Current Pharmaceutical Design - Volume 9, Issue 4, 2003

Although the cause of Crohn's disease remains unknown considerable progress has been made in recent years to unravel the pathogenesis of the inflammatory processes seen in chronic idiopathic inflammatory bowel diseases (IBD). Th-1 lymphocytes seem to orchestrate the inflammation through the production of pro-inflammatory cytokines such as IFN-γ, IL-1β and tumor necrosis factor (TNF). After isolation and characterization of TNF and its two receptors (p55 and p75) detailed regulatory processes for transcription, secretion and post receptor actions of TNF are now rapidly being discovered.Genetically engineered monoclonal antibodies, specifically directed against TNF are only the first drugs acting against TNF, available for clinical use now in the treatment of Crohn's disease. A single IV injection of these antibodies produces very dramatic clinical, endoscopic and histological responses in a majority of refractory patients. More data on long term safety and the exact role in combination with standard therapies are being awaited. In the mean time, these drugs should be reserved for patients not responding to standard antiinflammatory therapy.The exciting “TNF story” very nicely illustrates how the benchmark of basic immunological research now provides us with very potent and rationally designed drugs. Expected and unexpected safety toxicity data should caution clinicians to a certain extent against too liberal use of these agents interfering with very basic physiological events.

Proinflammatory cytokines have been demonstrated to play a crucial role in the pathogenesis and physiopathology of various chronic inflammatory conditions including Crohn's disease (CD). Among these cytokines, interleukin-6 (IL-6) must be especially important because increased serum concentrations of acute phase proteins, reduced level of serum albumin, and remarkable thrombocytosis are all well-explained by the increased level of IL-6. Moreover, IL-6 is capable of stimulating even IL-6 receptor (IL-6R) negative cells such as vascular endothelial cells when complexed to soluble form of IL-6R (sIL-6R), and serum level of IL-6 as well as sIL- 6R has been demonstrated to increase during inflammation. To investigate the therapeutic potential of IL-6 signaling blockade for CD, anti-IL-6R monoclonal antibody (mAb) was introduced to various murine models of colitis. Anti-IL-6R mAb successfully prevented wasting disease and the development of macroscopic and histological lesions. It suppressed the accumulation of ICAM-1 positive and Mac-1 positive cells in the lamina propria (LP) and the expression of ICAM-1 and VCAM-1 by vascular endothelial cells. Expansion of colonic and splenic CD4+ T cells was reduced as well as the colonic expression of tumor necrosis factor α (TNF-α), IL-1β, and interferon γ (IFN-γ) mRNA without affecting the production of transforming growth factor β (TGF-β), IL-10, and IL-4 mRNA. The treatment also suppressed established colitis by inducing LP T cell apoptosis. These results strongly suggest that specific targeting of IL-6 / sIL-6R pathway will be a promising new approach for the treatment of CD, and the clinical trial of humanized anti-IL-6R mAb is now under way.

Background The administration of steroids is not always effective for the treatment of ulcerative colitis (UC). Their long-term use often causes adverse effects which sometimes result in their stoppage and acute exacerbation. Therefore, an alternative treatment is necessary in order to decrease steroid dosage and avoid the clinical problems associated with steroids.Methods The effectiveness and adverse effects of a leukocytapheresis (LCAP) were investigated in a controlled multicenter trial with randomized assignment of 76 active-stage UC patients in two groups. In the LCAP group (39 patients), LCAP weekly for 5 weeks as an intensive therapy was added to the on-going drug therapy, while steroids were maintained but not increased, and then LCAP was gradually reduced to once every 4 weeks as a maintenance therapy. In the high dose prednisolone (h-PSL) group (37 patients), PSL was added or increased 30∼40 mg / day for moderately severe and 60∼80 mg / day for severe patients and then gradually tapered.Findings The LCAP group showed a significantly higher effectiveness (74% vs. 38%, p=0.005) and lower incidence of adverse effects (24% vs. 68%, p<0.001). The patients were able to continue the trial for a longer period in the LCAP group than the h-PSL group (p=0.012). Clinical activity and endoscopic indexes showed the LCAP group had better improvements than the h-PSL group.Interpretation The results of the trial show that LCAP permits a reduction in total PSL dosage and is more effective and safer than high-dose PSL administration for intensive therapy, and LCAP may maintain remission longer than PSL.

Even with the development of new therapeutic agents, such as infliximab, enteral nutrition (EN) and parenteral nutrition (PN) therapies remain important for the treatment of Crohn's disease because Crohn's patients often require nutritional support. Furthermore, nutritional therapies can be used in the control of disease activity. Elemental diets, which are mainly used in EN therapy, consist of a refined amino acid mixture, glucose or maltodextrins and minimal essential fatty acids. EN therapy can reduce mucosal inflammation by the elimination of dietary antigens, which induce inflammation, and by reductions in fat, which activates inflammation. EN is applied not only as induction therapy, but also as maintenance therapy after remission (home EN). However, the unpalatability of elemental diets, difficulties related to self-intubation and the high cost of EN have limited its application as a primary therapy in western countries. PN is utilized as complete bowel rest supporting nutrition. However, since the therapeutic efficacies of EN and PN are similar, the indications for PN are limited and PN is mainly utilized in patients with bowel obstructions or severe fistulas. PN is also used as home therapy in the treatment of Crohn's patients with short bowel syndrome. However, long-term PN sometimes causes life-threatening complications including catheter-induced sepsis, liver failure and lethal mineral deficiencies. We suggest that gastroenterologists should recognize the advantages and limitations of all therapies and choose carafully or combine various therapies in order to maintain the quality of life in individual patients even if in cases where remission can not be achieved.

Because the intestinal microflora play an important role in the development of inflammatory bowel disease (IBD), there is currently some interest in the manipulation of the composition of the microflora towards a potentially more remedial community. This review summarizes the clinical and experimental efficacy of the manipulation of microflora by the use of prebiotics, probiotics, synbiotics, and antibiotics in IBD. Prebiotics, defined as nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of one or a limited number of bacterial species already resident in the colon, can modulate the colonic microbiota by increasing the number of specific bacteria and thus changing the composition of the microbiota. Prebiotics for IBD include lactosucrose, oligofructose, inulin, bran, psyllium, and germinated barley foodstuff (GBF). GBF, which mainly consists of dietary fiber and glutamine-rich protein, is a prebiotic foodstuff for ulcerative colitis. GBF has shown to be converted into a preferential nutrient for colonocytes through Eubacterium and Bifidobacterium and also inactivate nuclear factor kappa B (NFkB). Moreover, it exhibits a potent waterholding capacity and bile-acid binding capacity. Probiotics, which are microbial food supplements that beneficially affect the host by improving the intestinal microbial balance, have been used to change the composition of colonic microbiota. The approaches for IBD include VSL No.3, Nissle1917, Clostridium butyricum and Bifidobacterium-fermented milk. Use of Lactococci secreting IL-10 provides excellent results. The combination of prebiotics and probiotics in a synbiotic has not been studied in IBD but is promising. The use of antibiotics continues to be of interest. Although these strategies hold great promise and appear to be useful in some settings, more clinical study is needed to firmly establish the relevance of these therapies.

Luminal nutrition is important for maintenance of gastrointestinal mucosal structure and function. In particular, short chain fatty acids (SCFAs), metabolic products of anaerobic bacterial fermentation of dietary fiber and resistant starch, are particularly important as the preferred respiratory fuel of the colonocytes. A variety of biological effects of SCFAs have been reported, and there is now increasing number of experimental works showing new aspects of these molecules. For example, as the mechanisms mediating anti-inflammatory effects of SCFAs, several investigators identified the inhibitory effect of butyrate on proinflammatory cytokineinduced NF-κB activation. Various inflammatory responses are now discussed with the central role of NF-κB activation, and thus the inhibition of NF-κB activation represents the efficacy of dietary fiber and SCFAs in the treatment with inflammatory bowel disease. Furthermore, recent advance in molecular technology has identified mechanisms mediating anti-tumor effects of SCFAs. SCFAs modulate expression of cell cycle-regulating proteins and induce apoptosis in colon cancer cells. SCFAs increase the susceptibility of colon cancer cells to complement-mediated cell injury. In this review, new aspects of functions of SCFAs are focused and summarized.