Kazuaki Yoneno

TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony‐stimulating factor and interferon‐γ (Mγ‐Mϕs), which are similar to the human intestinal lamina propria CD14+ Mϕs that contribute to Crohns disease (CD) pathogenesis by production of pro‐inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor‐α production in Mγ‐Mϕs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5–cAMP pathway to induce phosphorylation of c‐Fos that regulated nuclear factor‐κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non‐inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14+ Mϕs, a TGR5 agonist could inhibit tumour necrosis factor‐α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.

Immune aspects of the pathogenesis of inflammatory bowel disease

Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohns disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFα and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy.

Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway

Dendritic cells (DCs) are known as antigen‐presenting cells and play a central role in both innate and acquired immunity. Peripheral blood monocytes give rise to resident and recruited DCs in lymph nodes and non‐lymphoid tissues. The ligands of nuclear hormone receptors can modulate DC differentiation and so influence various biological functions of DCs. The role of bile acids (BAs) as signalling molecules has recently become apparent, but the functional role of BAs in DC differentiation has not yet been elucidated. We show that DCs derived from human peripheral blood monocytes cultured with a BA produce lower levels of interleukin‐12 (IL‐12) and tumour necrosis factor‐α in response to stimulation with commensal bacterial antigens. Stimulation through the nuclear receptor farnesoid X (FXR) did not affect the differentiation of DCs. However, DCs differentiated with the specific agonist for TGR5, a transmembrane BA receptor, showed an IL‐12 hypo‐producing phenotype. Expression of TGR5 could only be identified in monocytes and was rapidly down‐regulated during monocyte differentiation to DCs. Stimulation with 8‐bromoadenosine‐cyclic AMP (8‐Br‐cAMP), which acts downstream of TGR5 signalling, also promoted differentiation into IL‐12 hypo‐producing DCs. These results indicate that BAs induce the differentiation of IL‐12 hypo‐producing DCs from monocytes via the TGR5‐cAMP pathway.

Applicability of second-generation colon capsule endoscope to ulcerative colitis: a clinical feasibility study.

Colon capsule endoscopy has already been used for colon visualization and detection of polyps but its applicability to inflammatory bowel disease is still unconfirmed. The aim of this study was to assess the feasibility of evaluating the severity of mucosal inflammation in patients with ulcerative colitis (UC) using a second‐generation colon capsule endoscope (CCE‐2).

Activated hepatic stellate cells mediate the differentiation of macrophages.

Liver macrophages play integral roles in both the progression and resolution of hepatic inflammation and fibrosis, comprising opposing functions that largely coincide with the activation state of nearby hepatic stellate cells (HSC). While cross‐talk between HSC and macrophages may be essential at various stages of inflammation and fibrogenesis, many facets of this interaction have yet to be thoroughly explored. Here, we examine the potential roles of HSC‐derived signaling molecules as mediators of liver macrophage differentiation.

Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation

Background Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear. Objective To explore the contribution of intestinal IgG plasma cells to UC pathogenesis. Methods We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (FcγR) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation. Results IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19+CD27low, CCR10lowCXCR4high) compared with IgA plasma cells (CD19+/−CD27high, CCR10highCXCR4−/low). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcγRI and FcγRII, and induced the extensive production of pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1β (IL-1β), comparable to the effect of commensal bacteria stimulation. Co-stimulation with IgG-IC and commensal bacteria increased TNF and IL-1β production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23. Conclusions Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of ‘pathogenic’ intestinal CD14 macrophages via IgG-IC-FcγR signalling.

Modified bowel preparation regimen for use in second-generation colon capsule endoscopy in patients with ulcerative colitis

We have reported that second‐generation colon capsule endoscopy (CCE‐2) might be feasible for assessing the severity of mucosal inflammation in ulcerative colitis (UC). However, because of the low rate (69%) of complete evaluation of the colon and owing to inadequate cleansing. We believe that the method of bowel preparation could be improved by reducing volume. In the present study, we attempted to improve the colon‐cleansing regimen in order to optimize the usefulness of CCE‐2 in the management of UC patients.

Role of enhanced visibility in evaluating polyposis syndromes using a newly developed contrast image capsule endoscope.

Background/Aims A flexible spectral imaging color enhancement system was installed in new capsule software for video capsule endoscopy. Contrast image capsule endoscopy (CICE) is a novel technology using light-emitting diodes selected for the main absorption range of hemoglobin. We assessed the feasibility and diagnostic effi cacy for small bowel surveillance in patients with polyposis syndromes. Methods Six patients with polyposis syndromes, four with familial adenomatous polyposis and one each with Cowden syndrome (CS) and Cronkhite-Canada syndrome (CCS) were examined using CICE. We conducted three evaluations to assess the effect on the numbers of the detected polyps; compare polyp diagnostic rates between adenoma and hamartoma; and assess polyp visibility. Results The numbers of detected polyps and diagnostic accuracy did not differ signifi cantly between pre-contrast and contrast images. However, 50% of the adenomatous polyps displayed enhanced visibility on contrast images. CICE contrast images exhibited clearly demarcated lesions and improved the visibility of minute structures of adenomatous polyps. Hamartomatous polyp micro-structures in patients with CS and CCS were more clearly visualized on contrast than pre-contrast images. Conclusions CICE is an effective tool for enhancing the visibility of polyps in patients with polyposis syndrome.

Early Intervention with Adalimumab May Contribute to Favorable Clinical Efficacy in Patients with Crohn's Disease

Background: We evaluated the clinical efficacy of adalimumab (ADA) for Crohns disease (CD) and analyzed predictive factors for clinical remission and long-term prognosis. Methods: We retrospectively reviewed the medical records of 45 patients treated with ADA for CD at Keio University Hospital between October 2010 and March 2014. Clinical remission was defined as a Harvey-Bradshaw index of ≤4. Results: Twenty-eight of 45 patients (62.2%) achieved clinical remission at week 4. Among these 28 patients, 18 patients (64.3%) maintained clinical remission at week 26, and among these, 16 patients (88.9%) maintained clinical remission at week 52. Absence of a history of bowel resection and absence of prior anti-tumor necrosis factor (anti-TNF) therapy were significant predictive factors for clinical remission at week 4 upon multivariate logistic regression analyses. Younger age and a disease duration of ≤3 years correlated with clinical remission at week 26 upon univariate analyses. Patients without a history of bowel resection showed significantly better long-term prognosis than those with a history of bowel resection (p = 0.01). None of the patients contracted a serious infectious disease. Conclusions: Younger age, shorter duration of disease, being naive to anti-TNF antagonists, and absence of a history of bowel resection were associated with the efficacy of ADA in CD patients.

Polyp detection rate in transverse and sigmoid colon significantly increases with longer withdrawal time during screening colonoscopy

Background The guidelines for colonoscopy present withdrawal time (WT) and adenoma detection rate (ADR) as the quality indicator. The purpose of this retrospective study is to analyze the predicting factors with polyp detection rate (PDR) as a surrogate for ADR by using comprehensive health checkup data, and assess the correlation between PDR per each colonic segment and WT, and factors influencing WT. Methods One thousand and thirty six consecutive health checkup cases from April 2015 to March 2016 were enrolled in this study, and 880 subjects who undertook colonoscopy without polyp removal or biopsy were divided into the two groups (polyp not detected group vs polyp detected group). The two groups were compared by subjects and clinical characteristics with univariate analysis followed by multivariate analysis. Colonoscopies with longer WT (≥ 6 min) and those with shorter WT (< 6 min) were compared by PDR per each colonic segment, and also by subjects and clinical characteristics. Results A total of 1009 subjects included two incomplete colonoscopies (CIR, 99.9%) and overall PDR was 35.8%. A multiple logistic regression model demonstrated that age, gender, and WT were significantly related factors for polyp detection (odds ratio, 1.036; 1.771; 1.217). PDR showed a linear increase as WT increased from 3 min to 9 min (r = 0.989, p = 0.000) and PDR with long WT group was higher than that with short WT group per each colonic segment, significantly in transverse (2.3 times, p = 0.004) and sigmoid colon (2.1 times, p = 0.001). Not only bowel preparation quality but also insertion difficulty evaluated by endoscopist were significant factors relating with WT (odds ratio, 3.811; 1.679). Conclusion This study suggests that endoscopists should be recommended to take more time up to 9 min of WT to observe transverse and sigmoid colon, especially when they feel no difficulty during scope insertion.