Cytokine imbalance in irritable bowel syndrome: a systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology; although infection and inflammation have recently been considered as important etiologic agents. A recent meta-analysis showed correlations between cytokine [interleukin-10 (IL-10) and tumor necrosis factor (TNF)] gene polymorphisms and IBS; however, it is still unknown whether patients with IBS have different cytokine profiles compared to healthy population. METHODS: To determine the relationships between serum/plasma levels or mucosal expression of IL-10/TNF-α and IBS, we conducted a systematic review and meta-analysis based on case-control studies retrieved from PubMed and EMBASE search through August 2013. Standardized mean difference (SMD) was generated by using the inverse variance method. Heterogeneity was assessed based on I(2) values. KEY RESULTS: Serum/plasma levels of TNF-α tended to be higher in IBS vs controls (p = 0.09); this reached significance in IBS subtypes vs controls and in female patients with IBS. However, serum/plasma levels of IL-10 were not significantly different in IBS patients vs controls. Further analysis of serum/plasma IL-10 levels in IBS subtypes did not show any difference; however, analysis based on gender showed a significantly lower serum/plasma IL-10 levels in male patients with IBS vs male controls (p = 0.02). Colonic IL-10 mRNA had a significantly lower expression in IBS vs control (p = 0.001). CONCLUSIONS & INFERENCES: There is an imbalance of proinflammatory TNF-α, and anti-inflammatory IL-10, cytokines in IBS. Stratifying IBS patients based on cytokine profile may represent an opportunity for personalized treatment of this condition.

Altered peripheral toll-like receptor responses in the irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a stress-related disorder with disturbed brain-gut communication, gastrointestinal homeostasis and, based on recent evidence, low grade inflammation and an altered microbiota. The immune system is a critical regulator of the brain-gut axis. Toll-like receptors (TLRs) are pattern recognition molecules regulating innate immunity. AIM: To characterise toll-like receptor activity in IBS. METHODS: Thirty IBS patients and 30 healthy controls (HC) were recruited. Venous blood was collected, and cultured with a panel of toll-like receptor agonists for 24 h. Cell supernatants were analysed using a multiplex ELISA approach to measure IL1ß, IL6, IL8 and TNFα. Plasma was analysed for levels of inflammatory cytokines and cortisol. RESULTS: Toll-like receptor agonist-induced cytokine (IL1ß, IL6, IL8 and TNFα) release was markedly enhanced in stimulated whole blood from IBS (n = 30) patients compared with healthy controls (n = 30). An exaggerated response to the TLR8 agonist for all cytokines investigated was seen in IBS patients. In addition, enhanced TLR2-induced TNFα release, TLR3-induced IL-8 release, TLR4-induced IL1ß and TNFα release, TLR5-induced IL1ß and TNFα release and TLR7-induced IL-8 release were also observed in IBS patients. No differences in TLR1, TLR6 or TLR9 activity were detected. In addition, plasma levels of cortisol, IL-6 and IL-8 were significantly increased in IBS patients. CONCLUSION: Taken together, these data demonstrate elevated cytokine levels and toll-like receptor activity in the periphery of patients with the irritable bowel syndrome, indicating some immune dysregulation in these patients.

Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype.

Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TLRs) are pattern-recognition molecules that initiate inflammation. Our objective was to investigate the peripheral TLR activity in psychosis. Forty schizophrenia patients, twenty bipolar patients and forty healthy controls (HC) were recruited. Donated whole blood was cultured with TLR agonists for 24 h. Cell supernatants were analysed using a multiplex enzyme-linked immunosorbent assay approach to measure IL-1ß, IL-6, IL-8 and tumour necrosis factor-α (TNFα). Plasma was analysed for cytokines, cortisol and acute phase proteins. Here, we show that selective TLR agonist-induced cytokine (IL-1ß, IL-6, IL-8 and TNFα) release is enhanced in stimulated whole blood from schizophrenia and bipolar patients compared with HC. An exaggerated release of IL-1ß, IL-6 and TNFα following treatment with the TLR2 agonist HKLM was detected in both disorders compared with controls. Enhanced TLR4-induced increases in IL-1ß for both disorders coupled with TNFα increases for bipolar patients were observed. TLR8-induced increases in IL-1ß for both disorders as well as IL-6 and TNFα increases for bipolar patients were detected. TLR9-induced increases in IL-8 for schizophrenia patients were also observed. No differences in TLR1, TLR3, TLR5, TLR6 or TLR7 activity were detected. Plasma levels of IL-6 were significantly elevated in bipolar patients while TNFα levels were significantly elevated in schizophrenia patients compared with controls. Plasma acute phase proteins were significantly elevated in bipolar patients. These data demonstrate that specific alterations in TLR agonist-mediated cytokine release contribute to the evidence of immune dysfunction in psychotic disorders.

The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat.

BACKGROUND: Irritable bowel syndrome (IBS) is characterized by recurrent abdominal pain and altering bowel habit with a high percentage of patients displaying comorbid anxiety. Growing clinical and preclinical evidence suggests that probiotic agents may restore the altered brain-gut communication in IBS. In this study, we evaluated the efficacy of repeated treatment with three different probiotics in reducing visceral pain in visceral normosensitive (Sprague-Dawley [SD]) and visceral hypersensitive (Wistar-Kyoto [WKY]) rat strains. METHODS: Following 14 days oral gavage of Lactobacillus salivarius UCC118, Bifidobacterium infantis 35624, or Bifidobacterium breve UCC2003 both SD and WKY rats were exposed to a novel stress, the open field arena and their behavior was recorded. Subsequently, the effects of probiotics on visceral nociceptive responses were analyzed by recording pain behaviors during colorectal distension (CRD). KEY RESULTS: It was found that there was a difference in the open field behavior between strains but none of the probiotic treatment altered behavior within each strain. Interestingly, the probiotic B. infantis 35624 but not others tested significantly reduced CRD-induced visceral pain behaviors in both rat strains. It significantly increased the threshold pressure of the first pain behavior and also reduced the total number pain behaviors during CRD. CONCLUSIONS & INFERENCES: These data confirm that probiotics such as B. infantis 35624 are effective in reducing visceral pain and may be effective in treating certain symptoms of IBS.