Colonic Edema Research Articles

Ganjiang Huangqin Huanglian Renshen Decoction protects against ulcerative colitis by modulating inflammation, oxidative stress, and gut microbiota

BackgroundUlcerative colitis (UC) is a disease that is difficult to treat and has been associated with high rates of recurrence. Moreover, the current medications for UC induce serious side effects following prolonged use. Ganjiang Huangqin Huanglian Renshen Decoction (GJHQHLRSD), has been traditionally used to treat UC. However, its protective mechanisms have not been fully studied. PurposeIn this study the mechanisms by which GJHQHLRSD treats UC was investigated. MethodsThe GJHQHLRSD and GJHQHLRSD drug-containing serum (GJHQHLRSD-DS) were characterized using LC-MS/MS. The therapeutic effect of GJHQHLRSD on dextran sodium sulfate (DSS)-induced UC was explored by assessing various parameters including intestinal flora 16S rRNA, intestinal barrier function, oxidative stress (OS) response, inflammatory cytokines, colonic histopathological injury, colon length, disease activity index (DAI) and body weight. ResultsTreatment with GJHQHLRSD increased body weight, ameliorated colon length shortening and edema, reduced the DAI score, improved the pathological injury, down-regulated the levels of IL-1β, IL-6, IL-8, TNF-α, LPS, LDH, TLR4, and NLRP3, and up-regulated the ZO-1 and Occludin levels in UC mice. It also decreased intestinal oxidative stress in UC mice and improved mitogenic activity by modulating mitochondrial ultrastructure as well as the expression level of PINK1, LC3-II/Ⅰ, Beclin-1, p62, and Parkin proteins. In addition, we found that the effects of GJHQHLRSD on UC mice were inhibited by 3-MA.GJHQHLRSD treatment reduced the imbalance of intestinal flora in UC mice, by regulating the inflammation and oxidative stress. ConclusionThese findings suggested that GJHQHLRSD effectively attenuated inflammatory responses, inhibited the TLR4/NF-κB/NLRP3 signalling, oxidative stress, and modulated the gut microbiota, and alleviated the DSS-induced UC symptoms, making it a promising and innovative therapeutic option for the treatment of UC.

Genistein and/or sulfasalazine ameliorate acetic acid-induced ulcerative colitis in rats via modulating INF-γ/JAK1/STAT1/IRF-1, TLR-4/NF-κB/IL-6, and JAK2/STAT3/COX-2 crosstalk

Ulcerative Colitis (UC) is a chronic idiopathic inflammatory bowel disease in which the colon’s lining becomes inflamed. Exploring herbal remedies that can recover mucosal damage is becoming popular in UC. The study aims to investigate the probable colo-protective effect of a natural isoflavone, genistein (GEN), and/or a drug, sulfasalazine (SZ), against acetic acid (AA)-induced UC in rats, in addition to exploring the possible underlying mechanisms. UC was induced by the intrarectal installation of 1–2 ml of 5% diluted AA for 24 h. Ulcerated rats were allocated into the disease group and three treated groups, with SZ (100 mg/kg), GEN (100 mg/kg), and their combination for 14 days, besides the control groups. The anti-colitic efficacy of GEN and/or SZ was evidenced by hindering the AA-induced weight loss, colon edema, and macroscopic scores, besides reduced disease activity index and colon weight/length ratio. Furthermore, treatments attenuated the colon histopathological injury scores, increased the number of goblet cells, and lessened fibrosis. Both treatments reduced the up-regulation of INF-γ/JAK1/STAT1 and INF-γ /TLR-4/ NF-κB signaling pathways and modulated the IRF-1/iNOS/NO and IL-6/JAK2/STAT3/COX-2 pathways and consequently, reduced the levels of TNF-α and IL-1β. Moreover, both treatments diminished oxidative stress, which appeared by reducing the MPO level and elevating the SOD activity, and hindered apoptosis; proved by the decreased immunohistochemical expression of caspase-3. The current findings offer novel insights into the protective effects of GEN and suggest a superior benefit of combining GEN with SZ, over either drug alone, in the UC management.

Design of mesalamine loaded micro-particles: Preparation, in vitro and in-vivo characterization

The goal of this study was to develop mesalamine (MS) microparticles that could be ingested by the colon without first passing via the stomach and small intestines. Without resorting to the time-consuming and laborious double emulsion solvent diffusion method, microparticles were successfully fabricated using the Box-Behnken Design method. Microparticle production was optimized, and the effects of many parameters were analyzed (X1: Eudragit S100, X2: Span 80 and X3: agitation speed). Using the Box-Behnken design (BBD), we compared the chosen optimized microparticles to the pure drug solution utilizing in vivo pharmacokinetic study for particle size (Y1), entrapment efficiency (Y2), and drug-release (Y3). It was simple to create spherical, free-flowing, smooth-surfaced microparticles with a zeta potential of −36.52 mV and a size distribution of 264.35 ± 6.28–652.34 ± 6.49 nm. Coefficients of 264.35 ± 6.28–652.34 ± 6.49%, 42.31 ± 2.43–89.74 ± 2.17%, and 52.31 ± 0.43–93.51 ± 0.33% from a quadratic model best fit the observed values of dependent variables. Formulation F4 was selected as the best option because it prevented the drug from being released in the upper GIT before it was ready and instead released it only in the colon, where the pH is optimal. The formulation had a particle size of 266.597 μm, an entrapment efficiency of 93.735%, a cumulative drug release of 95.578 percent, and a desirability factor of 0.998. In comparison to drug solution pharmacokinetics, microparticle pharmacokinetics showed a 6.35-fold decrease in Cmax and MS with an appropriately increased half-life of 8.13 h. (13.67 and 3.46). This enhanced bioavailability of MS released from microparticles is probably due to an increase in the half-life, mean residence time (MRT), and area under the concentration–time curve (AUC0-24) of MS. Over a long length of time with no increase in plasma MS level, it became clear that the novel method of MS-loaded microparticles would provide successful therapy for ulcerative colitis. A pharmacodynamic study found that mesalamine-loaded microparticles dramatically decreased colon edema, necrosis, and bleeding compared to free drug solution. Results from this study suggest that mesalamine-loaded microparticles may be an effective pharmaceutical delivery strategy for the management of ulcerative colitis.

Alternanthera brasiliana (L.) Kuntze decreases pain and inflammation in acute colitis model without hepatotoxicity

Objectives: To investigate antinociceptive and anti-inflammatory activities of the keto-alcoholic extract of A. brasiliana leaves in a mice model of acute colitis. Methods: The experiments were performed in Swiss mice; the keto-alcoholic extract of A. brasiliana leaves was prepared and flavonoids were quantified. The antinociceptive/analgesic activity was evaluated by the writhing test. The keto-alcoholic extract of A. brasiliana, saline and Dipyrone monohydrate were tested. Acute colitis was induced by 7.5% (v/v) acetic acid intrarectally and the animals were treated, by gavage, with keto-alcoholic extract of A. brasiliana, saline and Mesalazine. After euthanasia, intestinal segments of the mice were analyzed by macroscopic index and quantification of colonic edema. The mechanical hyperalgesia test was performed after induction of acute colitis with acetic acid and treatment of the mice using the electronic Von Frey test. Hepatotoxicity of the keto-alcoholic extract of A. brasiliana was tested by plasma dosage of the aspartate transaminase (AST) and alanine transaminase (ALT) enzymes. Data were analyzed by ANOVA followed by Tukey post-test considering P < 0.05 as significant. Results: In vivo results indicate that mice treated with the keto-alcoholic extract of A. brasiliana leaves at 100 and 300 mg/kg (0.872 and 2.616 mg total flavonoids/kg) showed a significant decrease in the number of writhing compared to the negative control. Between the two concentrations that were shown to be effective, no significant difference was observed. The Von Frey test points that mice treated with A. brasiliana extract at 30 (0.2616 mg of total flavonoids/kg), 100 and 300 mg/kg showed greater hyperalgesia. Regarding colitis, the mice treated with keto-alcoholic extract of A. brasiliana leaves at 10, 30, 100 and 300 mg/kg showed no lesions or lower-grade lesions when compared to the untreated group. In the quantification of edema no significant difference was observed among any experimental group. Plasma AST and ALT values were within normal reference values indicating no liver damage by the extract. Conclusion: The keto-alcoholic extract of A. brasiliana shows antinociceptive/analgesic and anti-inflammatory activity in an acute colitis model in mice without causing hepatotoxicity in the mice.

Effect of Firocoxib and Flunixin Meglumine on Large Colon Mural Thickness of Healthy Horses

Nonsteroidal anti-inflammatory drug (NSAID) administration carries risks of gastrointestinal toxicity. Selective COX-2 inhibitors (“coxibs”) were designed to reduce risks of adverse effects but are still associated with gastrointestinal complications in humans. The effect of coxibs on colonic inflammation and integrity in horses is unknown. The study objective was to compare the effects of the coxib firocoxib and the nonselective NSAID flunixin meglumine on ultrasonographic indicators of colonic inflammation in healthy horses. Twelve healthy adult horses were administered flunixin meglumine (1.1 mg/kg IV q12h) and omeprazole (1 mg/kg PO q24h) for 5 days, allowed a 6-month washout period, then administered firocoxib (0.3 mg/kg PO once, then 0.1 mg/kg PO q24h for 4 days) and omeprazole. Transabdominal ultrasonographic examination and serum chemistry profiles were performed at the beginning and end of each treatment week. Colon wall thickness increased over time when horses received firocoxib (median post treatment 5.8 mm, interquartile range 2.8 mm; P < .001), but not flunixin (median 3 mm, interquartile range 1.2 mm; P = .7) and was significantly greater following firocoxib compared to flunixin (P = .003). Subjectively, colonic edema was noted more frequently following treatment with firocoxib (11/12 horses), compared to flunixin (1/12 horses). There were no clinically significant alterations in hematologic parameters after administration of either drug. The increase in colon wall thickness following treatment with the COX-2 selective NSAID firocoxib may suggest a risk of subclinical colitis in healthy horses. Monitoring colonic health when NSAIDs are used in a clinical setting is warranted.

Acetic acid-induced colitis modulating potential of total crude alkaloidal extract of Picralima nitida seeds in rats.

The total crude alkaloidal extract of Picralima nitida seeds (PNE) is known to possess anti-inflammatory activity among other therapeutic benefits although its benefits in colitis has not been investigated. The current study therefore seeks to investigate the anti-colitis potential of PNE using acetic acid-induced colitis model in rats. Sprague Dawley rats were treated with oral 500 mg/kg sulphasalazine or 30, 100, and 300 mg/kg of PNE daily for 8 days with induction of colitis on the fourth day with acetic acid. Rats were killed 24 h after the last treatment and whole blood was obtained from the jugular vein for hematological analysis and biochemical assays. Colons were extirpated for assessment of macroscopic and histological damage to the colon. Treatment with PNE protected against colonic injury induced with acetic acid by decreasing mucosal ulceration, epithelial erosion, inflammatory cell infiltration, and colonic edema. Thus, PNE preserved mucosal architecture and suppressed goblet cells depletion. Moreover, treatment with PNE was associated with improved hematological parameters and reductions in the expression of serum tumor necrosis factor-alpha, interleukin-1β, and p38 mitogen-activated protein kinase. Also, PNE treatment exerted antioxidant effects by reducing nitric oxide production and increasing glutathione levels. In addition, PNE inhibited colonic lipid peroxidation by decreasing myeloperoxidase activity and malondialdehyde production. It can be concluded that PNE attenuates intestinal oxidative and inflammatory damages following intrarectal acetic acid challenge. Thus, demonstrates potential for use in chronic intestinal inflammatory diseases such as ulcerative colitis.

Probing the effects of MR120 in preclinical chronic colitis: A first-in-class anti-IBD agent targeting the CCL20/CCR6 axis

Concerning the growing interest in the role played by the CCL20/CCR6 axis in IBD pathogenesis and in the search for novel anti-IBD small molecules, we have recently discovered the first small-molecule (MR120) endowed with protective action against TNBS-induced colitis and zymosan-induced peritonitis. This protective action occurs through interference with the CCL20/CCR6 signaling. The aim of the present work is to expand the preclinical investigation of MR120, evaluating its beneficial anti-inflammatory effect on a model of chronic colitis obtained by cyclically exposing C57BL/6 mice to 3% DSS. Subcutaneous administration of MR120 at 1 mg/kg, the same dose effective against acute inflammation, helped attenuate several systemic and local inflammatory responses induced by DSS. Besides significantly improving murine health conditions, MR120 counteracted mucosal macroscopic injury, the increase of colonic edema and neutrophils oxidative activity, and mitigated spleen enlargement, while not significantly lowering intestinal IL-6 concentration. Overall, repeated daily treatment with MR120 for approximately 30 days was well tolerated and showed moderate protection in a relevant model of chronic colitis, in line with the beneficial effect previously observed in acute models of intestinal inflammation. Although more potent analogues of MR120 will be needed to more fully evaluate their clinical translatability, the present work provides a valuable example of in vivo efficacy of CCL20/CCR6 modulators in a chronic model of IBD.

Neuropeptide W Exhibits Preventive and Therapeutic Effects on Acetic Acid-Induced Colitis via Modulation of the Cyclooxygenase Enzyme System.

The novel peptide neuropeptide W (NPW) was originally shown to function in the control of feeding behavior and energy homeostasis. The aim of this study was to elucidate the putative preventive and therapeutic effects of NPW on colitis-associated oxidative injury and the underlying mechanisms for its action. Sprague-Dawley rats in the acute colitis groups received NPW (0.5, 1 or 5µg/kg/day) injections prior to induction of colitis with acetic acid, while the chronic colitis groups were treated after the induction of colitis. In both acute and chronic colitis (CC) groups, treatments were continued for 5days and the rats were decapitated at the 24th hour of the last injections and colon tissues were collected for assessments. NPW pretreatment given for 5days before colitis induction, as well as treating rats with NPW during the 5-day course of CC, abolished colonic lipid peroxidation. NPW treatment prevented colitis-induced reduction in blood flow, diminished neutrophil infiltration, and pro-inflammatory cytokine responses. NPW pretreatment only at the higher dose reduced colonic edema and microscopic score and preserved colonic glutathione stores. Elevations in cyclooxygenase (COX) enzyme activity and COX-1 protein level during the acute phase of colitis as well as reduction in COX-2 were all reversed with NPW pretreatment. In contrast, NPW treatment was effective in reducing the elevated COX-2 concentration during the chronic phase. NPW alleviates acetic acid-induced oxidative colonic injury in rats through the upregulation of colonic blood flow as well as the inhibition of COX-2 protein expression and pro-inflammatory cytokine production.

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model.

Although dysautonomia was documented in inflammatory bowel disease, with activation of the stress-related sympathetic system, the role of agonists/antagonists of the adrenergic receptors is not conclusive. Moreover, ulcerative colitis was recently linked to dementia, but the potential role of the presenilin 1(PS1)/BACE-1/beta-amyloid (Aβ) axis has not been evaluated. Hence, we investigated the impact of mirabegron (β3-agonist) and/or carvedilol (β1/β2 antagonist) on iodoacetamide-induced ulcerative colitis with emphasis on the novel pathomechanism of the PS1/BACE-1/Aβ axis in ulcerative colitis, and its relation to the inflammatory cascade, fibrotic processes, and the gut barrier dysfunction. Ulcerated rats were either left untreated or treated for 8days with mirabegron and/or carvedilol. Besides minimizing colon edema and weight loss, and improving colon structure, mirabegron and/or carvedilol abated colonic PS1/BACE-1/Aβ axis and the NOTCH1/NICD/HES1 hub besides the inflammatory cascade GSK3-β/NF-κΒ/TNF-α, and the oxidative stress marker malondialdehyde. The anti-fibrotic effect was verified by boosting SMAD-7 and inhibiting TGF-β1, α-SMA immunoexpression, and MTC staining. Moreover, the drugs improved the gut barrier function, attested by the increased goblet cells and expression of E-cadherin, and the inhibited expression of p (Y654)-β-catenin to preserve the E-cadherin/β-catenin adherens junction (AJ). These signaling pathways may be orchestrated by the replenished PPAR-γ, a transcription factor known for its anti-colitic effect. Conclusion: Besides maintaining the gut barrier, mirabegron and/or carvedilol mediated their anti-colitic effect by their anti-oxidant, anti-inflammatory, and anti-fibrotic capacities. The therapeutic effect of these drugs depends partly on suppressing the harmful signaling pathways PS1/BACE-1/Aβ, NOTCH1/NICD/HES1, GSK3-β/NF-κΒ/TNF-α, and TGF-1β/α-SMA while enhancing PPAR-γ, SMAD-7, mucus, and AJ.

S3445 Microscopic Enteritis: A Rare Manifestation of T-cell Promyelocytic Leukemia

Introduction: An abnormal infiltration of intraepithelial lymphocytes in the intestinal mucosa is described as microscopic enteritis (ME). ME is a heterogeneous condition that can be found in, but not limited to, celiac disease, autoimmune disorders, food protein intolerance, parasitic infections, and NSAID use. Thus, an obvious cause of ME is difficult to elucidate and requires thorough work up. We report a case of a patient who was found to have ME thought to be secondary to infiltrative T-cell promyelocytic leukemia (T-PLL). Case Description/Methods: A 68-year-old male with a history of type II diabetes and hyperlipidemia presented with intermittent fever, abdominal pain, nausea, and emesis. He was found to have small bowel obstruction with severe enteritis of 3/4 of the small bowel (distal jejunum to the ileocecal valve). He had a small bowel resection with pathology revealing necrotizing lymphocytic enteritis. Bidirectional endoscopy revealed mild colonic, ileal and duodenal edema with biopsies revealing increased intraepithelial lymphocytes. He was empirically treated with intravenous methylprednisolone with resolution of fevers. He was discharged home with a follow up with gastroenterology for ME and with hematology for persistent leukocytosis. He continued to have recurrent fevers with persistent lymphocytic leukocytosis (14,200 WBC/microliter). Infectious (acid fast bacteria, fungi, cytomegalovirus, adenovirus, syphilis) and rheumatologic diagnostics were unrevealing. He underwent bone marrow biopsy and peripheral blood examination with immunostains, flow cytometry, and cytogenetic studies and was found to have clonal T-cell receptor gamma gene rearrangement concerning for T-PLL. He was treated with alemtuzumab; however developed worsening disease and disseminating opportunistic infections (cytomegalovirus and aspergillosis). He passed away shortly after his diagnosis. Discussion: ME is a challenging diagnosis as its etiology can be difficult to elucidate. Prompt, timely evaluation should be prioritized to improve outcomes. T-PLL is a rare leukemia due to abnormal growth of T-lymphocytes and typically presents with leukocytosis, weight loss, and infection; however, gastrointestinal symptoms may be a presenting symptom.

S2175 Now You See Me, Now You Don’t: A Case of Campylobacter Jejuni Colitis Presenting as a Colonic Mass

Introduction: Campylobacter jejuni is responsible for 3-6% of diarrheal illnesses in the United States. Inoculation follows ingestion of a contaminated source such as poultry, unpasteurized milk, or drinking water. The presentation of a C. jejuni infection may radiographically and endoscopically mimic other pathologies such as colonic malignancy and inflammatory bowel disease (IBD). Case Description/Methods: A 66-year-old man with a past medical history of prostate cancer in remission and a 6mm colonic polyp removed 5 years prior presented to the emergency department with 5 days of watery diarrhea. He complained of 6 watery bowel movements per day associated with colicky abdominal pain and bloating. He was hemodynamically stable with a physical exam notable for severe tenderness in the right lower quadrant. Serum chemistries did not reveal any abnormalities. Computed tomography revealed severe, focal bowel wall thickening in the ascending colon and a 1.7cm hypodense lesion in the right hepatic lobe which was confirmed on magnetic resonance of the abdomen. The radiologist’s interpretation emphasized concern for colonic malignancy with metastasis to the liver (Figure). Endoscopic evaluation revealed diffusely erythematous, granular and ulcerated mucosa throughout the colon with concern for infectious vs inflammatory colitis. Histologic evaluation of ascending colonic mucosal biopsy revealed moderately active chronic colitis with extensive cryptitis and crypt abscesses. Stool polymerase chain reaction was notable for C. jejuni infection and the patient achieved clinical and endoscopic remission without antimicrobial therapy. Discussion: In patients with C. jejuni enterocolitis, radiographic imaging may reveal signs of bowel wall edema or ulcerations which may resemble colonic malignancy or IBD. Endoscopic findings of campylobacter enterocolitis are non-specific, however, may reveal edematous, erythematous, and friable mucosa which may be associated with hemorrhage. Inflamed mucosa can be either isolated or discontinuous. Colonic ulcers may present as either aphthous or linear (may resemble cobblestoning as seen in Crohn's Disease). Histologic evaluation can reveal cryptitis and crypt abscess formation similar to findings of ulcerative colitis. This case highlights the range of radiographic and endoscopic presentations of C. jejuni Colitis. Infectious colitis should remain on the differential for radiographic evidence of colonic edema in the right clinical setting.Figure 1.: A and B: CT Abdomen/Pelvis showing ascending colon wall thickening resembling mass; C: CT of Hypoechoic liver mass; D: T2-weighted MRI Abdomen of ascending colon wall thickening resembling a mass; E: Colonoscopy image revealing inflamed mucosa of ascending colon; F: Ulcerated mucosa of the sigmoid colon.

Annickia polycarpa extract attenuates inflammation, neutrophil recruitment, and colon damage during colitis

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) are complex inflammatory disorders of the digestive tract. Dysfunctional intestinal epithelial barrier, uncontrolled neutrophil recruitment into the colon, and oxidative stress are major features of IBD. IBD cannot be cured, but symptoms can be alleviated with anti-inflammatory drugs, which often show adverse effects. Thus, safer alternative treatment options are needed. Given the known anti-inflammatory properties of Annickia polycarpa extract (APE), we hypothesized that APE improves the outcome of the inflammatory response during colitis. We assessed APE effects on colon histology, epithelial barrier function and neutrophil recruitment during DSS-induced colitis in mice treated with APE. APE treatment significantly reduced the disease activity index and prevented DSS-induced colon damage as evidenced by reduced colon shortening, ulcerations, crypt dysplasia, edema formation, and leukocyte infiltration. Expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β were significantly diminished in APE-treated mice. Importantly, APE administration reduced neutrophil infiltration into the lamina propria leading to reduced oxidative stress, tight junction disruption and epithelial permeability in the colon. Thus, we propose APE as additional treatment strategy to attenuate colitis symptoms and enhance life quality of individuals with IBD.

Analysis of the Therapeutic Effect of Changyanning on Intestinal Flora in Inflammatory Bowel Disease.

Research Purposes. Inflammatory bowel disease (IBD) is an autoimmune disease coinduced by genes, environment, and immune response, mainly including ulcerative colitis (UC) and Crohn's disease (CD). There are a large number and variety of intestinal bacteria in the human intestinal tract. These bacteria maintain a balance with the human environment and participate in the normal physiological processes of the human body. They play a unique role in defending against pathogen invasion, maintaining the homeostasis of the human immune system and metabolizing substances. Intestinal flora imbalance may be one of the pathogenic factors of IBD, and restoring the disturbed intestinal flora has become a research hotspot in the prevention and treatment of IBD. Changyanning is mainly composed of Dijincao grass, yellow hairy ear grass, camphor tree roots, maple leaves, and so on. Clinical studies have shown that Changyanning alone or in combination has a significant effect on ulcerative colitis, but the treatment mechanism is not yet clear. In this study, we established an IBD animal model to explore the therapeutic mechanism of Changyanning on inflammatory bowel disease and its effect on intestinal flora. Research Methods. Male C57BL/6 SPF mice were given free access to 4% dextran sulfate sodium (DSS) solution for 7 days to establish an ulcerative colitis model. After the model was established, different doses of Changyanning tablets, Changyanning granules, and sulfasalazine were given by gavage for 7 days. The relieving effects of the above drugs on the symptoms of inflammatory bowel disease were evaluated by evaluating the mouse/rat body weight, survival rate, disease activity index, colon length, pathological tissue score, and other indicators. Results. The DSS-induced IBD mouse model showed significant increases in weight loss, DAI score, and pathological score. Both Changyanning tablets and granules can relieve the weight loss of mice, restore the colon length, and protect the colon tissue structure of mice. In reducing DAI and pathological scores in mice, Changyanning granules had a better effect. In conclusion, Changyanning can significantly improve the quality of life of IBD model animals, relieve intestinal inflammatory response, and relieve colonic edema, ulceration, and necrosis. The results show that Changyanning has a certain therapeutic effect on IBD. This study also provides experimental evidence for the application of Changyanning in the treatment of IBD, which is of great significance to its clinical application. The trail is registered in ChiCTR with number (TRN) ChiCTR2000028830.

S2977 Eosinophilic Ascites: Rare Presentations of Eosinophilic Gastroenteritis (EGE)

Introduction: Eosinophilic gastroenteritis (EGE) is a rare disorder characterized by eosinophilic infiltration of the gastrointestinal tract in the absence of other causes of intestinal eosinophilia. We describe a case of EGE presenting with eosinophilic ascites. Case Description/Methods: A 33-year-old male with schizophrenia and suspected familial adenomatous polyposis (FAP) was admitted with 2 days of nausea, vomiting, and diarrhea associated with 10 lbs. weight loss over the past 2 weeks. The exam was notable for abdominal distension with shifting dullness and diffused tenderness. Initial labs showed normal electrolytes and liver chemistries, WBC 13.8x103/µL (4.3-10x103/µL) with eosinophil predominance (60%, 8.29X103/µL (0.04-0.54X103/µL), CRP 17.43mg/L (0-3mg/L), and creatinine 1.5mg/dL (0.7-1.3mg/dL). Stool studies were negative for bacterial, ova, and parasitic infections. Further blood work showed normal IgE, fecal calprotectin, and Strongyloides IgG. Flow cytometry did not reveal any myelolymphoproliferative findings. Abdominal ultrasound showed hepatosplenomegaly with large ascites. He underwent paracentesis revealed WBC 12,154 with 97% eosinophil count and negative gram stain and AFB culture. He underwent push enteroscopy which showed esophagitis, duodenitis, and normal jejunum, and flexible sigmoidoscopy which showed distal colonic edema with patchy erythematous mucosa (Figure 1). Random biopsies were obtained from different parts of the gastrointestinal tract revealed increased eosinophils (up to 50 eosinophils/HPF) in the duodenum consistent with eosinophilic gastroenteritis (EGE) (Figure 2). The patient was started on 14 days of prednisone 40mg daily with taper. The patient was seen in the clinic 2 weeks later with normal eosinophil count and resolution of symptoms. Discussion: Clinical presentations of EGE are related to the layers and the extent of the bowel involved. While eosinophilic infiltration on an endoscopic biopsy suggests predominantly mucosal disease, patient with subserosal involvement typically presents with eosinophilic ascites. Our patient has evidence of both mucosal and subserosal involvement which eventually responds to steroid therapy. EGE should be suspected in patients presenting with gastrointestinal symptoms associated with eosinophilic ascites and peripheral eosinophilia. Endoscopic evaluation should be pursued to confirm the diagnosis.Figure 1.: Endoscopic finding A) esophagitis, B) duodenitis, C & D) distal colonic edema with patchy erythematous mucosa

Mechanism of Sanhuang Decoction in alleviating dextran sulfate sodium induced ulcerative colitis in mice with Candida albicans colonization:based on high-throughput transcriptome sequencing

This study explored the mechanism of Sanhuang Decoction(SHD) in treating dextran sulfate sodium(DSS)-induced ulcerative colitis(UC) in mice with Candida albicans(Ca) colonization via high-throughput transcriptome sequencing. Specifically, the animal model was established by oral administration of 3.0% DSS for 7 days followed by intragastrical administration of Ca suspension at 1.0 × 10~8 cells for 4 days and then the mice were treated with SHD enema for 7 days. Afterwards, the general signs were observed and the disease activity index(DAI) was recorded every day. After mice were sacrificed, colon length and colon mucosa damage index(CMDI) were determined and the histomorphology was observed with the HE staining method. The fungal loads of feces were detected with the plate method. Anti-saccharomyces cerevisiae antibody(ASCA) and β-1,3-glucan in serum, and TNF-α, IL-1β, and IL-6 in serum and colon were detected by ELISA. High-throughput RNA sequencing method was adopted to identify transcriptome of colon tissues from the control, model and SHD(15.0 g·kg~(-1)) groups. Differentially expressed genes(DEGs) among groups were screened and the GO and KEGG pathway enrichment analysis of the DEGs was performed. The expression levels of NLRP3, ASC, caspase-1, and IL-1β genes related to the NOD-like receptor signaling pathway which involved 9 DEGs, were examined by qRT-PCR and Western blot. The results demonstrated that SHD improved the general signs, decreased DAI and Ca loads of feaces, alleviated colon edema, erosion, and shortening, and lowered the content of β-1,3-glucan in serum and TNF-α, IL-1β, and IL-6 in serum and colon tissues of mice. Transcriptome sequencing revealed 383 DEGs between SHD and model groups, which were mainly involved in the biological processes of immune system, response to bacterium, and innate immune response. They were mainly enriched in the NOD-like signaling pathway, cytokine-cytokine interaction pathway, and retinol metabolism pathway. Moreover, SHD down-regulated the mRNA and protein levels of NLRP3, caspase-1, and IL-1β. In a word, SHD ameliorates DSS-induced UC in mice colonized with Ca, which probably relates to its regulation of NOD-like receptor signaling pathway.

Chemotactic factor inducing Interleukin-8 (IL8) gene is transcriptionally elevated in experimental enterotoxaemia in goats caused by Clostridium perfringens type D

The current study was designed to analyse the effects of experimental induction of enterotoxaemia through intra-duodenal inoculation of C. perfringens type D culture isolated from spontaneous outbreaks in goats. Twenty goats (6–9 month age) were divided into four groups and C. perfringens type D culture was inoculated intra-duodenally as per following: Group-I (whole cultures-WC), group-II (culture supernatant-CS), group-III (washed cells-WS), and group-IV (uninfected control-C). The treated animals were sacrificed after 72 h post infection (hpi), and necropsy showed gross changes including haemorrhages and congestion in the ileal and colon mucosa, pulmonary congestion and edema in lung. Kidney, brain and spleen exhibited severe to moderate congestion. Microscopic changes like haemorrhages, degenerative and necrotic changes in the mucosal epithelium of intestine and haemorrhages in kidney parenchyma were observed in the H&E stained sections. Lung alveolar sacs were filled with proteinaceous fluid. Immunohistochemistry revealed positive immunolabelling for etx (epsilon toxin) in the mucosa of intestine in WC and CS group. Control animals did not exhibit any significant gross or microscopic changes. PCR amplification of DNA extracted from intestinal tissues of WC and CS groups showed positive for etx gene demonstrating the production of epsilon toxin. Transcriptional responses in experimental groups were assessed by quantitative reverse transcription real time PCR (qRT-PCR). Genes including IL-1β and IL2 showed up-regulation in all the experimental groups (WC, CS&WS). Specifically the toxin-based experimental groups (WC&CS) showed up-regulation of the gene responsible for chemotaxis viz. IL-8, while the washed cells group (WS) showed higher transcriptional response to Cathepsin-L (Cat-L) gene denoting the acute inflammatory response due to neutrophil elastase activity. These results take a cue on the evolving nature of the enterotoxaemia in goats due to various strains circulating in the field. The host response and its modulation due to the novel enterotoxaemia strains throws light on the current challenges in efficient control of the disease in goats.

Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo

The prevalence of autoimmune diseases is on the rise globally. Currently, autoimmunity presents in over 100 different forms and affects around 9% of the world’s population. Current treatments available for autoimmune diseases are inadequate, expensive, and tend to focus on symptom management rather than cure. Clinical trials have shown that live helminthic therapy can decrease chronic inflammation associated with inflammatory bowel disease and other gastrointestinal autoimmune inflammatory conditions. As an alternative and better controlled approach to live infection, we have identified and characterized two peptides, Acan1 and Nak1, from the excretory/secretory component of parasitic hookworms for their therapeutic activity on experimental colitis. We synthesized Acan1 and Nak1 peptides from the Ancylostoma caninum and Necator americanus hookworms and assessed their structures and protective properties in human cell–based assays and in a mouse model of acute colitis. Acan1 and Nak1 displayed anticolitic properties via significantly reducing weight loss and colon atrophy, edema, ulceration, and necrosis in 2,4,6-trinitrobenzene sulfonic acid–exposed mice. These hookworm peptides prevented mucosal loss of goblet cells and preserved intestinal architecture. Acan1 upregulated genes responsible for the repair and restitution of ulcerated epithelium, whereas Nak1 downregulated genes responsible for epithelial cell migration and apoptotic cell signaling within the colon. These peptides were nontoxic and displayed key immunomodulatory functions in human peripheral blood mononuclear cells by suppressing CD4+ T cell proliferation and inhibiting IL-2 and TNF production. We conclude that Acan1 and Nak1 warrant further development as therapeutics for the treatment of autoimmunity, particularly gastrointestinal inflammatory conditions.

Hepatic encephalopathy induced by Lenvatinib and anti-PD-1 mAb in a patient with advanced hepatocellular carcinoma: A case report.

Previous studies have reported that the combinational therapy of Lenvatinib and anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb) produced a longer overall survival in patients with hepatocellular carcinoma (HCC). The current case report presented a a patient with HCC who had hepatic encephalopathy (HE) following treatment with Lenvatinib and anti-PD-1 mAb. The 42-year-old patient was diagnosed with stage IVa HCC accompanied with cirrhosis and Child-Pugh C. Computed tomography (CT) imaging revealed collateral circulation of the portal vein, causing significant varicose veins in the gastric fundus, mesenteric varices and colon edema. The patient was administered 12 mg Lenvatinib once daily combined with 240 mg anti-PD-1 mAb. After 3 days of treatment, he presented with a disorder of psychoneurosis and blood ammonia (248 µg/dl; normal levels, 40-80 µg/dl). A cranial CT scan exhibited no significant abnormalities. The patient rapidly progressed from grade 1 to grade 3 HE. Lenvatinib treatment was discontinued. After admission to the intensive care unit, the patient's blood ammonia level dropped to 132 µg/dl, after which he was discharged. It was concluded that the portal vein collateral circulation in the patient with HCC may have caused HE development whilst receiving Lenvatinib and anti-PD-1 mAb combinational therapy.

A197 COLONIC AMYLOIDOSIS: A CAUSE OF RECURRENT HYPOVOLEMIA

Abstract Background Systemic amyloidosis is a multi-organ disease characterized by abnormal extracellular protein deposition. The most common type is primary (AL) amyloid relating to underlying plasma cell dyscrasias. Other major variants include secondary (AA) amyloid from chronic inflammation, dialysis related amyloid (DRA) with β2-microglobulin, and heritable protein mutations. Management of the underlying disorder can limit further organ damage; however, no definitive treatment exists for familial causes. While uncommon, gastrointestinal involvement is variable and can cause asymptomatic infiltration, liver impairment, bleeding, or chronic diarrhea. Aims To discuss an unusual case of gastrointestinal amyloidosis as a cause of recurrent diarrhea and hypovolemic shock. Methods The patient records were examined, and a review of the literature was performed. Results An 87-year-old male with dementia, coronary artery disease and end stage renal disease from PCKD presented in hypovolemic shock. He had a two-week history of gradual onset, non-bloody, watery diarrhea with up to 20 bowel movements daily. He denied fever, sick contacts, travel, or recent antibiotic use. He had previously foregone endoscopy for a remote history of self-resolved hematochezia. Examination was notable for an uncomplicated inguinal hernia. Labs showed an anion-gap metabolic acidosis but no leukocytosis. He initially received iv hydration, vasopressors, and empiric antibiotics. CT showed diffuse wall thickening of the terminal ileum, colon and rectum with relative sigmoid sparing concerning for enterocolitis. Stool culture grew C. albicans, but C. difficile toxin and Ova and Parasite PCR were negative. He clinically improved with loperamide and was discharged only to be readmitted four days later with recurrent diarrhea and hypovolemia. Repeat cultures were negative. Endoscopy showed diffuse well-demarcated clean-based ulcers and colonic edema. Biopsies excluded viral causes but showed a classic appearance of apple-green birefringence on Congo red staining suggesting amyloid deposition. Raised light chain immunoglobulins and lysozyme on proteomic analysis indicated either AL or a heritable amyloid but excluded AA and DRA. Full diagnostic criteria for AL were not met as free light chain ratio was preserved without clear monoclonality. While his diarrhea again improved, next-of-kin opted for palliative care due to repeated admissions for delirium and generalized deterioration. Conclusions This case was indicative of atypical AL amyloidosis versus a rare lysozyme mutation involving renal and GI systems. AL amyloid has a classic appearance on special stains and mass spectrometry that distinguishes it from most subtypes, however, given elevated lysozyme levels further genetic analysis is needed to guide management. In the appropriate clinical context, gastrointestinal amyloidosis can be considered as a rare cause of recurrent unexplained diarrhea. Funding Agencies None

The Effect of Artemisinin on Inflammation-Associated Lymphangiogenesis in Experimental Acute Colitis.

Inflammatory bowel disease (IBD) is characterized by inflammation, angiogenesis, and lymphangiogenesis. Artemisinin (Art), a chemical compound isolated from Artemisia annua L. (sweet wormwood), has several biochemical properties including antibacterial, anticancer, anti-inflammation, and anti-angiogenesis effects. We investigated the effects of Art on inflammation-induced lymphangiogenesis in a dextran sulfate sodium (DSS)-induced mouse acute colitis model. The mice were orally administered Art for 7 days before being evaluated using the disease activity index (DAI) and documenting colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), proinflammatory cytokine levels, and vascular endothelial growth factor (VEGF)-C and VEGF-D/VEGF receptor (VEGFR)-3 mRNA expression levels in colon tissue. Art reduced DSS-induced lymphatic vessel endothelial hyaluronan receptor-1-positive LVD. Art also reduced the symptoms of colitis, improved tissue histology, and relieved inflammatory edema in mice affected by colitis. In addition, Art decreased the infiltration of immunomodulatory cells and inflammatory cytokines, which involved reduction of VEGF-C, -D, and VEGFR-3 expression. Taken together, our findings suggest that Art ameliorates inflammation-driven lymphangiogenesis in an experimental colitis mouse model via the VEGF-C/VEGFR-3 signaling pathway, implicating this pathway as a potential target for the treatment of IBD.