα remain unclear. The gut microbiome has been increasing implicated in the regulation of behavior.
Moreover, a healthy gut microbiome appears to provide overall health benefits which has led to the broad societal intake of supplements, including probiotics, to beneficially alter the gut microbiome. Furthermore, probiotic consumption has been shown to alter brain function and behavior in healthy humans. Specifically, probiotic ingestion can have beneficial effects on mood and cognition,
The mechanism whereby probiotic ingestion leads to changes in brain function and behavior remain unclear, but have been linked to changes in gut flora (although not routinely observed), changes in gut permeability, and shifts in systemic immunity with decreased production of proinflammatory cytokines, including TNFα. Gut microbiome changes have been identified in patients with chronic liver disease, and these changes have been implicated in altered behavior and HE through a gut-liver-brain axis.
VSL#3 is a probiotic mixture that is widely used clinically. Furthermore, VSL#3 intake has recently been linked to an effect on brain function in that VSL#3 ingestion altered gene expression within the brain.
Based on these observations, we hypothesized that VSL#3 treatment would alter systemic immunity and improve adverse behaviors in the setting of liver disease. To examine this we administered VSL#3 to mice with liver inflammation and determined its effects on liver disease-associated alterations in behavior. In addition, we delineated the mechanism whereby oral VSL#3 administration leads to changes within the brain. Our findings highlighted the existence of a novel pathway whereby probiotic administration mediated improvements in liver disease-associated adverse behaviors by altering systemic immunity, decreasing microglial activation within the brain, and reducing recruitment of TNFα-secreting monocytes to the brain
Although the exact mechanism through which gut microbiota influences the brain and behavior remains unclear, these experiments demonstrate a novel pathway where probiotic ingestion affects systemic immune activation and circulating TNFα levels, microglial activation, monocyte–CEC interaction, and leukocyte infiltration of the brain ultimately resulting in improvements in behavior.
and may activate circulating immune cells via Toll-Like Receptors-4 (e.g. TLR4) to induce cytokine production. Platelets secrete cytokines and chemokines, and also express adhesion molecules such as P-selectin that enable leukocyte adhesion to vascular endothelium, greatly facilitating leukocyte-endothelial cell adhesion in vascular beds such as the brain where P-selectin expression is low.
For example, peripheral blood monocytes when bound to platelets promote a proinflammatory monocyte phenotype; an effect prevented by blocking monocyte–platelet interactions with an Anti-P-Selectin Glycoprotein 1 (PSGL-1) (counter-receptor for P-selectin) antibody.
Therefore, we hypothesized that platelet–monocyte interactions within the circulation would be important for monocyte activation, an effect driven by TLR4 activation, and that formation of MPAs would lead to the induction of changes within the CNS that alter behavior in liver disease. Indeed, we found that in experimental liver disease MPA formation was important for circulating monocyte activation and TNFα production, as well as monocyte recruitment to the brain and associated adverse liver disease-associated behavior development.
In addition, liver disease is commonly associated with the appearance of a systemic inflammatory response, including increased circulating cytokine levels (especially TNFα) and immune cell activation, which can be of variable severity and linked to increased gut permeability and elevated systemic levels of gut-related products, such as endotoxin.
In the context of cirrhosis, these changes can be further amplified, with more pronounced increases in gut permeability, enhanced circulating levels of endotoxin, proinflammatory cytokines and ammonia, and the formation of MPAs within the peripheral circulation.
Microglia activation within the brain is an important component of the neuroinflammatory response during HE, is linked to systemic inflammation, and occurs widely throughout the brain in the context of HE.
Therapeutics targeted at altering the gut microbiome (and presumably the generation of gut microbiome-derived byproducts such as endotoxin and ammonia) are the mainstay of treatment for HE, and include the antibiotic rifaximin and the oral oligosaccharide lactulose.
Probiotics are also beneficial in cirrhotic patients with HE, and the probiotic VSL#3 decreases plasma levels of proinflammatory cytokines (e.g., TNFα), improves adverse behavioral changes associated with advanced liver disease and QoL, and reduces hospitalizations for HE.
The mechanism of this effect is unclear, however it has been linked to changes in the gut flora, changes in gut permeability, and shifts in systemic immunity and the production of cytokines such as TNFα.
Therefore, systemic inflammation, linked to changes in the gut microbiome (i.e. dysbiosis), occurs commonly in patients with liver disease. Immune activation, which is closely associated with systemic inflammation in liver disease, is an important driver of subsequent microglia activation within the brain and associated neuroinflammation.
Importantly, these changes in brain function exist as a continuum in patients with advanced liver disease, and can augment the clinical expression of HE (Figure 1). Therefore, alterations in brain function can manifest clinically as symptoms ranging from mild cognitive changes, altered mood (e.g. depression, anxiety) and fatigue in patients with cirrhosis but without HE, to behavioral changes that are more classically associated with HE, including slowed mentation and confusion that can progress ultimately to unresponsiveness and coma.
Systemic inflammation in patients with liver disease drives changes within the brain that are linked to a wide spectrum of behavioral alterations ranging from mild changes in cognition and mood, to overt confusion and coma observed in the setting of advanced HE. An enhanced understanding of the pathways that link the gut, liver and the brain in patients with liver disease, to generate altered brain function and behavior, will allow for the development of targeted therapies to better manage the neurological and behavioral complications of liver failure.
Conflicts of interest
The authors have no conflicts of interest relevant to this manuscript.
This work was supported by a CIHR Team Grant (MGS, PI) and by the Cal Wenzel Family Foundation Chair in Hepatology .
Hepatic encephalopathy: a critical current review.