Inflammatory Bowel Diseases (IBD) include the two major forms Crohn’s disease (CD) and ulcerative colitis (UC). These disorders are characterized by episodes of inflammatory flares and periods of remission. IBD pose a substantial socio-economic burden to our healthcare systems: Patients typically suffer from abdominal pain, diarrhea, anemia, weight loss and fatigue, symptoms that may severely affect the quality of life and ability to hold down an employment. Moreover, IBD is a common inflammatory disease with more than 400.000 patients only in Germany. IBD typically affects young people, with a peak disease onset between 15 and 30 years of age. Finally, IBD currently cannot be cured, as the pathophysiology of this disease is incompletely understood. Thus, there is an urgent need for collaborative basic and clinical research on IBD.
It is nowadays widely accepted that IBD is driven by dysregulated intestinal immune responses against the patients’ microbiota and maybe other environmental factors. However, the cause of this dysregulation is unknown. Another unresolved question is the pathophysiological origin of the differences between the clinical features of both prototypic forms of IBD. Inflammation in Crohn’s disease can affect all parts of the gastrointestinal tract, although the ileum and ascending colon are most frequently affected. Such inflammation may cause strictures and stenosis of the small or large bowel. Patients with CD may also develop fistulas particularly in the perianal region. A pathophysiological interesting feature of CD is that inflammation can be discontinuous with inflamed bowel parts separated by uninflamed areas. In contrast, ulcerative colitis typically initiates in the rectum and can involve other parts of the colon in a continuous manner. Another major difference between CD and UC is given by the fact that inflammation in CD can be transmural, affecting all parts of the bowel wall, while in UC patients inflammation is restricted to the mucosa and submucosa. Additional important features of IBD are the appearance of extraintestinal manifestations, such as inflammatory lesions in the joints, the skin and the eyes, and the susceptibility of patients with a long disease history of IBD to colon cancer. How these diseases are linked to the pathophysiology of IBD and whether these are unspecific consequences of an overly excessive immune response or an independent consequence of a yet to be defined immune disease is currently unclear.
Since the cause of CD and UC are still unknown, there is currently no causative therapy available for patients with IBD. Clinical practice therefore aims at mitigating the symptoms associated with these diseases. Therapy in general is dominated by immunosuppressive drugs, such as corticosteroids that aim at downregulating the excessive immune responses within the intestinal mucosa. However, clinical practice demonstrates that currently available therapies induce remission only in subgroups of patients. Moreover, many patients develop a steroid-refractory or steroid-dependent disease course upon long-term treatment with corticosteroids. Additionally, immunosuppressive agents such as azathioprine (CD, UC) or cyclosporine A (UC) have been successfully used in IBD patients, but also these drugs are effective in subgroups of patients only. In severe therapy refractory cases, surgery is necessary to remove inflamed bowel parts in CD or the colon in UC.
IBD research aims at developing selective and specific drugs, which interfere with pathophysiologically important pathways, while at the same time leaving the patient as immunocompetent as possible. The downside of this approach is that development of targeted therapies requires a very detailed understanding of the pathophysiology of IBD in order to identify specific mechanisms. Development of such targeted strategies is a major aim of the collaborative research center TRR241. Clinical practice demonstrates that individual patients respond to certain drugs while they do not respond to others. This observation indicates that there might be different causes of IBD and different pathomechanisms of mucosal inflammation may be present in patients. This concept implies that individual patients might benefit from different therapeutic regimes. In the future, clinical practice might therefore personalize drug therapies in order to provide each patient with the optimal drug.
IBD most likely is caused by a combination of several factors, including genetics, mucosal immunity, the intestinal microbiota and environmental factors. In the past decades, genome-wide association studies (GWAS) have led to the identification of more than 200 gene loci associated with IBD. Most of these loci were found to be associated with both CD and UC, implicating that both IBD forms share many, but not all pathophysiological features. It is striking that many genes associated with IBD encode for proteins involved in maintaining the intestinal epithelial barrier and in innate immune defense mechanisms. Support for a barrier-related etiology also comes from human studies, as IBD patients frequently show increased intestinal permeability. One might therefore speculate that IBD is initially caused by an aberrant translocation of luminal bacteria and/or an inappropriate handling of bacteria or bacterial products by innate immune cells. Recent mechanistic studies in mice have generated strong functional support for a crucial function of the intestinal epithelium in maintaining intestinal immune homeostasis. These studies evidenced that perturbations in the homeostatic regulation of epithelial turnover and also defects in epithelial cell functions including mucin secretion and release of antimicrobial peptides ultimately lead to a breakdown of the epithelial barrier, increased permeability and chronic intestinal inflammation with features similar to IBD in human patients.
Like patients with IBD, healthy individuals can also show increased intestinal permeability without developing IBD. It therefore appears that increased permeability alone is not sufficient to explain the development of IBD. It has been speculated that in the presence of barrier dysfunction, interactions between the epithelium and adjacent immune cells might lead to an aberrant activation of intestinal immune responses. Recent data from animal models of IBD indeed point to a key role of signaling pathways in gut resident cells, including Innate Lymphoid Cells (ILC) and their cytokines for immune homeostasis. ILCs have been extensively characterized and emerge as gatekeepers and regulators of the intestinal epithelial barrier. Another tissue resident cell population that contributes to the development and perpetuation of intestinal inflammation are sensory neurons. Despite stunning experimental evidence for their impact, it is currently unknown how they regulate intestinal immunity in IBD. Sensory neurons carry TRP (transient receptor potential)-channels, which control the release of immunomodulatory and –stimulatory neuropeptides. While the primary cause of IBD development remains unknown, it can be regarded as a fact that yet to be identified causative initial events culminate in persistent immune responses with infiltration of immune cells and tissue destruction. Immune cell populations present within the inflamed bowel wall of IBD patients have been extensively characterized and studied for many years. Studies that were focused on T lymphocytes have demonstrated that the mucosa of IBD patients is heavily infiltrated by effector T cells. Regulatory T cells (Treg) are also present within the lamina propria and these cells control the effector T cell populations mentioned above. Why such immune control mechanisms fail in IBD patients remains unknown. Interestingly, several gene loci that were identified in genomic studies point towards an aberrant regulation of T helper cell differentiation in IBD patients. Accordingly, associations between IBD and the genes for IL-12B, STAT3 and JAK2 were identified, molecules that are involved in the fine tuning of T cell responses and in the differentiation of T cells towards Th1, Th9, Th17 and Treg cells, respectively. Collectively, there is substantial evidence that dysregulated or overactive adaptive immune responses towards luminal antigens such as the microbiota are important contributors to the pathogenesis of IBD. Thus, while the healthy intestine is characterized by a balance of immunostimulatory and immunoregulatory mechanisms, protective mechanisms in patients with inflammatory bowel disease are not able to control the immune response.
Towards a new concept of IBD
In summary, over the years, IBD researchers have highlighted at least two important components in the pathophysiology of IBD, which have been mostly studied in an independent fashion:
- the various local immune cell populations and their associated mediators and
- the epithelial barrier as a shield of the bowel wall against the intestinal microbiota.
Our research within the TRR 241 will integrate aspects and knowledge of these two components into a new concept highlighting the role of immune-epithelial crosstalk in the pathogenesis of IBD.
It is now evident, that the intestinal epithelium should not be considered simply a physical barrier but rather a highly dynamic tissue, which responds to a plethora of environmental stimuli including the intestinal microbiota, as well as to local or systemic signals derived from the immune system or other cells. The epithelial response to these extrinsic signals in turn regulates barrier function, microbiota composition as well as mucosal immune homeostasis and inflammatory responses within the lamina propria. However, crucial insight is missing on how the crosstalk between the epithelium and immune cell populations as well as their associated mediators shape the long-term cellular responses that are instrumental in governing the outcomes of chronic inflammatory processes in IBD. From our standpoint, it is clear that substantial efforts will have to be made in filling this knowledge gap to achieve a more comprehensive understanding of cellular interactions in IBD.