Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice

Abstract

IBD, a chronic inflammatory disease, has been manifested as a growing health problem. No Crohn's and Colitis councils have officially ratified anti-depressants as a routine regimen for IBD patients. However, some physicians empirically prescribe them to rectify functional bowel consequences such as pain and alleviate psychiatric comorbidities. On the other side, SSRIs' prescription is accompanied by adverse effects such as sleep disturbances. Prolonged intermittent hypoxia throughout sleep disturbance such as sleep apnea provokes periodic reductions in the partial oxygen pressure gradient in the gut lumen. It promotes gut microbiota to dysbiosis, which induces intestinal inflammation. This phenomenon and evidence representing the higher amount of serotonin associated with Crohn's disease challenged our previous knowledge. Can SSRIs worsen the IBD course? Evidence answered the question with the claim on anti-inflammatory properties (central and peripheral) of SSRIs and illuminated the other substantial elements (compared to serotonin elevation) responsible for IBD pathogenesis. However, later clinical evidence was not all in favor of the benefits of SSRIs. Hence, in this review, the molecular mechanisms and clinical evidence are scrutinized and integrated to clarify the interfering molecular mechanism justifying both supporting and disproving clinical evidence. Biphasic dose-dependent serotonin behavior accompanying SSRI shifting function when used up for the long-term can be assumed as the parameters leading to IBD patients' adverse outcomes. Despite more research being needed to elucidate the effect of SSRI consumption in IBD patients, periodic prescriptions of SSRIs at monthly intervals can be recommended.

Keywords: Crohn’s disease; anti-inflammatory; antidepressant; dysbiosis; inflammatory bowel diseases; pro-inflammatory; serotonin uptake inhibitors; ulcerative colitis.

Figure 1

Serotonin Metabolism. Tryptophan intracellular transport is carried out by an L-amino acid transporter; then, it turns to 5-hydroxytryptophan, which is facilitated by tryptophan hydroxylase-1. In the second step, aromatic L-amino acid decarboxylase converts 5-hydroxytryptophan into 5-hydroxytryptamine; eventually, serotonin is stored in vesicles by Vesicular Monoamine Transporter. With the influx of Ca²⁺, serotonin is exocytosed into the extracellular matrix. After affecting the targeted receptors, it is reabsorbed by the serotonin transporter and degraded by Monoamine oxidases to 5-hydroxyindoleacetic acid.

Figure 2

Anti-Inflammatory properties of SSRIs. (A) CNS-mediated mechanisms: SSRIs target microglial cells to impact through TLR4 and CD14, resulting in decreased inflammatory cytokines generation (IL-1ß and TNF-α) and reduced free radicals production. HPA-axis activation via alteration in cytokine network comes up with inflammation decrement. (B) Peripheral mechanisms: T-cell activation is inhibited by diminished antigen presentation of intestine-habitant DC. Circulating immune cells are also impressed; increasing cAMP in monocytes and macrophages brings about inflammatory cytokines drop. Generic immune cells were targeted through decreased pro-inflammatory cytokine gene expression, followed by subsidence in the NF-κB pathway activity and B-cell activation. Also, alleviating TLR3 activity with the inhibition of the IRF3 pathway leads to an inflammation drop. SSRIs directly affect T-cell by reducing TLR2/4 expression, a decline in IFN-γ generation, a rise in IL-10 production, and disturbance in their proliferation.

Figure 3

The dual demeanor of Serotonin. (A) Anti-Inflammatory: The gut microbiota enter the Trp into Ahr and Kyn pathways and the 5-HT synthesis process. Initially, SSRIs inhibit 5-HT reabsorption in platelets and myenteric nerves and boost mucosal serotonin content, initiating anti-inflammatory mechanisms. Proliferation and resistance to ROS arise in the epithelium via the 5-HT4 receptor. 5-HT reduces TNF-α production by monocytes and macrophages (1) directly through their 5-HT4 and 5-HT7 receptors and (2) indirectly via the 5-HT4 receptor on the myenteric nerve, which is accompanied by releasing Ach that eventually comes up with IL-1ß, IL-6, and TNF-α decrement. Similar changes in TNF-α fabrication occur via B-cell, T-cell, and NK cell 5-HT2 receptors. Additionally, 5-HT7 on the DC turns down the IL-6 and IL-1ß and elevates IL-10. (B) Pro-inflammatory: Over time, SSRI dosage augmentation affects, directly and indirectly, the gut microbiota composition, and disrupts Ahr and Kyn pathways. Pathogens’ toxins pass the leaky epithelium created by dysbiosis and stimulate the gut toward inflammation. Moreover, the inhibition of 5-HT reabsorption is amplified, resulting in much more serotonin levels. This primes pro-inflammatory mechanisms, which are known as the endocrine-immune axis. Macrophage phagocytosis is reinforced, and through the 5-HT2 receptor, they release IL-2 that activates T-cells. In addition, by acting on DC, 5-HT activates T-cells and increases IL-17, IL-12, and IFN-γ via the NF-κB pathway. Monocyte 5-HT1A receptor provocation reduces the inhibitory effect on NK-Cell to increase IFN-γ production. On the other hand, the impacts on 5-HT3, 5-HT4, and 5-HT7 monocyte receptors increase IL-6, IL-8, and INF-1ß. Also, B-Cell proliferates and activates through 5-HT1A receptor instigation. The serotonin amount can boost neutrophil, basophil, and mast cell chemo-toxicity. This process is turned into a destructive cycle since increased T-cells (CD4⁺ types) initiate the immune-endocrine axis (EC cells proliferation and boosting the serotonin content). Eventually, the destructive cycle exacerbates the inflammation.