In inflammatory bowel diseases (IBD), the therapeutic benefit and mucosal healing from specific probiotics may relate to the modulation of dendritic cells (DCs). Herein, we assessed the immunomodulatory effects of four probiotic strains including Lactobacillus salivarius, Bifidobacterium bifidum, Bacillus coagulans and Bacillus subtilis natto on the expression of co-stimulatory molecules, cytokine production and gene expression of signal-transducing receptors in DCs from IBD patients. Human monocyte-derived DCs from IBD patients and healthy controls were exposed to four probiotic strains. The expression of co-stimulatory molecules was assessed and supernatants were analyzed for anti-inflammatory cytokines. The gene expression of toll-like receptors (TLRs), IL-12p40 and integrin αvβ8 were also analyzed. CD80 and CD86 were induced by most probiotic strains in ulcerative colitis (UC) patients whereas only B. bifidum induced CD80 and CD86 expression in Crohn’s disease (CD) patients. IL-10 and TGF-β production was increased in a dose-independent manner while TLR expression was decreased by all probiotic bacteria except B. bifidum in DCs from UC patients. TLR-4 and TLR-9 expression was significantly downregulated while integrin ß8 was significantly increased in the DCs from CD patients. IL-12p40 expression was only significantly downregulated in DCs from CD patients. Our findings point to the general beneficial effects of probiotics in DC immunomodulation and indicate that probiotic bacteria favorably modulate the expression of co-stimulatory molecules, proinflammatory cytokines and TLRs in DCs from IBD patients.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn’s disease (CD) and ulcerative colitis (UC) patients.Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD.Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3.Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

Inflammatory bowel diseases (IBDs) are immune-mediated, chronic relapsing diseases with a rising prevalence worldwide in both adult and pediatric populations. Treatment options for immune-mediated diseases, including IBDs, are traditional steroids, immunomodulators, and biologics, none of which are capable of inducing long-lasting remission in all patients. Dendritic cells (DCs) play a fundamental role in inducing tolerance and regulating T cells and their tolerogenic functions. Hence, modulation of intestinal mucosal immunity by DCs could provide a novel, additional tool for the treatment of IBD. Recent evidence indicates that probiotic bacteria might impact immunomodulation both in vitro and in vivo by regulating DCs’ maturation and producing tolerogenic DCs (tolDCs) which, in turn, might dampen inflammation. In this review, we will discuss this evidence and the mechanisms of action of probiotics and their metabolites in inducing tolDCs in IBDs and some conditions associated with them.

In Crohn’s disease (CD) a small bowel study—in addition to colonoscopy—is considered necessary for diagnosis/staging. In this study we re-examined the role of capsule endoscopy (CE), colonoscopy, imaging tests [magnetic resonance enterography/computed tomographic enterography (MRE/CTE)], and inflammatory markers [fecal lactoferrin and C-reactive protein (FL/CRP)] in CD patients who had undergone intestinal resection and in those who never had surgery. In this retrospective study 43 consecutive patients underwent CE because of staging/symptoms unexplained by colonoscopy/imaging. We compared colonoscopy, imaging, and FL/CRP with CE and evaluated the impact of the latter on clinical management and outcomes. In patients who never had surgery imaging was negative with a positive CE in 8/15 (53%) of cases. Colonoscopy was insufficient for disease staging in 10/20 (50%) cases. CRP and FL were normal with a positive CE in 35% and 28% of cases, respectively. CE findings changed the management in 6/20 (30%) of cases, with 83% showing clinical/biochemical improvement after up to 15 months of follow-up. In postoperative patients CE was positive with negative imaging in 6/8 (75%) cases. Colonoscopy was insufficient for disease staging in 13/22 (59%) cases. CRP and FL were normal in 42% and 31.8% of patients with positive CE. In these patients CE findings changed the management in 12/23 (52%) cases with 83% of them showing clinical/biochemical improvement after up to 18 months of follow-up. Omitting CE from diagnostic/staging algorithms in CD tends to underdiagnose clinically significant small bowel lesions, thus impacting on patients’ management and outcomes.

Fecal lactoferrin accurately reflects mucosal inflammation in inflammatory bowel disease

Background: Predicting the response of inflammatory bowel disease (IBD) patients to infliximab (IFX) is an unmet clinical need. The expression and density of transmembrane tumor necrosis factor‐α in circulating leukocytes maybe directly related to response by promoting apoptosis.Aim: We tested the hypothesis that direct apoptosis assessment by real‐time polymerase chain reaction evaluation of pro‐apoptotic (Bax) and anti‐apoptotic (Bcl‐2) proteins in peripheral blood mononuclear cells (PBMCs) might be associated with response to IFX.Methods: IFX naïve patients (Crohn's disease, 32 and ulcerative colitis, 20; 35 responders and 17 non‐responders) were evaluated for Bax and Bcl‐2 mRNA expression levels before and 2 weeks after the first infusion. In a subset of patients, apoptosis was also evaluated using flow cytometry.Results: After the first infusion, Bax increased more in responders than in non‐responders (0.7± 0.38 vs 0.81 ± 0.32 and 0.86 ± 0.37 vs 0.87 ± 0.45, respectively, p = 0.071). Bcl‐2 decreased more in responders than in non‐responders (0.71 ± 0.12 vs 0.63 ± 0.13 and 0.81 ± 0.28 vs 0.77 ± 0.27, respectively, p = 0.038). The Bax/Bcl‐2 ratio increased more in responders than in non‐responders (0.99 ± 0.5 vs 1.3 ± 0.51 and 1.03 ± 0.17 vs 1.1 ± 0.28, respectively, p = 0.005). The Bax/Bcl‐2 ratio was able to predict response in 33/52 patients and was correlated to flow cytometry‐assessed apoptosis (r = 0.911; p < 0.001).Conclusions: An increased Bax/Bcl‐2 ratio in PBMCs was associated with therapeutic response to IFX in IBD patients.