Modulation by luminal factors on the functions and migration of intestinal innate immunity.

Luminal antigens, nutrients, metabolites from commensal bacteria, bile acids, or neuropeptides influence the function and trafficking of immune cells in the intestine. Among the immune cells in the gut, innate lymphoid cells, including macrophages, neutrophils, dendritic cells, mast cells, and innate lymphoid cells, play an important role for the maintenance of intestinal homeostasis through a rapid immune response to luminal pathogens. These innate cells are influenced by several luminal factors, possibly leading to dysregulated gut immunity and intestinal disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and intestinal allergy. Luminal factors are sensed by distinct neuro-immune cell units, which also have a strong impact on immunoregulation of the gut. Immune cell trafficking from the blood stream through the lymphatic organ to lymphatics, an essential function for immune responses, is also modulated by luminal factors. This mini-review examines knowledge of luminal and neural factors that regulate and modulate response and migration of leukocytes including innate immune cells, some of which are clinically associated with pathological intestinal inflammation.

Transgenerational impacts of oral probiotic administration in pregnant mice on offspring gut immune cells and colitis susceptibility.

BACKGROUND AND AIM: The study of the impact of environmental factors during pregnancy on fetal development has so far been focused primarily on those negatively affecting human health; however, little is known about the effects of probiotic treatment during pregnancy on inflammatory bowel diseases (IBD). In this study, we investigated whether oral administration of heat-killed probiotics isolated from fermented foods decreased the vulnerability of offspring to IBD. METHODS: Probiotics were administered to the pregnant mice until the birth of pups, after which the parent mice were maintained with autoclaved water. Partial pups were evaluated for dextran sodium sulfate-induced colitis. The influence of CD11c+ CD103+ dendritic cells (DCs) and regulatory T cells (Tregs) in mesenteric lymph nodes of parent mice and their pups was analyzed. RESULTS: Oral administration of heat-killed probiotics to pregnant dams significantly decreased inflammation induced by dextran sodium sulfate in pups. Probiotic treatment increased the number of CD103+ DCs, and the expression of ß8-integrin in CD103+ DCs and Tregs in mesenteric lymph nodes, not only in dams themselves but also in their offspring. CONCLUSIONS: Oral administration of probiotics during gestation induced transgenerational immunomodulatory effects on the gut-associated immune system and resilience to experimental colitis in the offspring. Our results suggest that consumption of fermented foods during pregnancy can be effective in preventing inflammatory diseases such as IBD beyond generation.

Relevance of pepsinogen, gastrin, and endoscopic atrophy in the diagnosis of autoimmune gastritis.

Simple objective modalities are required for evaluating suspected autoimmune gastritis (AIG). This cross-sectional study aimed to examine whether pepsinogen, gastrin, and endoscopic findings can predict AIG. The diagnostic performance of endoscopic findings and serology in distinguishing AIG was evaluated. AIG was diagnosed in patients (N = 31) with anti-parietal cell antibody and/or intrinsic factor antibody positivity and histological findings consistent with AIG. Non-AIG patients (N = 301) were seronegative for anti-parietal cell antibodies. Receiver operating characteristic curve analysis of the entire cohort (N = 332) identified an endoscopic atrophic grade cutoff point of O3 on the Kimura-Takemoto classification (area under the curve [AUC]: 0.909), while those of pepsinogen-I, I/II ratio, and gastrin were 20.1 ng/mL (AUC: 0.932), 1.8 (AUC: 0.913), and 355 pg/mL (AUC: 0.912), respectively. In severe atrophy cases (≥ O3, N = 58, AIG/control; 27/31), the cutoff values of pepsinogen-I, I/II ratio, and gastrin were 9.8 ng/mL (AUC: 0.895), 1.8 (AUC: 0.86), and 355 pg/mL (AUC: 0.897), respectively. In conclusion, endoscopic atrophy is a predictor of AIG. High serum gastrin and low pepsinogen-I and I/II ratio are predictors even in the case of severe atrophy, suggesting their usefulness when the diagnosis of AIG is difficult or as serological screening tests.

Novel probiotic yeast from Miso promotes regulatory dendritic cell IL-10 production and attenuates DSS-induced colitis in mice.

BACKGROUND: Yeasts are a type of fungi thought to have probiotic functions. In this study, we isolated a novel probiotic yeast (Zygosaccharomyces sapae strain I-6) from Miso (a traditional Japanese fermented food). We examined its effects on phenotypic changes in intestinal dendritic cells (DCs), and evaluated its anti-inflammatory effects in dextran sulfate sodium (DSS)-induced colitis. METHODS: A single colony was selected from homogenized Miso, based on its ability to produce interleukin (IL)-10 in CD11c+ bone marrow DCs (BMDCs) in vitro. The anti-inflammatory effects of strain I-6 on CD11c+ BMDCs and CD11c+ CD103+ DCs were analyzed in mouse mesenteric lymph nodes in vitro and in a DSS mouse model. RESULTS: The IL-10 concentrations in the co-culture BMDC supernatants treated with I-6 were dramatically higher than in those treated with Saccharomyces cerevisiae (Sc). IL-10 production is mediated by both TLR2 and Dectin-1. ß-Glucan extracted from I-6 also induced higher levels of IL-10 production in BMDCs than ß-glucan from Sc. The number of mesenteric lymph node CD11c+ CD103+ DCs was significantly increased by I-6 administration, compared with Sc administration. Strain I-6 showed strong anti-inflammatory effects on DSS-induced colitis compared to Sc. Moreover, the adoptive transfer of I-6-treated BMDCs showed anti-inflammatory effects on DSS-induced colitis in mice without oral administration of I-6 cells. CONCLUSIONS: Strain I-6 induced phenotypic changes in intestinal CD11c+ DCs characterized by high IL-10 production and exerted strong anti-inflammatory effects on DSS-induced colitis. Traditional Japanese fermented foods may be a valuable source of probiotic yeasts for effective IBD therapy and treatment.

Relation of geriatric nutritional risk index with clinical risks in elderly-onset ulcerative colitis.

BACKGROUND AND AIM: Worldwide increasing aging societies have many elderlies with intractable diseases including ulcerative colitis (UC). Reportedly, each patients' frailty as well as chronological age is a clinical risk factor of elderly-onset UC (EOUC). Because malnutrition is one of the major manifestations of frailty, we aimed to investigate the effect of malnutrition on the prognosis of EOUC with geriatric nutritional risk index (GNRI), a prognostic tool for several diseases in the elderly to estimate malnutrition, and to evaluate clinical risks among EOUC patients in Japan, the world-leading aging society. METHODS: The EOUC patients (≥ 65 years at diagnosis, n = 2778) in the previous nationwide survey were classified by age and GNRI, and odds ratios (ORs) of hospitalization and UC-related surgery were determined to evaluate the effects of malnutrition on the EOUC patients as well as aging. RESULTS: The risks of hospitalization and surgery were elevated as age advanced. The value of GNRI, negatively correlated with disease activity (r = -0.53), could distinguish severe activity (cutoff ≤ 86.82, sensitivity = 0.79, and specificity = 0.77) and discriminate the EOUC patients suffering from surgery and hospitalization. In a multivariate analysis, GNRI ≤ 86.82 was a higher risk of hospitalization (OR: 4.0, 95% CI, 2.5-6.5) and surgery (OR: 2.7, 95% CI, 0.98-7.4) than cutoff age ≥ 75 years old (OR of hospitalization and surgery were 1.4 [95% CI, 0.99-2.0] and 2.3 [95% CI, 0.8-6.3], respectively). CONCLUSION: Malnutrition estimated by GNRI was significantly related with poor clinical courses of the EOUC patients, suggesting that evaluation of nutritional status at the onset might be useful for predicting risks of clinical courses.

Non-adherence to Medications in Pregnant Ulcerative Colitis Patients Contributes to Disease Flares and Adverse Pregnancy Outcomes.

BACKGROUND: Adherence to medications is important to maintain disease under control and to prevent complications in pregnant patients with ulcerative colitis (UC). To evaluate the incidence of non-adherence during pregnancy and its effect on relapse and pregnancy outcomes, we conducted a multicenter prospective study using a patient self-reporting system without physician interference. METHODS: Sixty-eight pregnant UC women were recruited from 17 institutions between 2013 and 2019. During the course of pregnancy, questionnaires were collected separately from patients and physicians, to investigate the true adherence to medications, disease activity, and birth outcomes. Multivariable logistic regression analysis was performed to identify the risk factors for the relapse or adverse pregnancy outcomes. RESULTS: Of 68 pregnancy, 15 adverse pregnancy outcomes occurred in 13 patients. The rate of self-reported non-adherence was the greatest to mesalamines in the first trimester, which was significantly higher than physicians' estimate (p = 0.0116), and discontinuation was observed in 42.1% of non-adherent group. Logistic regression analysis revealed non-adherence as an independent risk factor for relapse [odds ratio (OR) 7.659, 95% CI 1.928-30.427, p = 0.038], and possibly for adverse pregnancy outcome (OR 8.378, 95% CI 1.350-51.994, p = 0.023). Among the subgroup of patients treated with oral mesalamine alone, the non-adherence was confirmed to be an independent risk factor for relapse (p = 0.002). CONCLUSION: Non-adherence to mesalamine was underestimated by physicians in pregnant UC patients and contributed to disease relapse and possibly on pregnancy outcomes. Preconceptional education regarding safety of medications and risk of self-discontinuation is warranted.

Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells.

AIM: We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non-alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin-like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. METHODS: Angptl4-deficient or wild-type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine- and choline-deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4-deficient HSCs. RESULTS: In the NASH model, Angptl4-deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4-deficient mice than in those from wild-type mice. Treatment with Angptl4 reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-ß (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-ß-induced activation in vivo and in vitro. CONCLUSIONS: Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH.

Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPARγ2 and transportin (Tnpo)1 complex via redox-sensitive disulfide bonds between cysteine (Cys)176 and Cys180 of the former and Cys512 of the latter. Using hepatocyte cultures and mouse models, we show that cytosolic H2O2/Tnpo1-dependent nuclear translocation enhances the amount of DNA-bound PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases.

Symptomatic hyponatremia: a rare but reversible adverse reaction of lubiprostone.

Several intestinal secretagogues became available for the patients with irritable bowel syndrome. We report a case of symptomatic hyponatremia after lubiprostone ingestion. A male patient was visiting our office to manage chronic kidney disease. He suffered chronic hepatitis (type C), which was successfully treated with asunaprevir and daclatasvir. He took lubiprostone due to constipation, and then watery diarrhoea was frequently developed. Next morning, he came to our hospital due to consciousness disturbance. Physical examination showed dehydration and laboratory data exhibited hyponatremia (110 mEq/L). Subsequent treatment against hypovolemic hyponatremia recovered his consciousness without any sequels. This case suggests that intestinal secretagogues can accompany severe electrolyte disturbance. Potential mechanisms for hyponatremia were discussed.

Dietary emulsifier polysorbate-80-induced small-intestinal vulnerability to indomethacin-induced lesions via dysbiosis.

BACKGROUND AND AIM: Dietary emulsifiers are widely used in processed foods and officially approved as safe for intake. However, recent studies have demonstrated that some emulsifiers alter the colonic microbiota, leading to colonic low-grade inflammation, in mice. The effect of dietary emulsifiers on small-intestinal microbiota, which is important for gut immunity, has not been studied. We aimed to investigate the effect of a representative dietary emulsifier, polysorbate-80 (P80), on the small-intestinal microbiota in normal mice. METHODS: Some mice were pretreated with P80 for 8 weeks with or without indomethacin administration on the last 2 days, and intestinal damage was evaluated histologically. The ileal and colonic microbiota composition was assessed using 16S rRNA polymerase chain reaction. RESULTS: Polysorbate-80 increased the Gammaproteobacteria abundance and decreased the α-diversity in the small intestine. No decrease in α-diversity was observed in the colon. P80 pretreatment exacerbated the indomethacin-induced small-intestinal lesions and significantly increased the interleukin-1ß expression. Culture of ileal content on deoxycholate hydrogen sulfide lactose agar showed that P80 significantly increased the colonies of the sulfide-producing bacteria Proteus spp. (genetically identified as Proteus mirabilis). Antibiotic pretreatment abolished the P80-induced aggravation of indomethacin-induced ileitis. Motility assay in semisolid agar showed that adding 0.02% P80 to the agar significantly increased the diameter of P. mirabilis colonies but not that of Escherichia coli colonies. CONCLUSIONS: Polysorbate-80 enhances the vulnerability of the small intestine to indomethacin-induced injury by inducing ileal dysbiosis. Direct enhancement of the motility of specific flagellated microbiota by P80 might be related to dysbiosis and intestinal injury.

Previous Helicobacter pylori infection-induced atrophic gastritis: A distinct disease entity in an understudied population without a history of eradication.

Individuals with chronic atrophic gastritis who are negative for active H. pylori infection with no history of eradication therapy have been identified in clinical practice. By excluding false-negative and autoimmune gastritis cases, it can be surmised that most of these patients have experienced unintentional eradication of H. pylori after antibiotic treatment for other infectious disease, unreported successful eradication, or H. pylori that spontaneously disappeared. These patients are considered to have previous H. pylori infection-induced atrophic gastritis. In this work, we define these cases based on the following criteria: absence of previous H. pylori eradication; atrophic changes on endoscopy or histologic confirmation of glandular atrophy; negative for a current H. pylori infection diagnosed in the absence of proton-pump inhibitors or antibiotics; and absence of localized corpus atrophy, positivity for autoantibodies, or characteristic histologic findings suggestive of autoimmune gastritis. The risk of developing gastric cancer depends on the atrophic grade. The reported rate of developing gastric cancer is 0.31%-0.62% per year for successfully eradicated severely atrophic cases (pathophysiologically equal to unintentionally eradicated cases and unreported eradicated cases), and 0.53%-0.87% per year for spontaneously resolved cases due to severe atrophy. Therefore, for previous H. pylori infection-induced atrophic gastritis cases, we recommend endoscopic surveillance every 3 years for high-risk patients, including those with endoscopically severe atrophy or intestinal metaplasia. Because of the difficulty involved in the endoscopic diagnosis of gastric cancer in cases of previous infection, appropriate monitoring of the high-risk subgroup of this understudied population is especially important.

Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)-specific LPL-knockout (LplHSC-KO ) mice, LPL-floxed (Lplfl/fl ) mice, or double-mutant toll-like receptor 4-deficient (Tlr4-/- ) LplHSC-KO mice were fed a high-fat/high-cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high-fat/high-cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity-related factors, such as free fatty acid, leptin, and interleukin-6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC-KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL-mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL-mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

Chitinase 3-like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis.

AIM: Chitinase 3-like 1 (CHI3L1), an 18-glycosyl hydrolase-related molecule, is a member of the enzymatically inactive chitinase-like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. METHODS: Chitinase 3-like 1-deficient (Chi3l1-/- ) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline-deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. RESULTS: In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1-/- mice compared to that in wild-type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1-/- mice compared to that in wild-type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1-/- mice. Chitinase 3-like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. CONCLUSIONS: Chitinase 3-like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.

Crohn's Disease Accompanied with Small Intestinal Extramedullary Plasmacytoma.

We herein present the case of an immunocompetent 63-year-old man who had previously undergone resection of Crohn's disease (CD)-related small intestinal obstruction more than 30 years ago. He had not been receiving any medication for many years, but had recently started to suffer from ileus. A stenosed site of ileo-cecal anastomosis was identified and therefore was surgically resected, which was diagnosed as CD with small intestinal extramedullary plasmacytoma (EMP). The subsequent progression of CD was successfully controlled by anti-TNFα agents without any recurrence of EMP for over 3 years, implying the clinical benefit and safety of the biological therapy. This was the first known case of a patient who received anti-TNFα agents after a resection of small intestinal EMP accompanied with CD.

Depression Promotes the Onset of Irritable Bowel Syndrome through Unique Dysbiosis in Rats.

Background/Aims: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. Methods: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. Results: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. Conclusions: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS.

Atypical Clinical Presentation of Crohn's Disease with Superior Mesenteric Vein Obstruction and Protein-losing Enteropathy.

We herein report a 44-year-old man suffering from systemic edema due to protein-losing enteropathy (PLE) with superior mesenteric vein (SMV) obstruction and development of collateral veins, which subsequently proved to be a chronic result of thrombosis and a complication of Crohn's disease (CD). PLE was supposedly induced by both intestinal erosion and thrombosis-related lymphangiectasia, which was histologically proven in his surgically-resected ileal stenosis. Elemental diet and anti-TNFα agent improved his hypoalbuminemia after surgery. The rarity of the simultaneous coexistence of SMV obstruction and PLE and the precedence of these complications over typical abdominal symptoms of CD made the clinical course complex.

Nicotine treatment ameliorates DSS-induced colitis by suppressing MAdCAM-1 expression and leukocyte recruitment.

The enhanced recruitment of leukocytes to the inflamed colon is a key feature of ulcerative colitis (UC). The gut-specific adhesion molecules involved in leukocyte recruitment have emerged as recent therapeutic targets. Nicotine absorbed from smoking has been reported to work protectively in UC patients. Our hypothesis is that nicotine may suppress the aberrant leukocyte recruitment and colonic inflammation via the suppression of the overexpressed gut-specific adhesion molecules in the inflamed colon. To test this hypothesis, the severity of colitis and the degree of leukocyte recruitment induced by gut-specific adhesion molecules were assessed in dextran sulfate sodium (DSS) colitis mice (C57BL/6J mice treated with 3% DSS) with or without nicotine treatment. We also studied the in vitro changes in the expression of adhesion molecules by using a vascular endothelial cell line. DSS-induced colitis was accompanied by increases in disease activity index (DAI), histological score, recruitment of leukocytes, and the expression of adhesion molecules, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and VCAM-1. Nicotine treatment significantly attenuated MAdCAM-1 expression, leukocyte recruitment, DAI, and histological score. The expression of ß7-integrin, the ligand for MAdCAM-1, on leukocytes was not affected by nicotine treatment. In vitro study, the TNF-α-enhanced mRNA expression of MAdCAM-1 was reduced by the coadministration of nicotine in a dose-dependent manner, possibly via nicotinic receptor activation. These results supported our hypothesis that nicotine treatment ameliorated colitis through the suppression of MAdCAM-1 expression on the microvessels in the inflamed colon. Further investigation is warranted on the role of nicotine in the treatment of UC.

Clinical differences between elderly-onset ulcerative colitis and non-elderly-onset ulcerative colitis: A nationwide survey data in Japan.

BACKGROUND AND AIM: Studies on the characteristics of elderly-onset ulcerative colitis (EOUC) and non-elderly-onset ulcerative colitis (NEOUC) have reported conflicting findings. The aim of this study was to compare disease characteristics of EOUC and NEOUC by analyzing the database of the Japanese nationwide inflammatory bowel disease (IBD) registry. METHODS: We analyzed the age of disease onset, sex, disease severity, and disease extent in patients with ulcerative colitis that were newly diagnosed and registered within 1 year between 2004 and 2009 (n = 28 179). We also analyzed the medical treatment, rate of IBD-related surgery, and postoperative complications. We compared them between younger than 65 years old (NEOUC group) and 65 years old or older (EOUC group) patients. RESULTS: A total of 25 401 (90.1%) and 2778 (9.9%) patients were included in the NEOUC and EOUC groups, respectively. In the EOUC group, disease activity was significantly higher, and extent of pathological changes in the colon more extended significantly. Laboratory findings showed that inflammatory markers were elevated significantly in the EOUC group. The proportion of those with IBD-related hospitalization was significantly higher in the EOUC group (54.2% vs 35.7%, P < 0.001). The proportion of patients who were treated with corticosteroids was significantly higher in the EOUC group (36.7% vs 30.8%, P < 0.001). Significantly more number of patients underwent IBD-related surgery in the EOUC group (0.68% vs 0.27%, P < 0.001). CONCLUSION: Elderly patients show higher disease activity, with a higher proportion requiring IBD-related hospitalization and IBD-related surgery, according to the nationwide registry in Japan.

Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis.

Incidence of nonalcoholic steatohepatitis (NASH), which is considered a hepatic manifestation of metabolic syndrome, has been increasing worldwide with the rise in obesity; however, its pathological mechanism is poorly understood. Here, we demonstrate that the hepatic expression of aortic carboxypeptidase-like protein (ACLP), a glycosylated, secreted protein, increases in NASH in humans and mice. Furthermore, we elucidate that ACLP is a ligand, unrelated to WNT proteins, that activates the canonical WNT pathway and exacerbates NASH pathology. In the liver, ACLP is specifically expressed in hepatic stellate cells (HSCs). As fatty liver disease progresses, ACLP expression is enhanced via activation of STAT3 signaling by obesity-related factors in serum. ACLP specifically binds to frizzled-8 and low-density lipoprotein-related receptor 6 to form a ternary complex that activates canonical WNT signaling. Consequently, ACLP activates HSCs by inhibiting PPARγ signals. HSC-specific ACLP deficiency inhibits fibrosis progression in NASH by inhibiting canonical WNT signaling in HSCs. The present study elucidates the role of canonical WNT pathway activation by ACLP in NASH pathology, indicating that NASH can be treated by targeting ACLP-induced canonical WNT pathway activation in HSCs.