Inflammatory Bowel Disease (IBD), which comprises Crohn’s disease and ulcerative colitis, is a chronic inflammatory condition with a relapsing course. As IBD is associated with psychiatric disorders such as depression and anxiety as well as cognitive impairment, it was suggested that these psychological factors might predispose an individual to develop the disease. Now it is clear that there is bi-directional communication between the gut and the central nervous system (Kennedy et al, 2012) and our recent finding identifies a new mechanism by which IBD might cause behavioral manifestations (Zonis et al, 2015).

The generation of new neurons continues throughout adulthood in the subgranular zone of the dentate gyrus of the hippocampus. It is well accepted that adult hippocampal neurogenesis is involved in memory and learning (Aimone et al, 2014) and various aspects of emotion and the stress response (Cameron and Glover, 2015). Thus, disruption of hippocampal neurogenesis could have profound effects on a wide range of behaviors. Among many other factors, inflammation and pro-inflammatory cytokines negatively affect neurogenesis. Peripheral inflammation can signal the brain by activating the vagus nerve and Toll-like receptors in the circumventricular organs, and pro-inflammatory cytokines can enter the brain through saturable transport systems. Engagement of this immune-to-brain communication ultimately leads to the activation of resident microglia, which is a major source of pro-inflammatory cytokines in the brain.

Previously we found that during acute systemic inflammation, cytokines upregulated in the hippocampus trigger p21Cip1 (p21) induction in cells of neuronal lineage (Zonis et al, 2013). p21 is a cyclin-dependent kinase inhibitor that restrains cell cycle progression, thereby reducing neurogenesis. Neuronal progenitors treated in vitro with the pro-inflammatory cytokine interleukin-6 (IL-6) exhibit p21 induction and decreased proliferation, whereas IL-6 had no effect on the proliferation of progenitor cells derived from mice lacking p21. Thus, a direct inhibitory effect of IL-6 on neurogenesis is mediated by the induction of p21.

Unlike acute transient inflammation, chronic inflammatory disease might have continuing and long-lasting effects on neurogenesis. To assess the effects of chronic peripheral inflammation, we utilized the dextran sodium sulfate mouse model of IBD (Strober et al, 2002). This model produces colonic epithelial cell lesions and later chronic intestinal inflammation beginning 20 days after treatment. We found increased plasma levels of IL-6, indicative of the presence of systemic inflammation and this was accompanied by increased expression of Iba1, a marker of activated microglia, and the induction of IL-6, IL-1β, and p21 in the hippocampus. We also found a decrease in the number of newly developing neurons, likely due to cytokine-induced p21 expression in early neuronal progenitors. Subsequent in vitro experiments with neuronal progenitor cells confirmed that in addition to IL-6, the pro-inflammatory cytokines IL-1β, and TNF-α also increase p21 expression (Zonis et al, 2015).

Our findings demonstrate that cytokine-induced p21 might have an important role in restraining neurogenesis during acute and chronic inflammation. These data reveal a previously unknown and potentially important signaling pathway for gut–brain interactions. Continuous immune signaling as a consequence of peripheral inflammation occurs in many chronic disorders, such as autoimmune disease, cancer, diabetes and obesity, and these illnesses manifest behavior abnormalities including cognitive impairment and depression. It is possible that the disruption of hippocampal neurogenesis might underlie some of the behavioral sequelae of IBD and other disorders associated with chronic inflammation (Figure 1).

Figure 1
figure 1

A proposed model for gut–hippocampus interaction. Peripheral inflammatory cytokines released during chronic intestinal inflammation activate microglia with subsequent induction of cytokines and p21 in early neuronal progenitors, effectively halting hippocampal neurogenesis and affecting behavior. SGZ-subgranular zone.

PowerPoint slide

Funding and Disclosure

This work was supported by NIH grant MH79988 and NARSAD Independent Investigator Award (VC). The authors declare no conflict of interest.