Therapeutic resources for inflammatory bowel disease

Autoimmune disease in general and inflammatory bowel disease in particular arise from a constellation of causes that should be investigated and addressed on an individual basis. Nonetheless, methods that calm the inflammatory cascade (without harmful side-effects) are important practical tools. As forthcoming posts will describe in greater detail, nitric oxide production is a critical step in the production of damaging inflammation. A paper published in the European Journal of Clinical Investigation highlights this fact:

"Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn's disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO..."

And of interest for clinical case managment...

"The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis."

A study published in the British Journal of Pharmacology examines the ability of the natural flavonoid quercitrin (related to quercitin) to inhibit production of iNOS ('inducible nitric oxide synthase, the 'bad' nitric oxide producing enzyme). The authors state:

"Quercitrin, 3-rhamnosylquercetin, is a bioflavonoid with antioxidant properties, which exerts anti-inflammatory activity in experimental colitis. In the present study, different in vivo experiments were performed in order to evaluate the mechanisms of action involved in this effect, with special attention to its effects on proinflammatory mediators, including nitric oxide (NO)."

They examined the effects of quercitrin on inflammation of the intestinal mucosa ('lining') induced by DSS (dextran sodium sulfate) both preventatively and, in another cohort, on already established colitis. The results were significant:

"Oral treatment of quercitrin...ameliorated the evolution of the inflammatory process induced when administered in a preventative dosing protocol...on established colitis, it facilitated the recovery of the inflamed mucosa...The beneficial effects exerted by quercitrin were evidenced both histologically and biochemically, and were associated with an improvement in the colonic oxidative status..."

Regarding the role of NO and inflammatory bowel disease...

"...a reduction of colonic NO synthase activity was observed, probably related to a decreased expression in the inducible form of the enzyme [iNOS] via downregulation in the colonic activity of the nuclear factor-κB."

The authors discuss their findings in summary:

"During the last decade, it has become increasingly clear that NO overproduction by iNOS is deleterious to intestinal function...thus contributing significantly to gastrointestinal immunopathology...the results obtained in the present study reveal that colonic inflammation is associated with a higher colonic NOS activity, mainly attributed to an increase in iNOS expression...the effect showed by quercitrin is most probably related to an inhibition of the expression of this enzyme, which is upregulated as a consequence of the colonic inflammatory process...The antioxidant and/or scavenging properties ascribed to this flavonoid could also contribute to its intestinal anti-inflammatory effect..."

A study published in the European Journal of Immunology sheds more light on the use of quercitin for inflammatory bowel disease. Examining the relationship between quercitrin and quercitin, the authors find...

"...that the in vivo effects of quercitrin...can be mediated by the release of quercetin generated after glycoside's cleavage by the intestinal microbiota. This is supported by the fact that quercetin, but not quercitrin, is able to down-regulate the inflammatory response of bone marrow-derived macrophages in vitro."

They also describe evidence for the effect of quercitin on iNOS and the the NF-κB pathway:

"Moreover, we have demonstrated that quercetin inhibits cytokine and inducible nitric oxide synthase expression through inhibition of the NF-κB pathway...(both in vitro and in vivo). As a conclusion, our report suggests that quercitrin releases quercetin in order to perform its anti-inflammatory effect..."

A paper published in the journal Digestive Diseases examines the ability of quercitin to help repair the gut barrier in inflammatory bowel disease. Regarding the intestinal epithelial barrier ('lining') the authors state:

"In inflammatory bowel disease (IBD), epithelial barrier function is impaired contributing to diarrhea by a leak flux mechanism and perpetuating inflammation by an increased luminal antigen uptake. This barrier of the intestinal epithelium is composed of the apical enterocyte membrane and the epithelial tight junction (TJ) and can be affected by TJ alterations, induction of epithelial apoptoses and appearance of gross lesions like erosions or ulcers as well as by accelerated transcytotic antigen uptake."

They note that in addition to therapies that oppose Th1 cytokine activity in Crohn's disease  and Th2 cytokine activity in ulcerative colitis, other agents have been shown to improve barrier function:

"...zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown. Finally, food components can strengthen the epithelial barrier as for example the flavonoid quercetin which has been shown to upregulate claudin-4 within the epithelial TJ."

Curcumin (extracted from the yellow spice turmeric) should also be considered in the functional management of inflammatory bowel disease. The authors of a study published in the journal Inflammatory Bowel Diseases observe:

"Neutrophils (PMN) are the first cells recruited at the site of inflammation. They play a key role in the innate immune response by recognizing, ingesting, and eliminating pathogens and participate in the orientation of the adaptive immune responses. However, in inflammatory bowel disease (IBD) transepithelial neutrophil migration leads to an impaired epithelial barrier function, perpetuation of inflammation, and tissue destruction via oxidative and proteolytic damage. Curcumin (diferulolylmethane) displays a protective role in mouse models of IBD and in human ulcerative colitis, a phenomenon consistently accompanied by a reduced mucosal neutrophil infiltration."

They investigated the phenomenon of neutrophil modulation by curcumin in vitro and in vivo. Their accumulated data demonstrated that...

"Curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and secretion of macrophage inflammatory protein (MIP)-2, interleukin (IL)-1β, keratinocyte chemoattractant (KC), and MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a well as the IL-8-mediated chemotaxis of human neutrophils. At nontoxic concentrations, curcumin inhibited random neutrophil migration, suggesting a direct effect on neutrophil chemokinesis."

In other words, curcumin was shown to significantly attenuate proinflammatory cytokine expression and white blood cell 'attack movements'. Thus the authors conclude:

"Our results indicate that curcumin interferes with colonic inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil chemotaxis and chemokinesis."

A double-blind, placebo-controlled trial of curcumin for the treatment of ulcerative colitis was reported in the journal Clinical Gastroenterology and Hepatology. The authors state:

"Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC)."

They divided a cohort of 89 patients with quiescent UC into a treatment group of 45 who added 1 gram of curcumin taken two times per day to their usual therapy. The other 44 got a placebo.  After 6 months the relapse percentages were 4.65% for those who received curcumin and 20.51% for the placebo group.

"Furthermore, curcumin improved both CAI [clinical activity index] and EI [endoscopic index], thus suppressing the morbidity associated with UC."

The authors conclude:

"Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings."

It's also worth noting a paper published in the journal Current Pharmaceutical Design examines the multiple anti-inflammatory effects of curcumin. The authors first state:

"Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life... it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines."

They note that earlier research has demonstrated that curcumin inhibits inflammation through action on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-κB, a key factor in the production of proinflammatory cytokines), and has a strong anti-oxidant effect.

"Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles..."

And in an early successful human IBD study..

"...patients were given curcumin (360mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD."

While it's difficult to predict ahead of time which patients will have the best response to agents such as curcumin and quercitin, since they are so safe and wholesome we can welcome the authors' conclusion:

"The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-α, IFN-γ, NF-κB and its unrivaled safety profile suggest that it has bright prospects in the treatment of IBD."