The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease.

Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.

Chronic Intestinal Inflammation Suppresses Brain Activity by Inducing Neuroinflammation in Mice.

Chronic gut inflammation such as inflammatory bowel disease is believed to be associated with neurodegenerative diseases in humans. However, the direct evidence for and the underlying mechanism of this brain-gut interaction remain elusive. In this study, manganese-enhanced magnetic resonance imaging was used to assess functional brain activity from awake and freely moving mice with chronic colitis. Manganese ion uptake (indicative of Ca2+ influx into neuronal cells) and accumulation were reduced in the hippocampus of chronic colitis mice compared with control mice. Long-term memory declined and neuroinflammatory signals, including IL-1ß production and activation of caspase-1, caspase-11, and gasdermin, were induced. High-mobility group box 1 (HMGB1) levels were elevated both in the serum and in the hippocampus; however, lipopolysaccharide (LPS) levels remained at low levels without significant changes in these samples. The blood-brain barrier permeability was increased in chronic colitis mice. In the presence of LPS, HMGB1 treatment induced the activation of caspase-11 and gasdermin in the mouse microglial cell line SIM-A9. These findings suggest that HMGB1 released from the inflamed intestine may move to the brain through the blood circulatory system; in conjunction with a low level of endogenous LPS, elevated HMGB1 can subsequently activate caspase-mediated inflammatory responses in the brain.

A Serological Biomarker of Laminin Gamma 1 Chain Degradation Reflects Altered Basement Membrane Remodeling in Crohn's Disease and DSS Colitis.

BACKGROUND: The laminin gamma 1 chain (LMγ1) is abundant along the crypt-villus axis in the intestinal basement membrane. AIMS: We investigated whether a serological biomarker of laminin degradation was associated with disease activity in patients with Crohn's disease (CD) and in rats with dextran sulfate sodium (DSS)-induced colitis. METHODS: Serum samples from CD patients (n = 43), healthy subjects (n = 19), and Sprague Dawley rats receiving 5-6% DSS water for five days and regular drinking water for 11 days were included in this study. The LG1M biomarker, a neo-epitope degradation fragment of the LMγ1 chain generated by matrix metalloproteinases-9 (MMP-9), was measured in serum to estimate the level of laminin degradation. RESULTS: Serum LG1M was elevated in CD patients with active and inactive disease compared to healthy subjects (p < 0.0001). LG1M distinguished CD patients from healthy subjects, with an area under the curve (AUC) of 0.81 (p < 0.0001). Serum LG1M was decreased in DSS rats compared to controls 2 days after DSS withdrawal, and increased upon reversal of the disease. CONCLUSIONS: Increased serum LG1M in active and inactive CD patients supports the evidence of altered LM expression in both inflamed and non-inflamed tissue. Moreover, lower LG1M levels in the early healing phase of DSS-induced colitis may reflect ongoing mucosal repair.

IL-6 downregulates hepatic carboxylesterases via NF-κB activation in dextran sulfate sodium-induced colitis.

Ulcerative colitis (UC) is associated with increased levels of inflammatory factors, which is attributed to the abnormal expression and activity of enzymes and transporters in the liver, affecting drug disposition in vivo. This study aimed to examine the impact of intestinal inflammation on the expression of hepatic carboxylesterases (CESs) in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Two major CESs isoforms, CES1 and CES2, were down-regulated, accompanied by decreases in hepatic microsomal metabolism of clopidogrel and irinotecan. Meanwhile, IL-6 levels significantly increased compared with other inflammatory factors in the livers of UC mice. In contrast, using IL-6 antibody simultaneously reversed the down-regulation of CES1, CES2, pregnane X receptor (PXR), and constitutive androstane receptor (CAR), as well as the nuclear translocation of NF-κB in the liver. We further confirmed that treatment with NF-κB inhibitor abolished IL-6-induced down-regulation of CES1, CES2, PXR, and CAR in vitro. Thus, it was concluded that IL-6 represses hepatic CESs via the NF-κB pathway in DSS-induced colitis. These findings indicate that caution should be exercised concerning the proper and safe use of therapeutic drugs in patients with UC.

Poly-pharmacokinetic strategy represented the synergy effects of bioactive compounds in a traditional Chinese medicine formula, Si Shen Wan and its separated recipes to normal and colitis rats.

Si Shen Wan is a classic traditional Chinese medicine formula, which has been used to treat chronic colitis for thousands of years. Many research and experience show that Si Shen Wan was developed by the combination of two sets of "Herb Pairs," Er Shen Wan and Fructus Schisandrae Chinensis Powder. This research aimed to revealing the effective substances, guide the clinical treatment, and represent the synergy effects from the view of pharmacokinetics. An ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for simultaneous quantification of 26 main bioactive compounds in normal and colitis rat plasma after oral administration of Si Shen Wan and its "Herb Pairs" extract. The method validation results illustrated that the experimental method was reliable and reproducible for quantitative determination of the biological samples. The pharmacokinetic behaviors in different groups were compared and discussed comprehensively, which indicated that the treatment of Si Shen Wan has a superiority in synthetic action of the "Herb Pairs" for the higher peak concentrations and bioavailability of some mainly components. Furthermore, the synergy effect was still existing backed up again for the longer eliminate time and a better bioavailability in colitis groups. The pharmacokinetics research of multiple components in Si Shen Wan and its "Herb Pairs" supplied a significant basis for better understanding the metabolic mechanism of these formulas in both normal and pathological state.

Extracellular DNA Correlates with Intestinal Inflammation in Chemically Induced Colitis in Mice.

Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.

Metabolic Profiling by UPLC-Orbitrap-MS/MS of Liver from C57BL/6 Mice with DSS-Induced Inflammatory Bowel Disease.

Liver disorder often occurs in patients with inflammatory bowel disease (IBD); however, the changes in IBD-induced liver disorder at the intrinsic molecular level (chiefly metabolites) and therapeutic targets are still poorly characterized. First, a refined and translationally relevant model of DSS chronic colitis in C57BL/6 mice was established, and cecropin A and antibiotics were used as interventions. We found that the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the liver tissues of mice were highly increased in the context of DSS treatment but were lowered by cecropin A and antibiotics. Subsequently, an untargeted metabolomics analysis was performed by UPLC-Orbitrap-MS/MS to reveal the metabolic profile and attempt to find the potential therapeutic targets of the liver disorders that occur in IBD. Notably, 133 metabolites were identified by an integrated database. Metabolism network and pathway analyses demonstrated that the metabolic disturbance of the liver in IBD mice was mainly enriched in bile acid metabolism, arachidonic acid metabolism, amino acid metabolism, and steroid hormone biosynthesis, while those disturbances were regulated or reversed through cecropin A and antibiotic treatment. Furthermore, the top 20 metabolites, such as glutathione, maltose, arachidonic acid, and thiamine, were screened as biomarkers via one-way analysis of variance (one-way ANOVA, p < 0.05) coupled with variable importance for project values (VIP >1) of orthogonal partial least-squares discriminant analysis (OPLS-DA), which could be upregulated or downregulated with the cecropin A and antibiotics treatment. Spearman correlation analysis showed that the majority of the biomarkers have a significant correlation with cytokines (TNF-α, IL-1ß, IL-6, and IL-10), indicating that those biomarkers may act as potential targets to interact directly or indirectly with cecropin A and antibiotics to affect liver inflammation. Collectively, our results extend the understanding of the molecular alteration of liver disorders occurring in IBD and offer an opportunity for discovering potential therapeutic targets in the IBD process.

Effects of IFNG-AS1 and ANRIL on intestinal epithelial cells and their relationship with colitis.

OBJECTIVE: To explore the effects of IFNG-AS1 and ANRIL on intestinal epithelial cells and their relationship with colitis. PATIENTS AND METHODS: From May 2017 to May 2019, 118 colitis patients admitted to our hospital were selected as the research group (RG), and 124 healthy controls were selected as the control group (CG). In addition, the normal intestinal epithelial cells HIEC and HIEC-6 were purchased to detect the IFNG-AS1 and ANRIL in the peripheral blood of patients in the two groups, and the effects of IFNG-AS1 and ANRIL on the intestinal epithelial cells were analyzed. RESULTS: IFNG-AS1 and ANRIL were highly expressed in colitis (p<0.050), and their combined detection had good diagnostic value for the occurrence of colitis and complications (p<0.050). In intestinal epithelial cells transfected with IFNG-AS1 and ANRIL, it was found that inhibition of IFNG-AS1 and ANRIL remarkably increased the proliferation and decreased the apoptosis of intestinal epithelial cells (p<0.050). CONCLUSIONS: IFNG-AS1 and ANRIL are highly expressed in colitis, and inhibiting their expression can promote the proliferation of intestinal epithelial cells and reduce apoptosis, which may be potential therapeutic targets for Crohn's colitis in the future.

Elevated trefoil factor 3 plasma levels in critically ill patients with abdominal sepsis or non-infectious abdominal illness.

Trefoil factor 3 (TFF3) is a small peptide secreted mainly by goblet cells in the gut, where it plays a key role in gastrointestinal defence and repair. Plasma TFF3 has been reported as a biomarker of intestinal injury and as such it has been evaluated as a marker of disease activity in colitis. Impaired gut barrier function has been postulated as the "motor" of critical illness. We here sought to determine the temporal dynamics of plasma TFF3 in adult patients admitted to intensive care unit with abdominal sepsis or after major abdominal surgery for a non-infectious condition (post-op GI patients). TFF3 was measured in plasma obtained from 143 patients with abdominal sepsis and 98 post-op GI patients on admission to the intensive care (day 0) and at days 2 and 4 thereafter. Abdominal sepsis patients showed sustained elevated plasma TFF3 levels from day 0 to 4 relative to healthy control values, while in post-op GI patients admission TFF3 levels were not increased, only rising at day 2 and 4. In both patient groups, the presence of shock was associated with higher TFF3 levels. Moreover, patients with 3 or more organs failing had higher plasma TFF3 concentrations. While plasma TFF3 was higher in sepsis patients who did not survive until day 30, TFF3 levels were not independently associated with 30-day mortality in a Cox regression analysis. These results could support the theory that intestinal injury contributes to the pathogenesis of critical illness. Future studies are needed to elucidate whether the proposed gut dysfunction precedes or supersedes organ dysfunction in time.

Effects of Linoleic Acid-Rich Diet on Plasma Profiles of Eicosanoids and Development of Colitis in Il-10-/- Mice.

Dietary intake of linoleic acid (LA, 18:2ω-6) has risen dramatically in recent decades. Previous studies have suggested a high intake of LA could increase tissue concentrations of proinflammatory and protumorigenic ω-6-series eicosanoid metabolites, increasing risks of inflammation and associated diseases. However, the effects of a LA-rich diet on in vivo profiles of eicosanoids and development of inflammatory diseases are understudied. Here, we treated spontaneous colitis-prone (Il-10-/-) mice with a control diet (∼3 Cal% LA) or a LA-rich diet (∼9 Cal% LA) for 18 weeks and analyzed the effects of the LA-rich diet on profiles of eicosanoids and development of colitis. We found that treatment with the LA-rich diet increased the tissue level of LA: the liver levels of LA were 5.8 ± 0.6% in the control diet-treated mice versus 11.7 ± 0.7% in the LA-rich diet-treated mice (P < 0.01). The plasma concentrations of a series of LA-derived metabolites, including 9-hydroxyoctadecadienoic acid (HODE), 9,10-dihydroxyoctadecenoic acid (DiHOME), 12,13-DiHOME, and 13-HODE were significantly increased by treatment with the LA-rich diet (P < 0.05). However, the LA-rich diet had little effect on the severity of colitis in the treated Il-10-/- mice. These results suggest a limited role of increased consumption of dietary LA on promoting colitis in the Il-10-/- model.

Therapeutic effects of vitamin D on acetic acid-induced colitis in rats.

PURPOSE: To analyze the effect of calcitriol treatment on acute colitis in an experimental rat model. METHODS: A total of 24 adult Sprague Dawley albino rats were randomly separated into 3 equal groups: control group (n:8), colitis group (n:8), calcitriol administered group (n:8). A single dose of acetic acid (1 ml of 4% solution) was administered intrarectally to induce colitis. Group 1 was given 1 ml/kg 0.9% NaCl intraperitoneally; rats belonging to Group 2 were administered calcitriol 1 µg/kg for 5 days. RESULTS: Plasma tumor necrosis factor alpha, Pentraxin 3, and malondialdehyde levels were significantly lower in the calcitriol administered colitis group than in the standard colitis group (p<0.01). In the Calcitriol group, there was a significant histological improvement in hyperemia, hemorrhage and necrotic areas in the epithelium compared to the placebo group (p <0.000). CONCLUSION: The findings suggest that calcitriol may be an agent that could be used in acute colitis treatment.

Dynamic alterations in serum IgG N-glycan profiles in the development of colitis-associated colon Cancer in mouse model.

BACKGROUND: Alternative glycosylation of serum IgG has been shown to be closely associated with colorectal cancer (CRC). Currently, a dynamic study which can not only minimize the influence of genetic background, environment and other interfering factors during cancer development, but also focus on investigating carcinogenic characteristics of IgG glycan is lacking. METHODS: Serum IgG N-glycans were characterized at four stages of CRC development by ultra-performance liquid chromatography in a typical colitis-related CRC mouse model induced by azoxymethane-dextran sodium sulfate. Furthermore, the expression of related glycosyltransferases in splenic B lymphocytes at the corresponding time was also assessed. RESULTS: The relative abundance of seven IgG glycans, which can be classified as monoantennary, core fucose, sialic acid, galactose and bisecting, was changed during tumor growth. The abundance of some glycans was altered during the first stage of cancer induction. Correspondingly, the expression of glycosyltransferases in splenic B lymphocytes and different tissues in cancer groups was also decreased compared to that in controls. CONCLUSIONS: This study represents the comprehensive analysis of IgG glycosylation in the dynamic process of colitis-associated CRC. To our knowledge, this is the first report that the expression of glycosyltransferases in mouse splenic B lymphocytes is consistent or inconsistent with the alterations of IgG N-glycans, and the variation tendency is tissue nonspecific. GENERAL SIGNIFICANCE: Providing a novel approach to identify the IgG glycans related to the development of CRC and laying a foundation for research on structure and function of glycans using mouse.

PIK3R3 regulates ZO-1 expression through the NF-kB pathway in inflammatory bowel disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) are the major risk factor for developing colitis associated cancer (CAC). Previously, we have reported that Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was overexpressed in colorectal cancer (CRC), but we don't know the role of PIK3R3 in IBD. METHODS: We investigated the differential expression of PIK3R3 and ZO-1 in IBD patients by using Immunohistochemical (IHC) and Gene Expression Omnibus (GEO) database analysis. Caco-2 cells were exposed to different conditions to assess protein level changes of PIK3R3 and ZO-1. Caco-2 cell monolayers were transfected with PIK3R3/siPIK3R3 to assess transepithelial electrical resistance. Tight junction protein integrity was assessed by immunoblot and immunofluorescence. For further, intestinal permeability and tight junction protein integrity were assessed in animal study to assess the treatment role of PIK3R3 specific inhibitor TAT-N 15 (N15). RESULTS: PIK3R3 was increased in IBD patients, and negatively controlled the expression of ZO-1. In vitro, PIK3R3 regulates ZO-1 by activating NF-kB pathway. Overexpression of PIK3R3 in Caco-2 cells decreased transepithelial electrical resistance (TEER), an opposite result was observed in siPIK3R3 cells. In animal study, inhibition of PIK3R3 by N15 contributed to amelioration of DSS-induced intestinal permeability. Mice treated with N15 exhibited less disruption of TJs in colon tissues. CONCLUSIONS: PIK3R3 was increased in clinical IBD patients with accompanying disruption of ZO-1 expression. Inhibition of PIK3R3 attenuated DSS-induced IBD symptoms in a mouse model. These findings indicated that PIK3R3 could be a therapeutic target for IBD.

A novel method of sacral nerve stimulation for colonic inflammation.

BACKGROUND: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms. METHODS: Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with the parameters set at 5 Hz, 10 seconds on, 90 seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5 Hz intermittent stimulation vs 14 Hz-210 µs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed. KEY RESULTS: Both SNS-1h and SNS-3h significantly ameliorated intestinal inflammation; SNS-1h was superior to SNS-3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5 Hz intermittent stimulation but not the 14 Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. CONCLUSION & INFERENCES: Bipolar stimulation for 1 hour daily using intermittent 5 Hz parameters is most effective in improving colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function.

Polysaccharide from flammuliana velutipes improves colitis via regulation of colonic microbial dysbiosis and inflammatory responses.

The aim of this study is to investigate whether Flammuliana Velutipes Polysaccharide (FVP) could aid in the prevention of colitis. Effect of FVP on colitis was evaluated using dextran sulfate sodium (DSS)-induced colitis in rats. Influence of FVP on the expression of inflammation related biomarkers and signal pathway element of TLR4\NF-κB were assessed. The composition and taxonomy of colonic microbiota were analyzed by 16S rDNA high throughput sequencing, and the concentrations of caecal short fatty chain acids were assessed by chromatography-mass spectrometry. Our results showed that FVP treatment could regulate the colonic microbial dysbiosis and promote the levels of caecal short fatty chain acids, leading to down-regulation of TLR4\NF-κB signal pathway, which finally ameliorate the colitis. Thus, the present study is the first attempt to elucidate the effect of FVP on colitis and support the potential application of FVP as a functional food ingredient or preventive drugs for colitis.

The α-D-glucan from marine fungus Phoma herbarum YS4108 ameliorated mice colitis by repairing mucosal barrier and maintaining intestinal homeostasis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology with increasing incidence world widely. Previous studies have indicated that the α-D-glucan YCP purified from the mycelium of the marine fungus Phoma herbarum YS4108 had certain immunomodulatory activities in animal and cell models. In the study, the therapeutic effect and intestinal regulatory activity of YCP (40 mg/kg, intraperitoneal injection) on UC were investigated in dextran sulfate sodium (DSS)-induced colitis mice. The results showed YCP could improve the general symptoms, reestablish the intestinal immune balance, and repair the mucosal barrier in colitis mice. The administration of YCP also significantly increased butyrate and isovaleric acid levels. In addition, YCP resulted in prominent alterations on specific microbiota including Firmicutes, Bacteroidetes, Proteobacteria, Clostridiales, and Lachnospiraceae which are closely related to immune regulation and mucus repair. Therefore, YCP may be a candidate for curing UC because of its conspicuous effects comparable to 5-aminosalicylic acid (5-ASA).

Application of a DSS colitis model in toxicologically assessing norisoboldine.

In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630.

Therapeutic effects of vitamin D on acetic acid-induced colitis in rats

Abstract Purpose To analyze the effect of calcitriol treatment on acute colitis in an experimental rat model. Methods A total of 24 adult Sprague Dawley albino rats were randomly separated into 3 equal groups: control group (n:8), colitis group (n:8), calcitriol administered group (n:8). A single dose of acetic acid (1 ml of 4% solution) was administered intrarectally to induce colitis. Group 1 was given 1 ml/kg 0.9% NaCl intraperitoneally; rats belonging to Group 2 were administered calcitriol 1 µg/kg for 5 days. Results Plasma tumor necrosis factor alpha, Pentraxin 3, and malondialdehyde levels were significantly lower in the calcitriol administered colitis group than in the standard colitis group (p<0.01). In the Calcitriol group, there was a significant histological improvement in hyperemia, hemorrhage and necrotic areas in the epithelium compared to the placebo group (p <0.000). Conclusion The findings suggest that calcitriol may be an agent that could be used in acute colitis treatment.

Andrographolide Derivative AL-1 Ameliorates Dextran Sodium Sulfate-Induced Murine Colitis by Inhibiting NF-κB and MAPK Signaling Pathways.

Trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulfate (DSS) are commonly used to induce experimental murine ulcerative colitis (UC). Our recent study has demonstrated that a novel andrographolide derivative, AL-1, ameliorated TNBS-induced colitis in mice. However, the effect of AL-1 on DSS-induced murine colitis and the underlying mechanisms are yet unknown. In the present study, we aimed to investigate the therapeutic potential of AL-1 against DSS-induced UC in mice and to define its mechanisms of action. Oral administration of AL-1 attenuated body weight loss, reduced colon length shortening, lowered the disease activity index score, and alleviated colon histological damage. AL-1 significantly inhibited myeloperoxidase activity and suppressed immune inflammatory responses in colonic tissues. Moreover, AL-1 reversed DSS-altered expression of inflammatory cytokines in DSS-induced colitis mice. Importantly, the efficacy of 45 mg/kg of AL-1 was higher than that of 100 mg/kg of the positive control drugs 5-aminosalicylic acid and mesalazine. AL-1 decreased lipopolysaccharide-induced generation of reactive oxygen species and nitric oxide in cultured macrophages in vitro; it also reversed the altered expression of inflammatory cytokines. In both in vivo and in vitro studies, Western blot analysis revealed that AL-1 reduced the expression of phosphorylated NF-κB p65 and IκBα, downregulated the expression of iNOS and COX-2, and attenuated the expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), ERK, and JNK. In conclusion, AL-1 alleviated DSS-induced murine colitis by inhibiting activation of the NF-κB and MAPK signaling pathways. Our data suggest that AL-1 could be a potential new treatment for UC.