Published: Oct 14, 2013 | Updated: Oct 16, 2013
By Charles Bankhead

Full Story:   http://www.medpagetoday.com/MeetingCoverage/ACG/42247

SAN DIEGO — Psychological comorbidity had a significant association with levels of an inflammatory cytokine in patients with irritable bowel syndrome (IBS), suggesting a centrally mediated effect, investigators reported here.

Patients had higher levels of interleukin-6 (IL-6) on initial and follow-up measurements as compared with a group of healthy individuals (7.72 to 8.95 pg/mL versus 5.77 pg/mL). Multivariate analysis showed that higher levels of IL-6 had significant associations with anxiety and depression but not with common symptoms of IBS.

Additionally, the patients had significantly lower levels of interferon-gamma, a key mediator of immune function.

Though suggestive, the results do not prove that psychological comorbidity in IBS is a driving force in the condition, Orla Craig, MB BCh, of University College Cork in Ireland, said at the American College of Gastroenterology meeting.

“The elevations of IL-6 were higher than normal, but they were not very high elevations, which may indicate that IL-6 is not a very good marker for the association with psychological comorbidity,” Craig told MedPage Today.

“These patients did not have severe depression but the mild type of depression that is often seen in patients with IBS,” she added.

The results build on previous studies showing an association between IBS and “subtle irregularities” in circulating cytokines, particularly IL-6. Increased levels of proinflammatory cytokines have been found in the colonic mucosa of patients with IBS, especially those patients with post-infectious IBS, said Craig.

Many patients with IBS have comorbid depression, which also has been linked to subtle increases in circulating proinflammatory cytokines.

Whether the irregularities in cytokine levels relate to IBS, psychological comorbidity, or IBS symptoms and associated stress remains unclear, Craig continued.

To examine factors associated with cytokine levels in patients with IBS, investigators studied 58 patients with clinical diagnoses of IBS and measured their circulating cytokine levels on as many as three occasions. For comparison, investigators recruited 21 healthy controls, whose cytokine levels were measured once.

Cytokines included in the analysis were IL-1beta;, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-alpha, and interferon gamma (IFN-gamma).

The IBS diagnosis, as well as IBS subtype and presence of other functional bowel disorders, was determined on the basis of Rome III criteria. Psychological comorbidity was assessed by means of several validated survey questionnaires.

Craig and colleagues compared cytokine levels in the control group with those of IBS patients who completed all three visits. They also compared cytokine levels of IBS subgroups with those of the control participants.

The primary analysis comprised 19 IBS patients who completed all three clinic visits and the 21 members of the control group.

The control group and patients differed significantly with respect to levels of two circulating cytokines: IFN-gamma and IL-6. The IBS patients had significantly lower levels of IFN-gamma, which averaged 1.76, 2.32, and 1.92 pg/mL on the three clinic visits versus 3.04 pg/mL in the control group (P<0.05).

The control group had a mean IL-6 level of 5.77 pg/mL as compared with means of 8.24, 7.72, and 8.95 pg/mL for the IBS patients (P<0.05). IL-6 was the focus of subsequent analyses.

A preliminary analysis showed that IL-6 levels in the IBS patients were significantly associated with IBS-diarrhea predominant subtype, IBS-mixed subtype, comorbid depression, severe abdominal pain, and a comorbid functional esophageal disorder.

By multivariate analysis comorbid depression and comorbid anxiety were the only significant predictors of higher IL-6 levels (P=0.0157, P=0.0047, respectively). IBS subtype, frequent or severe abdominal pain, functional esophageal disorders, and number of life stressors did not correlate with higher levels of IL-6.

The findings suggest that “disturbances in circulating cytokine levels in IBS may be centrally mediated, rather than reflecting inflammation at the mucosal level.”

Craig said several studies have evaluated the effect of antidepressant and anti-anxiety medications on IBS and associated symptoms, but to her knowledge, no studies have examined the effect of the medications on proinflammatory biomarkers.

Associations between psychological distress and proinflammatory markers have evolved into a “huge area of research in psychoneuroimmunology and for which there is considerable support,” said Mark L. Laudenslager, PhD, of the University of Colorado in Denver. The evidence base has grown to the point that several reviews have been written about the associations, making the observed association with IL-6 quite plausible.

“The problem is IBS is itself an inflammatory illness, so the real direction of causality is hard to discern,” Laudenslager told MedPage Today in an email. “Does stress cause IBS, e.g., via increased inflammation, or does the inflammation caused by IBS lead to affective disorders? Answering this would require a longitudinal study tracking both cytokines and affect and see whether the chicken or egg comes first.”

UPDATE: This article, originally published (Oct. 14, 2013, at 11:00 a.m., was updated with new material (Oct. 14, 2013, at 5:55 p.m.).