Original articleConjugated linoleic acid modulates immune responses in patients with mild to moderately active Crohn's disease
Introduction
Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disease of the gastrointestinal tract characterized by two clinical and histopathologic manifestations: Crohn's disease (CD) and ulcerative colitis (UC). CD results in transmural lesions that can affect the entire gastrointestinal tract, whereas in UC lesions are continuous, reside within the mucosal layer and are localized in the colon. The etiology of IBD is unknown although there is increasing evidence of an interplay between genetic susceptibility factors, environmental triggers and immune dysregulation.1 Dietary supplementation with anti-inflammatory agents provides a unique and potentially safer way of treating mucosal disease and has lead to the evolution of the field of nutritional immunology.2, 3
Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of octadecadienoic acid. Several CLA isomers, including cis-9, trans-11 CLA, are naturally found in milk, cheese and ruminant products. In addition to the well characterized benefit of CLA on body composition, CLA exerts numerous anti-inflammatory and anti-oxidant properties that have been characterized in animal models including arthritis,4 type I hypersensitivity5 and intestinal inflammation.6, 7, 8
Dietary CLA-supplementation suppresses colonic inflammation and up-regulates colonic PPAR γ expression in pigs with bacterial-induced colitis.6 In addition, activation of colonic peroxisome proliferator-activated receptor (PPAR) γ by CLA mediates protection from experimental IBD in mice7 and n-3 PUFA antagonizes the effects of CLA on PPAR γ in a pig model of DSS colitis.8 Dietary CLA has been shown to ameliorate inflammation-driven colorectal cancer by activating immune and epithelial cell PPAR γ in a mouse model.9 There have been reports documenting increases of PPAR γ expression and activity in adipocytes,10 skeletal muscle,11 colonic mucosa12 and macrophages13, 14 with CLA treatment or CLA-rich diets. However, a reduction in PPAR γ expression in adipocytes by CLA has also been reported.15, 16 This may be due to cell-type specificity of the response to CLA or isomer specificity since the t10, c12 reduced PPAR γ expression in adipocytes but the c9, t11 failed to show the same suppressive effect on PPAR γ activity.17 Interestingly, some probiotic bacteria produce c9, t11 CLA and other anti-inflammatory metabolites locally in the gut that targets PPAR γ in colonic lamina propria macrophages to suppress colitis.18
Modulation of gut inflammation through PPAR γ-dependent mechanisms has a precedent in IBD therapy, the intestinal anti-inflammatory effect of 5-aminosalycylate, a broadly used IBD therapy, is mediated by PPAR γ19 and rosiglitazone, a PPAR γ ligand used in diabetes has been shown to be effective in the treatment of ulcerative colitis.20 However, the universal application of rosiglitazone or other (thiazolidinediones) TZDs to IBD treatment is unlikely due to reports of increased cardiovascular effects including myocardial infarction and heart failure and the restrictions on rosiglitazone (Avandia) use set by the U.S. Food and Drug Administration (FDA).21
CLA has also demonstrated efficacy in modulating immune responses to vaccination and challenge in pig models, which have the advantage of closely resembling the human immune system. Specifically, dietary CLA-supplementation enhanced cellular immunity by modulating phenotype and effector functions of CD8+ T cells22 and enhanced anti-viral responses in pig models.23, 24 These results were in line with the findings of a human study suggesting modulation of immune responses to hepatitis B virus vaccination.25
Together the previous findings highlight the importance of CLA as a unique compound that can suppress inflammatory lesions in the gut while stimulating adaptive cellular immune responses to viral and bacterial pathogens. This is in contrast with current IBD therapies that have potent immune suppressive effects that can increase the risk of patients to infections. The objective of the present study was to characterize the systemic immune modulatory activity of CLA in patients with active CD and as a secondary endpoint to explore its effects on ameliorating disease activity and quality of life.
Section snippets
Patients
A total of 24 patients with mild to moderately active CD (estimated CDAI > 150 - < 450) were screened for enrollment into the study between August 2009 and February 2011. Patients were required to be on stable medications 2 months prior to entry and could not be on prednisone at the time of screening. There were 11 screening failures. Thirteen patients completed the study and 1 patient withdrew prior to the six-week evaluation due to side effects related to joint pain. Clinical and demographic
Patients
A total of 23 patients were screened for entry into this open label trial. There were 9 screening failures due to CDAI measurements under 200 and scheduling conflicts. There were 2 additional screening failures due to a concomitant flare of gout in one subject and introduction of an excluded medication in a second patient. One subject withdrew at 11 weeks due to lack of efficacy and increasing joint activity, however, data was included using the withdrawal visit at week 11 for the week 12 data.
Discussion
Current pharmacological therapies for CD are modestly successful for the long-term management of the disease and result in significant side effects, including infections and cancer resulting from immunosuppression caused by these drugs.30 Dissatisfaction with current traditional therapies, the chronicity of the disease and concern over side effects have resulted in increased use of naturally occurring and potentially safer compounds such as CLA.31 Accordingly, the incidence of complementary and
Statement of authorship
JBR, KLI and RH designed the experiments, interpreted the results, contributed to write the paper and directed the project. KLI, MS, RB and HHH performed the human subject recruitment. WTH conducted the cytokine and lymphoproliferation studies and prepared figures.
Conflict of interest
No conflicts.
Acknowledgments
Supported by a grant from Cognis GmbH, Monheim, Germany (Cognis is now part of BASF) to Josep Bassaganya-Riera.
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