The number of patients with allergic and inflammatory disorders has been increasing during the past several decades. Accumulating evidence has refined our understanding of the relationship between ...allergic diseases and the gut microbiome. In addition, the gut microbiome is now known to produce both useful and harmful metabolites from dietary materials. These metabolites and bacterial components help to regulate host immune responses and potentially affect the development of allergic diseases. Here, we describe recent findings regarding the immunologic crosstalk between commensal bacteria and dietary components in the regulation of host immunity and the influence of this relationship on the development of allergic diseases.
Background
The Japanese Society of Gastroenterology (JSGE) published ‘‘Daicho Polyp Shinryo Guideline 2014′’ in Japanese and a part of this guideline was published in English as “Evidence-based ...clinical practice guidelines for management of colorectal polyps” in the
Journal of Gastroenterology
in 2015. A revised version of the Japanese-language guideline was published in 2020, and here we introduce a part of the contents of revised version.
Methods
The guideline committee discussed and drew up a series of clinical questions (CQs). Recommendation statements for the CQs were limited to items with multiple therapeutic options. Items with established conclusions that had 100% agreement with previous guidelines (background questions) and items with no (or old) evidence that are topics for future research (future research questions: FRQs) were given descriptions only. To address the CQs and FRQs, PubMed, ICHUSHI, and other sources were searched for relevant articles published in English from 1983 to October 2018 and articles published in Japanese from 1983 to November 2018. The Japan Medical Library Association was also commissioned to search for relevant materials. Manual searches were performed for questions with insufficient online references.
Results
The professional committee created 18 CQs and statements concerning the current concept and diagnosis/treatment of various colorectal polyps, including their epidemiology, screening, pathophysiology, definition and classification, diagnosis, management, practical treatment, complications, and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumors/carcinomas).
Conclusions
After evaluation by the moderators, evidence-based clinical practice guidelines for management of colorectal polyps were proposed for 2020. This report addresses the therapeutic related CQs introduced when formulating these guidelines.
Vocatives (terms for calling and addressing) have been studied from various perspectives but there has been little research on them from the viewpoint of Gricean implicatures. The goal of the present ...paper is to show that a new light can be shed on vocatives by looking at them from the perspective of Gricean implicatures. After reviewing previous works on vocatives in terms of conventional implicatures and generalized conversational implicatures, I point out that there is a systematic way of yielding particularized conversational implicatures in vocatives. I argue that they are metaphoric in nature and can be captured by the Cooperative Principle and the first maxim of quality. Some theoretical implications of the findings are also discussed.
Atherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 ...fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.
Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid ...metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.
We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE.
Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment.
We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein–coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40.
17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.
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ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of ...allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12‐hydroxyeicosapentaenoic acid (12‐HEPE), which is a 12‐lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid‐rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12‐HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12‐HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12‐HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12‐HEPE as the dominant ω3 fatty acid metabolite in the skin.
Background
First reported in 1955, Cronkhite–Canada syndrome (CCS), a rare syndrome characterized by ectodermal abnormalities and inflammatory changes of the gastrointestinal tract mucosa, has been ...associated with a poor prognosis and life-threatening malignant complications. In a large population survey, we endeavored to characterize the course and treatment outcome of CCS through clinical and endoscopic assessment, and to explore its optimal treatment and surveillance strategy.
Methods
A retrospective analysis of 210 patients with CCS was conducted via a questionnaire-based nationwide survey of 983 teaching hospitals located throughout Japan. We assessed clinical features, endoscopic findings, treatments used, and short- and long-term outcomes.
Results
The average age at diagnosis was 63.5 years. In all cases, upper or lower gastrointestinal tract polyposis was confirmed, accompanied by characteristic ectodermal abnormalities. Of the treatments used, oral corticosteroids (30–49 mg/day) were the most effective treatment for active disease, with adjunctive nutritional support considered beneficial. With corticosteroid treatment, abdominal symptoms were relieved within a few months, whereas polyp regression often required more than 6 months. Maintenance of endoscopic remission with or without steroids for 3 years significantly lowered the development of CCS-related cancer, compared with relapsers or nonresponders, underscoring the importance of sustained endoscopic remission for cancer prevention.
Conclusions
The prognosis of CCS has greatly improved through the use of improved medical treatment. Although CCS continues to be relentlessly progressive, carrying a high cancer risk, a sufficient dose and duration of corticosteroid therapy accompanied by nutritional support and periodic endoscopic surveillance appears to improve its natural history.
Background
Recently in Japan, the morbidity of colorectal polyp has been increasing. As a result, a large number of cases of colorectal polyps that are diagnosed and treated using colonoscopy has now ...increased, and clinical guidelines are needed for endoscopic management and surveillance after treatment.
Methods
Three committees the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators were organized. Ten specialists for colorectal polyp management extracted the specific clinical statements from articles published between 1983 and September 2011 obtained from PubMed and a secondary database, and developed the CQs and statements. Basically, statements were made according to the GRADE system. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid.
Results
The professional committee created 91CQs and statements for the current concept and diagnosis/treatment of various colorectal polyps including epidemiology, screening, pathophysiology, definition and classification, diagnosis, treatment/management, practical treatment, complications and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumor/carcinoma).
Conclusions
After evaluation by the moderators, evidence-based clinical guidelines for management of colorectal polyps have been proposed for 2014.
Background
Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 ...polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups.
Methods
Contact hypersensitivity (CHS) induced by 2,4‐dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT‐PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC‐MS/MS.
Results
We show that maternal intake of linseed oil, containing abundant ω3 α‐linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14‐lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF‐related apoptosis‐inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA‐derived 14‐lipoxygenation products to mouse pups ameliorated their DNFB CHS.
Conclusion
These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.
Maternal intake of α‐linolenic acid increased ω3 DPA and its 14‐lipoxygenation products in the breast milk of dams. 14‐lipoxygenation products of ω3 DPA increased TRAIL expression on plasmacytoid dendritic cells in the pups, which suppressed the IFN‐γ‐producing T cells and consequently inhibited infant allergic dermatitis.
Background & Aims A random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a ...randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC. Methods We performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, n = 122) or the target group (biopsies collected from locations of suspected neoplasia, n = 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups. Results The mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679–2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group ( P = .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; P < .001). In the random group, all neoplastic tissues found in random biopsies were collected from areas of the mucosa with a history or presence of inflammation. Conclusions In a randomized controlled trial, we found that targeted and random biopsies detect similar proportions of neoplasias. However, a targeted biopsy appears to be a more cost-effective method. Random biopsies from areas without any signs of present or past inflammation were not found to contain neoplastic tissues. Clinical Trial Registry: UMIN000001608.
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