Project 4

Chronic psychosocial stress and colitis

Inflammatory disorders, such as Crohn's Disease (CD) and Ulcerative Colitis (UC) represent a major health concern, particularly in Western societies, with a life-time prevalence of approximately 0.1%. In addition to limiting quality of life due to abdominal cramps and pain, diarrhea, bloody stools, ulceration, fever, tiredness and other socially-unacceptable symptoms, inflammatory bowel disorders (IBD) are further linked to an increased risk for developing inflammation-related colorectal cancer (CRC).

The pathogenesis of IBD is still not completely understood. It is generally accepted that IBD has a complex and multi-factorial etiology, involving genetic and environmental factors, which are in turn associated with a dysregulation of the mucosal immune system. One environmental factor that is often discussed in this context during the last decades is the perceived level of life stress. Interestingly, available data suggest IBD to be rather associated with hypocortisolism than hypercortisolism.

In line with this hypothesis, we could already show that 19 days of chronic subordinate colony housing (CSC) not only result in basal evening hypocorticism but also reliably induce spontaneous colonic inflammation (Reber et al., 2007 PNEC; Reber et al., 2008 Stress; Reber et al., 2011 BBI; Reber, 2012 PNEC; Reber, 2016 PNAS; Fig. 5). The latter is causally mediated by a pronounced rise in CORT during the initial phase of CSC, preceding later development of hypocorticism and GC resistance, as well as by an increased bacterial translocation as consequence of disturbed colonic barrier functions. CSC-induced colitis is indicated by an increased histological damage score (Fig. 5), which is first detectable after 14 d of CSC, and increased numbers of colonic macrophages, dendritic and Th cells, and cytokine secretion from isolated lamina propria mononuclear and mesenteric lymph node cells, the latter lasting at least until day 8 following CSC termination. In addition, CSC mice show a pronounced reduction in the percentage of Treg cells in peripheral lymphoid organs (Schmidt et al., 2010 BBI), likely contributing to an overall increased inflammatory state and, consequently, to spontaneous colitis development.

Intriguingly, we just recently could show that CSC results in a pronounced expansion of enterohepatic helicobacter species (EHS) in the intestinal microbiome (Reber et al., 2016 PNAS) and that CSC-induced colitis does not develop under specific-pathogen-free (SPF) conditions (Langgartner et al., 2016 BBI), suggesting that translocation of certain pathobionts instead of commensal gut bacteria is critically required for development of stress-induced intestinal pathologies. Of note, stress-protective effects of M.vaccae pre-immunization were not mediated by preventing the colitogenic shift in the intestinal microbiome following CSC, but by inducing intestinal Treg cells, which in turn prevented that the colitogenic microbiome translates into colonic inflammation and tissue damage. Importantly, our data further indicate that CSC-induced HPA axis changes (i.e. hypocorticism) is not critically involved in CSC-induced colitis development (Reber et al., 2016 PNAS; Langgartner et al., 2016 BBI).

The value and clinical relevance of this interdisciplinary project has been acknowledged with the "Ismar-Boas Preis 2007" for excellent work in the field of gastroenterology from the "Deutsche Gesellschaft für Visceralchirurgie (DGVS)".

Currently we are investigating whether i) CSC-induced spontaneous colitis is causally involved in the increased anxiety state detected following CSC exposure and ii) colitis severity depends on the coping strategy of an individual shown during CSC exposure.

Funding: University intern budget; previously funded by the DFG grant RE-2911/2-1