Interleukin-6 in irritable bowel syndrome: A systematic review and meta analysis of IL-6 (-G174C) and circulating IL-6 levels

Background: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which presents with abdominal pain and alterations of the bowel habits. The pathophysiology of IBS is not well-recognized. Low grade inflammation has been suggested as one of the underlying mechanisms of IBS. Variations in the circulating pro-inflammatory interleukin-6 (IL-6) levels and IL-6 gene polymorphisms have been demonstrated in IBS. However, the results of published studies are not consistent, probably due to their small sample sizes. To address this inconsistency, we conducted the current systematic review and meta-analysis on serum/plasma IL-6 levels and IL-6 (-G174C; rs1800795) gene polymorphism in IBS. Methods: PubMed was searched in July 2016. Case-control studies on serum/plasma IL-6 levels and IL-6 (-G174C) gene polymorphisms in IBS versus control were retrieved. The quality of studies was evaluated based on the modified Newcastle-Ottawa Scale (NOS) with 0 indicating the lowest and 9 as the highest score. Results were pooled using: (a) the standardized mean difference (SMD) for IL-6 levels which was considered statistically significant when the 0 value was not within the 95% confidence interval (CI), or (b) odds ratio (OR; 95% CI) through converting and pooling the IL-6 (-G174C) genotypes and alleles data into individual 2 x 2 tables. Heterogeneity was assessed based on I-2 values; where I-2 <= 50% and I-2 > 50% designated using fixed and random effect models, respectively. Results: Circulating IL-6 levels are higher in IBS patients compared to controls (SMD: 2.40 [95%CI: 0.53-4.28]; p = 0.01). Categorizing data based on IBS subtypes, showed that IL-6 level is significantly higher in diarrhea predominant IBS (IBS-D) compared to control (SMD: 2.62 [95%CI: 0.29-4.95]; p = 0.03), while it is comparable in constipation predominant IBS (IBS-C) and alternating IBS (IBS-A) patients with healthy controls. The meta analysis of IL-6 (-G174C) polymorphism in IBS and based on IBS subtypes showed no difference in the distribution of genotypes or alleles compared to control. Conclusion: The higher IL-6 levels in IBS and more specifically in IBS-D suggests a pro-inflammatory phenotype in these patients, while this phenomenon is not supported by the polymorphism of IL-6 (-G174C). Increased IL-6 in IBS might be an acquired phenomenon or mediated by other genotypes. Any potential association between gene polymorphisms and IL-6 levels in IBS should be tested by assessing both IL-6 levels and IL-6 (-G174C) simultaneously in the same IBS subjects compared to their healthy controls. Categorizing patients based on their circulating IL-6 levels may introduce a new opportunity for personalized anti-inflammatory therapies of IBS.