Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression

Abstract

A growing body of evidence now highlights a key role for inflammation in mediating sickness behaviors and depression. Systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and chronic liver disease have high comorbidity with depression. How the periphery communicates with the brain to mediate changes in neurotransmission and thereby behavior is not completely understood. Traditional routes of communication between the periphery and the brain involve neural and humoral pathways with TNFα, IL-1β, and IL-6 being the three main cytokines that have primarily been 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 for their ability to modulate brain function. In this chapter we discuss periphery-to-brain communication pathways and their potential role in mediating inflammation-associated sickness behaviors and depression.

Fatigue in chronic liver disease: New insights and therapeutic approaches

“…Although the origin of vasomotor autonomic dysfunction in PBC remains unclear, there is evidence to suggest a central component, including a link between autonomic dysfunction and cognitive dysfunction . Interestingly, elevated circulating levels of the proinflammatory cytokine TNFα have been implicated in the development of sickness behaviours, including fatigue, in animal models of liver disease . Similar observations have been made in patients with chronic nonhepatic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease .…”

“…However, the gut microbiome is also an important regulator of brain function, and changes in the gut microbiome are capable of affecting mood, cognition and behaviour . Moreover, it is clear that changes in gut microbiota can modulate brain function in the setting of liver disease . Two main peripheral communication pathways have been implicated in gut microbiota—brain interactions; namely, the neural and humoral pathways (Figure ) .…”

“…Moreover, it is clear that changes in gut microbiota can modulate brain function in the setting of liver disease . Two main peripheral communication pathways have been implicated in gut microbiota—brain interactions; namely, the neural and humoral pathways (Figure ) . Given these observations, manipulations of the gut microbiome, for example using pro‐ and/or prebiotics, have been used to attempt to modify brain function and symptoms in the setting of numerous chronic diseases, including liver disease and chronic fatigue syndrome .…”

Near‐Infrared Spectroscopy Reveals Brain Hypoxia and Cerebrovascular Dysregulation in Primary Biliary Cholangitis

“…Dysregulation of cerebral blood flow and perfusion in these patients may result from two potential mechanisms: (1) disrupted efferent sympathetic nervous control of arterial blood pressure and/or (2) direct damage or injury to the vascular endothelial cells, both of which may cause dysfunctional vasomotor activity. Previously, we have shown that following bile duct ligation in mice, liver inflammation induces an immunological assault on the endothelial cells of cerebral blood vessels, providing evidence of the latter as a potential driver of altered cerebral vasomotor regulation of cerebral blood flow found in patients with chronic liver inflammation.…”

“…Although prevalence estimates vary geographically, a recent US study reports a PBC prevalence of 4.3 per 100,000 in women and 1.1 per 100,000 in men, and similar findings have been reported in Canada . PBC is commonly associated with a number of behavioral symptoms including fatigue, itch, altered mood, and cognitive changes, indicating that PBC can alter brain function . However, the mechanism whereby PBC can impact brain function remains unknown.…”