2. How Neuroinflammation Is Linked to Depression and Anxiety
CNS immune activation is a well-known phenomenon in depression and anxiety. Recent findings indicate that immune processes represent a key pathogenic driver rather than a pure epi-phenomenon in both conditions. This is supported by the notion that brain-resident immune cells including microglia and brain-resident CD4+ T cells are essential for neuronal homeostasis and physiological behavior
[36][37][38][39]. Moreover, microglia were reported to mediate behavioral deficits in models of depression and anxiety induced by chronic unpredictable stress or early-life inflammation induced by intraperitoneal LPS injection
[39][40][41][42]. Involved inflammatory pathways being potential therapeutic targets include microglia–astrocyte crosstalk via glutaminase-1
[4342], the NLRP3 inflammasome
[43][44][45] and the clearance of reactive oxygen species (ROS) via silent information regulator 2 homolog 1 (Sirt1)—nuclear factor erythroid 2-related factor 2 (Nrf2)—hemoxygenase 1 (Ho-1)—signaling
[45][46][47].
Interestingly, modulation of the BBB is also implicated in the etiology of stress-induced depression and anxiety in chronic social defeat stress. In particular, stress-susceptibility and depression-like behaviors were dependent on downregulation of the tight junction marker claudin-5 (Cldn5) in the hippocampus and nucleus accumbens, which was orchestrated via Tnf and histone deacetylase 1 (Hdac1) and facilitated vascular influx of Il-6 into the brain parenchyma
[47][48][49]. As chronic gastrointestinal inflammation was reported to cause BBB tight junction downregulation comparable to social stress, it might also represent a trigger for BBB-mediated depressive-like behavior. Furthermore, non-disruptive BBB alterations may contribute to anxiety-like behavior. Social stress-induced anxiety was mediated by Il1-receptor 1 producing endothelial cells, which were activated by Il-1β-expressing monocytes attracted to the BBB by microglia
[5049]. These findings suggest that endothelia closely interact with myeloid cells and may act as a gatekeeper to further develop neuropsychiatric symptoms. A better understanding of non-disruptive BBB changes in IBD is necessary to explore if such mechanisms are present during gastrointestinal inflammation.
Though these and other studies strongly imply the relevance of neuroinflammation in depression and anxiety, they do not precisely delineate how neuroinflammation alter the function of neuronal circuits involved in behavioral and emotional regulation to ultimately trigger psychiatric symptoms. In the context of IBD, this might be mediated by several pathways (
Figure 2).
Figure 2. Impaired neuronal functions in inflammatory gut-to-brain communication. Microglia, peripheral immune cells and endothelia contribute to immune-mediated impairment of neuronal functions in IBD by different mechanisms. First, reduced neurotrophic signaling by BDNF is induced by neuroinflammation and observed in IBD. Second, inflammation interferes with neurotransmitter metabolism, e.g., resulting in reduced availability of serotonin. Third, electrophysiological properties of distinct neuronal populations are modified, and synaptic plasticity is reduced. Fourth, adult hippocampal neurogenesis is impaired. Fifth, increased microglial engulfment of synapses may lead to aberrant synaptic degradation. Finally, inflammatory signaling could induce neuronal cell death. Intestinal microbiota essentially contribute to neuronal alterations in IBD, either by augmenting inflammatory activation of immune cells or by direct influence on neurons. Disturbed neuronal function is the pathological correlate of behavioral changes and neuropsychiatric comorbidity in IBD. BDNF: brain derived neurotrophic factor; ↑: increased; ↓: decreased. Figure created with
BioRender.com BioRender.com (accessed on 18 August 2022).
First, CNS immune activation may compromise neuronal activity and synaptic transmission in key regions involved in anxiety and depression. Microglial activation was recently shown to reduce neuronal excitability in the dorsal striatum in a prostaglandin-dependent manner. Thus, targeting cyclooxygenase-1 (Cox-1)-mediated prostaglandin synthesis in microglia may alleviate depressive symptoms
[4039]. In the basolateral amygdala, inflammation induced by peripheral LPS application leads to increased glutamate release and projection neuron excitability, which was linked to depressive and anxiety-like behavior
[5150]. In line with these findings, TNBS-induced colitis reduced synaptic plasticity and elicited enhanced synaptic transmission in hippocampal glutamatergic neurons
[5251]. Interestingly, manganese-enhanced MRI indicated reduced hippocampal activity in chronic DSS-induced colitis
[1817]. Recently, inflammation-induced dysregulation of neuronal circuits was proposed to diminish inhibitory input from the prefrontal cortex and hippocampus on hypothalamic corticotropin releasing hormone (CRH) secretion. This, in turn, might aggravate both colitis and depressive-like behavior
[5352]. Together, electrophysiological properties and synaptic transmission of defined neuronal subtypes may be impaired during IBD-related neuroinflammation.
Additionally, CNS immune activation can shift neurotransmitter metabolism, in particular resulting in reduced availability of serotonin. Impaired serotoninergic signaling is involved in depression and is a major target for antidepressant treatment. In IBD, peripheral serotonin may act as a double-edged sword by augmenting mucosal inflammation
[5453], but protecting the enteric nervous system
[5554]. Of note, antidepressant serotonergic treatment positively influenced the disease course among patients with CD and UC, decreasing systemic pro-inflammatory cytokine levels
[5655]. Activated microglia express indoleamine 2,3-dioxygenase (IDO) to catabolize tryptophan into kynurenine instead of serotonin. Kynurenine is further processed into excitotoxic metabolites
[5756]. In acute DSS-induced colitis, IDO expression was increased in the prefrontal cortex
[5857]. Moreover, chronic colitis induced by infection with
T. muris was accompanied by increased serum kynurenine levels
[7]. These data suggest impaired tryptophan-serotonin metabolism in IBD, but a direct link between IBD-related neuroinflammation, impaired serotonergic signaling, and behavioral deficits has not yet been drawn.
Additionally, microglia can engulf and prune synapses. Microglial synaptic pruning is essential for proper brain development, but is aberrantly upregulated during neurodegeneration
[5958]. Intriguingly, the complement system, which is essentially involved in synaptic pruning, was recently implicated in stress-induced depressive-like behavior
[6059]. Moreover, microglia-synapse interactions were altered in models of depression in a spatiotemporally distinct manner. Early-life LPS-induced inflammation enhanced microglial engulfment of glutamatergic neuronal spines in the anterior cingulate cortex and thereby elicited depressive-like behavior in adolescence
[4140]. Depression and anxiety provoked by chronic unpredictable stress were linked to upregulation of microglial phagocytosis by neuronal colony-stimulating factor (CSF) 1, leading to reduced dendritic spine density on pyramidal neurons in the medial prefrontal cortex
[4241]. In contrast, early-life stress disturbed microglial engulfment of excitatory synapses in stress-sensitive CRH-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus
[6160]. The resulting activation of the hypothalamo–pituitary–adrenal axis impaired behavioral stress response. In IBD, synaptic clearance and involved pathways like the complement system are yet to be investigated. First insights indicate loss of Map2-positive dendritic nerve fibers in the cortex and hippocampus during chronic DSS-induced colitis in aged mice
[3635].
Besides structural dynamics of synapses, neuroinflammation in IBD might cause neuronal cell death. In line with this, the number of total neurons in the cortex and hippocampus of aged mice with chronic DSS-induced colitis was reduced
[3635]. Correspondingly, elevated expression of caspase 3 indicated increased apoptotic cell death in the brain during acute colitis, although this was not yet assigned to particular cell types
[1615]. Besides apoptosis, other kinds of cell death were not addressed in the CNS during IBD. Altogether, neuroinflammation in IBD could contribute to psychiatric symptoms by inducing structural alterations or degradation of synapses or cell death of neurons.
Impairing neuronal plasticity is another pivotal mechanism by which neuroinflammation might be able to mediate neuropsychiatric symptoms. Adult neurogenesis, the generation of new neurons in the brain throughout adult life, only occurs in few niches including the subgranular zone of the hippocampal dentate gyrus. Adult hippocampal neurogenesis is involved in learning, memory, and pattern separation
[62][131]. However, impaired adult hippocampal neurogenesis is also linked to depression
[6361][6462]. Importantly, there is broad evidence for impaired adult hippocampal neurogenesis during neuroinflammation. While homeostatic microglia maintain adult hippocampal neurogenesis
[6563], inflammatory cytokines like Tnf
[6664], as well as Il-1β
[6765] and peripheral inflammation induced by LPS administration
[6866], inhibit NPC proliferation and maturation. Intriguingly, elevated blood levels of Ccl11, a chemokine also observed in the serum of CD and UC patients
[6967][70], decreased adult hippocampal neurogenesis during aging-related peripheral inflammation
[7168]. In the context of IBD, a direct mechanistic link between neuroinflammation and adult hippocampal neurogenesis was not yet shown, but several studies in acute and chronic DSS-colitis show impaired adult neurogenesis in the hippocampus
[7269][7370][7471][7572][7673]. Noteworthy, acute and chronic DSS-induced colitis altered distinct aspects of adult hippocampal neurogenesis. Acute colitis increased progenitor cell proliferation, but dysregulated cell cycle kinetics, while chronic colitis led to reduced migration and functional integration of newly generated neurons
[7269]. Collectively, adult hippocampal neurogenesis is vulnerable towards peripheral and cerebral inflammation and may contribute to IBD-linked neuropsychiatric symptoms.
Homeostatic brain functions, including adult neurogenesis, are governed by several trophic factors. One pivotal factor is the brain derived neurotrophic factor (BDNF), which signals via its receptor tyrosine receptor kinase b (Trkb). BDNF supports the release of neurotransmitters as well as the expression and function of neurotransmitter receptors and ion channels
[7774]. Moreover, BDNF augments synaptic plasticity and adult neurogenesis
[7774]. Interestingly, reduced BDNF levels were linked to depression
[4443], and a major mode of action of antidepressant drugs was recently revealed to be the amplification of BDNF-Trkb-signaling
[7875]. Of note, there is evidence for reduced BDNF signaling during neuroinflammation. The expression of BDNF is suppressed by Il-1β
[7976]. Furthermore, astrocyte-derived Il-33 was reported to reduce BDNF levels in the amygdala, which was linked to impaired signaling of GABAergic neurons
[8077]. In line with this, BDNF levels in the brain were reduced in acute and chronic DSS-induced as well as in DNBS-induced colitis
[2423][7471][7572][8178]. Treatment with liver hydrolysate rescued neuroinflammation and depressive-like behavior in acute DSS-induced colitis, putatively by inducing BDNF expression via adenosine monophosphate-activated protein kinase (AMPK)
[7572]. Though neuroinflammation and reduced BDNF levels were only coincident and not causally linked in IBD models, impaired BDNF signaling might be triggered by neuroinflammation and contribute to depression and anxiety in IBD.
In summary, neuroinflammation can trigger neuronal dysfunction via a plethora of distinct mechanisms, thereby mediating neuropsychiatric comorbidity in IBD. Though many of these potential mechanisms were described in animal models for IBD, a major limitation of most studies is the lack of a causal relation between coinciding neuroinflammation and depressive-like behavior. Only marginal data supporting this causality were generated in pharmacological studies. Inhibition of the DAMP S100a9 alleviated DSS-induced colitis, neuroinflammation, and behavioral impairment
[2423]. However, these effects might be explained solely by the reduction in colitis rather than interference with immune gut-to-brain communication. Interestingly, systemic inhibition of RNS did not affect TNBS-induced colitis but diminished hippocampal Tnf levels and reversed depressive-like behavior
[82][70]. Moreover, local intracerebroventricular administration of the antibiotic and immune modulatory drug minocycline reduced microglial activation and normalized synaptic plasticity in TNBS-induced colitis
[5279]. Though these findings link neuroinflammation and neuronal dysfunction in the context of IBD, the applied treatment paradigms are unspecific. Thus, more specific approaches are required to investigate the causal link between individual immune cell types, neuronal dysfunction and neuropsychiatric symptoms in IBD.