Terminal Ileum Biopsies Research Articles

Successful novel use of dupilumab for gastrointestinal involvement of idiopathic hypereosinophilic syndrome: case report and review of the literature.

Hypereosinophilic syndrome (HES) is characterized by blood and tissue hypereosinophilia leading to organ damage. Gastrointestinal involvement is the third most common manifestation. We present a patient with idiopathic HES with secondary eosinophilic esophagitis (EoE), gastritis, and enteritis, corticosteroids-dependent, azathioprine- and mepolizumab-refractory. The patient achieved clinical and histopathologic remission following dupilumab treatment. A 28year-old female presented with chronic episodic nausea and emesis since childhood and initial diagnosis of primary eosinophilic gastrointestinal disease (EGID), improved with corticosteroids, refractory to azathioprine. She was found to have peripheral eosinophilia and multifactorial anemia, with iron, B12, and folate deficiencies. Esophageal, gastric, duodenal, and terminal ileum biopsies showed significant eosinophilic infiltrate. Bone marrow biopsy at age 31 confirmed HES diagnosis. By age 32, she became total parental nutrition (TPN)-dependent. She failed trials of benralizumab and mepolizumab [anti-interleukin (IL)-5 inhibitors], and cromolyn (mast-cell stabilizer). After developing new esophageal stricture, we initiated dupilumab (IL-4/13 inhibitor), recently FDA-approved for EoE. After 9weeks, esophageal stricture, gut tissue eosinophilia, and prior intestinal ulcerations resolved. She ceased TPN and is tolerating a non-restricted diet, with complete symptom resolution. Our patient's complete remission with dupilumab shows promise for broadening its use in treating GI involvement in HES, along with primary EGIDs.

Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients.

Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients. We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR. In the post-SVR group, the microbial β-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients. In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.

Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease.

Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.

P121 Characterisation of the miRNAome in Crohn’s Disease patients reveals transcriptomic changes associated with tissue composition and drug treatment

Abstract Background Gene regulation plays a major role in Crohn's Disease (CD) susceptibility and drug response. MicroRNA (miRNA)-mediated mechanisms tune gene expression at the post-transcriptional level. MiRNAs are 20-to-25-nt long non-coding RNAs that repress protein expression by direct inhibition or cleavage of the targets. Evaluating the miRNAome is emerging as a promising tool to clarify pathogenesis and identify promising biomarkers. We characterised the regulatory miRNAome across disease subtypes, gut tissue locations and infliximab treatment in CD. Methods We generated 120 transcriptomic profiles from terminal ileum and left colon biopsies from Hospital Universitario de la Princesa (Madrid). This cohort is composed of 10 patients with active endoscopy, 10 quiescent CD cases, and 10 controls (30 in total). In a balanced setting, half of the samples were incubated with infliximab for 18 hours at 37ºC and the rest with basal medium (Table 1). We carried out an exploratory analysis to gain insights into the determinants of miRNAome variability, including variance partition analyses and linear mixed modelling to detect significantly altered miRNAs. We also harnessed results from several publications including GSE16879 dataset to perform a comparative study with infliximab response signatures. Results Tissue location is the primary determinant of miRNA expression variability. The Variance Partition model identified 30 top miRNAs whose variability is maximised across regions. However, patient-specific effects also play a relevant role. We also identified 96 differentially expressed miRNAs between terminal ileum and left colon, with an overrepresentation of molecules involved in stress and developmental pathways (Fig.1). Among these, we find miR200s and miR429, that are associated with suppression of epithelial-mesenchymal transition and are up-regulated in colon more than in ileum. Down-regulation of miR196 is also shown in terminal ileum. Regarding the effects of infliximab treatment, we detected nine deregulated miRNAs which are associated with cellular response pathways. These include miR200s and miR192, which targets NOD2 and down-regulates NF-κB. Our results show an up-regulation of miR192 upon infliximab incubation (log2FC=2.37), which is associated with a reduction in TNFα expression and, consequently, with induced overexpression of miR192. We conclude that this miRNA is a potential target for therapy development. Conclusion In short, tissue location, and to a lesser extent disease subtype, are the main determinants of miRNAome in CD. A few treatment-responsive miRNAs like miR192 and miR200s are identified, in spite of detection challenges, emphasizing the need to improve our comprehension of the miRNA dynamics associated with drug response.

Mucosal Architectural Change is an Important Feature in Distinguishing Crohn's Disease From Others in Terminal Ileum Ulcer Biopsy.

Besides Crohn's disease (CD), there are a variety of other causes that can also lead to ulcerations in the terminal ileum. The purpose of this study was to identify useful diagnostic features for CD when evaluating terminal ileum biopsies in patients with endoscopic finding of ulcers. Five hundred and seventy-one patients with endoscopic finding of ulcers were included in this retrospective study. Five main histological features were analysed, which were crypt irregularity, mucosal thickening, villous stromal widening (including villous atrophy), granulomas, and pseudopyloric gland metaplasia. Clinical and pathological features were determined by uni- and multivariable logistic regression. Then another independent cohort of 99 patients was established for verifying this nomogram. The crypt irregularity, mucosal thickening, and villous stromal widening were combined to be considered as one new variable named mucosal architectural change which was an independent variable in diagnosing CD. We found that mucosal architectural change, age <40 years, the presence of granulomas, and the presence of pseudopyloric gland metaplasia were independent factors for the pathological diagnosis of CD. Then nomogram was developed, with receiver operating characteristic (ROC) curve (area under the ROC curve [AUC] = 0.927) in training sets, and ROC curve (AUC = 0.913) in validation sets. We found mucosal architectural change is very helpful in distinguishing CD from non-CD patients. In the context of small biopsy which may lack full scope of changes, the model developed by combining these key features is valuable in predicting a diagnosis of CD, especially in younger patients (age <40 years).

THE UTILITY OF BIOPSYING ENDOSCOPICALLY NORMAL APPEARING TERMINAL ILEUM

Abstract INTRODUCTION The terminal ileum is often evaluated during colonoscopy procedures. A common indication for endoscopic examination and biopsy of an endoscopically normal appearing terminal ileum is in patients with inflammatory bowel disease (IBD). 1 In patients without IBD, indications for biopsying an endoscopically normal appearing terminal ileum are less clear and may be associated with increased cost and healthcare utilization, as well as increased levels of anxiety for patients. In this study, we aim to determine the indications for examining and biopsying an endoscopically normal appearing terminal ileum in patients without IBD and if, upon review of these biopsies, there is change in management. METHODS This was a retrospective chart review of patients who underwent colonoscopy with terminal ileum biopsy at Mayo Clinic between 1/1/2021 and 6/30/21. Patients were excluded if they had a history of IBD, prior ileocecal resection, or an endoscopically abnormal terminal ileum. Clinical and laboratory data, as well as outcomes of interest, were obtained from the electronic medical record. Comparisons between patients were performed using Pearson’s chi-square, Student’s and Mann-Whitney tests. RESULTS A total of two hundred consecutive patients were identified as having had biopsies from their endoscopically normal appearing terminal ileum. After reviewing the charts, 69 met inclusion criteria. Of the 69 patients, the majority were female (68.1%) and white (89.9%). Nearly half the patients had a BMI of 30 or above (49.3%). The most common indication for colonoscopy among these patients was chronic diarrhea followed by abdominal pain and hematochezia. Terminal ileum mucosa was histologically abnormal in 6 patients (8.7%): four patients had chronic ileitis, one had acute ileitis, and one had acute and chronic ileitis. All patients with either chronic or acute ileitis had chronic diarrhea listed as an indication for their colonoscopy. The patient with acute and chronic ileitis underwent colonoscopy for suspected Crohn’s disease due to incidental asymptomatic findings of small bowel inflammation on CT enterography. CONCLUSIONS In patients with a normal appearing terminal ileum, clinically significant histologic abnormalities on biopsies were found in a small percentage of patients. Although our sample size is small, there may not be diagnostic and therapeutic utility to routinely biopsy endoscopically normal appearing terminal ileum in patients, even in those with chronic diarrhea. Large prospective studies are needed to further support this observation. REFERENCES 1McHugh, Jonathan B et al. “The diagnostic value of endoscopic terminal ileum biopsies.” The American journal of gastroenterology vol. 102,5 (2007): 1084-9.

Characterization of the mucosal microbiota in patients with nodular lymphoid hyperplasia with concurrent irritable bowel syndrome compared to healthy controls.

Nodular lymphoid hyperplasia (NLH) is known as a lymphoproliferative lesion in which multiple small nodules appear on the intestinal wall. It has been documented that patients who struggle with irritable bowel syndrome (IBS) are at greater risk of developing NLH. Here, we aimed to investigate the previously reported pathogens and the abundance of a selection of mucosal microbiota in IBS + NLH patients compared to IBS, and healthy controls. Terminal ileum biopsies were collected from 37 IBS + NLH, 37 IBS, and 29 healthy controls. Bacterial culture and PCR was performed to detect the presence of pathogens in biopsies. A qPCR assay was applied to assess the abundance of a selection of bacterial taxa. Totally, five bacterial isolates including two enteropathogenic and one enteroaggregative Escherichia coli (EPEC, EAEC), one enterotoxigenic Staphylococcus aureus (SEA), and one Yersinia enterocolitica strains were detected among the IBS + NLH cases. The relative abundance of Bacteroidetes and Streptococcus spp. in IBS + NLH patients was significantly less than IBS and healthy controls. Firmicutes, Pseudomonas spp., Haemophilus spp., and Campylobacter spp. were notably more abundant in IBS + NLH than in IBS patients. The abundance of Verrucomicrobia was higher in NLH + IBS than in healthy controls. Actinobacteria was also significantly more abundant among NLH + IBS patients than the controls. Our results demonstrated that mucosal microbiota composition in NLH + IBS patients slightly differs from that of IBS patients and healthy controls. Further research using large-scale cohorts are needed to enhance current understanding of the contribution of the mucosal microbiota to NLH pathogenesis with concurrent IBS.

S2001 Chronic Norovirus Infection in a Double Solid Organ Transplant Patient

Introduction: Infectious diarrhea is a common complication in the postoperative course of a solid organ transplant (SOT) recipient. While self-limiting in immunocompetent patients, transplant patients on long-term immunosuppression can have severe, prolonged disease with significant morbidity. We present a case of chronic diarrhea due to recurrent norovirus infection in a double SOT patient to encourage early recognition. Case Description/Methods: A 61-year-old male presented with 35-pound weight loss despite a good appetite and large-volume watery diarrhea intermittently for 2 years. He had a liver-kidney transplant 14 years prior secondary to cryptogenic cirrhosis and renal cell carcinoma. Immunosuppression consisted of prednisone, tacrolimus, and mycophenolate mofetil (MMF). Stool PCR was positive for norovirus and negative for other viruses, bacteria, and parasites. His MMF dose was reduced with no benefit. He was discharged with supportive care with initial improvement in the diarrhea but returned to the hospital 4 other times with worsening diarrhea and weight loss. Infectious workup was persistently positive for norovirus. Bi-directional endoscopy with biopsies revealed colonic mucosa with rare epithelial apoptosis, chronic duodenitis, and increased intraepithelial lymphocytosis in the duodenum and ileum consistent with chronic norovirus (Figure). The full diagnostic workup is detailed in Table 1. He was managed conservatively during each hospitalization with fluids and antimotility agents and recently discharged home with plans to start nitazoxanide outpatient. Discussion: Norovirus infection among SOT patients can lead to severe and symptomatic chronic infection. Patients can develop dehydration, transplant rejection, and malnutrition making them higher risk for hospitalizations and death. It is unclear why some immunocompromised patients recover spontaneously while others demonstrate a protracted course but supportive care is the mainstay of therapy. Limited case series have shown nitazoxanide to be effective in treating SOT patients with chronic norovirus infection. However, nitazoxanide needs to be continued until stool RNA studies become negative. This case highlights the importance of considering chronic norovirus when a SOT patient presents with chronic diarrhea and weight loss. Early initiation of supportive care and nutrition consultation are imperative in reducing morbidity in these patients. Nitazoxanide can be effective in patients that are refractory to supportive therapy.Figure 1.: Duodenal biopsy (A): Focal intraepithelial lymphocytosis and lamina propria plasma cell infiltrates. Terminal ileum biopsies (B,C): Focal intraepithelial lymphocytosis and lamina propria plasma cell infiltrates (B); popcorn-like epithelial apoptosis (C). Table 1. - Diagnostic Workup Test/Procedure Result Creatinine, serum 2.1 mg/dl (baseline 1 mg/dl) Stool PCR -Positive for norovirus-Negative for Clostridium difficile toxins, Salmonella, Shigella, Yersinia, and Campylobacter Osmolality, feces 420 mOsm/kg Fecal fat Abnormal Duodenal biopsy -Mucosa with intraepithelial lymphocytosis, dense plasma cell infiltrates in the lamina propria, and rare apoptotic bodies-Negative for CMV, EBV, HSV Stomach biopsy -Gastric antral and oxyntic gland mucosa with chronic inactive gastritis-Negative for H. pylori Right colon biopsy Rare epithelial apoptosis Left colon biopsy Rare epithelial apoptosis Terminal ileum biopsy Mucosa with intraepithelial lymphocytosis, dense plasma cell infiltrates in lamina propria, and rare apoptotic bodies

S3474 Sevelamer-Induced Ischemic Ulcerative Colitis

Introduction: Sevelamer is phosphate binder used to treat hyperphosphatemia in patients with end stage renal disease (ESRD) on hemodialysis. Rarely, it has been shown to be a cause of ischemic colitis. This case provides an example of a patient presentation and key findings when considering sevelamer induced small bowel ischemic colitis. Case Description/Methods: A thirty-five-year-old male with ESRD on peritoneal dialysis presented with two days of hematochezia and severe abdominal pain. Diarrhea is described as maroon colored with four episodes in the span of 24 hours. Infectious work-up, including clostridium difficile and comprehensive GI panel, was negative for acute infection. CRP was elevated to 42.6 mg/L, WBC 12.9 10*3/uL, and hemoglobin 7.5 g/dL. CT angiography of the abdomen showed two short segments in the small bowel with inflammation concerning for ischemia. Colonoscopy and push enteroscopy were performed on day three of hospitalization showing ulcerative inflammation in D4 and in the terminal ileum 6cm proximal to the ileocecal valve. Biopsy results at the terminal ileum and D4 were showed mucosal necrosis and acute inflammation with crystalloid structures consistent with pill-associated mucosal necrosis. Further history was obtained from patient, he had been started on sevelamer a few weeks prior to hospitalization. Sevelamer was discontinued resulting in resolution of patient’s symptoms (Figure). Discussion: Although a rare complication, sevelamer has been documented to cause ischemic colitis (Yuste, Keri). These patients present similarly to the one discussed above with melena and abdominal pain. One of the hallmark findings reported on histopathological exam is “fish-scale” crystalloid structures in the mucosa. A review from 2017 examined published case reports in which sevelamer had caused ischemic colitis and the crystalloid structures were present in 13 out of 16 patients (Yuste). In ESRD patients on sevelamer, who present with symptoms consistent with gastrointestinal bleeding, it is important to recognize the sevelamer as a cause of ischemic colitis and to stop the sevelamer immediately. Furthermore, video capsule endoscopy or push enteroscopy should be considered if standard upper endoscopy and colonoscopy do not identify the source, as sevelamer induced enteritis can occur throughout the intestinal tract. If sevelamer is not stopped, complications such as perforation, acute anemia, stricture formation, and ulceration can continue to occur and worsen.Figure 1.: A) Diffuse ulcerated mucosa of the fourth portion of the duodenum. B) Patchy ulcerations of the terminal ileum. C) Terminal ileum biopsy showing crystalloid structures in an area of necrosis suspicious for pill-associated mucosal necrosis.

A case of enteritis induced by ipilimumab and nivolumab combination therapy

A 65-year-old man with a history of left renal cell carcinoma 25 years ago underwent left nephrectomy and was regularly followed up. Last year, positron emission tomography showed mediastinal lymph node enlargement. Bronchoscopic biopsy revealed cancer recurrence and metastasis. We administered ipilimumab (1 mg/kg) and nivolumab (4 mg/kg) combination therapy. A week later, he developed diarrhea and abdominal pain. Colonoscopy revealed a reddish edematous mucosa with erosions and ulcers from the terminal ileum to the ileocecal valve (Fig. 1A, B). Terminal ileum biopsy revealed lamina propria by inflammatory cell infiltration; however, no crypt abscess or apoptotic bodies were observed. The colon and esophagogastroduodenoscopy findings were normal (Figure 1C, D). Small intestinal capsule endoscopy revealed redness and edema in the jejunum (Figure 2 upper). From the deep jejunum to the ileum, and further into the ileum, common villi, erosions, and ulcers became apparent (Figure 2 lower). Tests for stool bacteria, cytomegalovirus, and other viruses were negative. Therefore, his condition was diagnosed with immune-related enteritis. His symptoms did not improve after stopping ipilimumab and nivolumab. Treatment with predonisolone 40 mg/day immediately improved his symptoms.

Comprehensive Evaluation and Unique Morphologic Features of Nonsteroidal Anti-Inflammatory Drug (NSAID) Enteropathy in the Terminal Ileum.

Differentiating NSAID enteropathy from Crohn disease can be challenging on terminal ileum biopsy. It is important to distinguish these two entities for management. In this study, clinical, radiographic, endoscopic, and histologic features of 30 patients diagnosed with NSAID enteropathy and 30 patients diagnosed with Crohn disease on terminal ileal biopsy were compared. None of the patients in the NSAID cohort demonstrated significant changes on imaging performed prior to biopsy. Depending on disease severity, patients with Crohn disease showed imaging findings ranging from minimal changes to significant bowel wall and/or luminal changes. Endoscopically, erythema, erosions, and/or ulcers in the terminal ileum were observed in a majority of NSAID cases. Patients with active Crohn disease were noted to have erythema, ulcers, strictures, and/or visible inflammation throughout the distal ileum and colon. Histologically, at least 80% of cases in each cohort showed ulceration/erosion and cryptitis/crypt abscesses. The Crohn disease cohort had significantly higher degree of lymphoplasmacytic inflammation in the lamina propria compared to the NSAID cohort. In contrast, a significantly higher percentage of the NSAID cohort had gland/crypt atrophy. A decrease in number of Paneth cells was found in the NSAID cohort. Decreased lamina propria lymphoplasmacytic inflammation was the most specific and the presence of gland atrophy the most sensitive feature favoring NSAID enteropathy. In summary, the combination of gland/crypt/Paneth cell atrophy with decreased lamina propria lymphoplasmacytic inflammation can aid in differentiating NSAID enteropathy from Crohn disease in terminal ileal biopsies; however, correlation with clinical, radiographic, and endoscopic findings is still required.

OP14 Interpreting genome-wide association studies of Inflammatory Bowel Disease through the lens of single-cell sequencing

Abstract Background Inflammatory bowel disease (IBD) is a complex disease characterised by chronic inflammation of the digestive tract. Genome-wide association studies (GWAS) have identified 241 risk loci significantly associated with the two common forms of IBD, Crohn’s disease and ulcerative colitis. The vast majority of these risk loci reside in non-coding regions of the genome, and we only know which gene is dysregulated to increase risk of disease for a minority. This knowledge gap makes it difficult to draw insights into disease pathology and identify new candidate drug targets. Methods To improve biological insights from IBD GWAS, we generated single cell RNA-sequencing data from ileal biopsies ascertained from 25 CD patients with active ileal inflammation and 26 non-IBD controls. We identified 49 different cell types among the ~140K sequenced cells (Fig.1), including all major immune, enterocyte, secretory and mesenchymal populations. Our optimized single-cell dissociation protocol preserves the top of villus epithelial cells, which are inherently prone to anoikis, enabling generation of high-quality transcriptomes for the first time. Fig. 1 Single-cell atlas of terminal ileum biopsies from Crohn’s disease and non-IBD individuals. Results We identified 797 unique genes differentially expressed between CD patients and controls, with notable expression differences in stem cell, secretory, and enterocyte populations. Genes involved in antigen presentation and interferon-gamma signaling were enriched among those most frequently dysregulated cell types. In an attempt to identify which of these expression differences are likely causal of disease, rather than simply a consequence of it, we integrated results from the latest IBD GWAS to assess the extent to which genes captured disease heritability, and in which cell-types. Genes specifically expressed in Tregs, monocytes and IL10RA-negative monocyte-derived macrophages captured a significant fraction of disease heritability, strongly implicating these cell types in disease pathogenesis. We investigated which genes were driving these enrichment signals and identified candidate effector genes at many IBD risk loci. Reassuringly, many confirmed IBD effector genes known to have a role in the normal functioning of these cell types were found, including NOD2, IL18RAP, IL23R, NCF4, and IL2RA. Conclusion Single-cell analysis combined with IBD genetics has generated strong evidence for a causal role of novel disease mechanisms that have therapeutic potential. Further experiments are underway to validate this finding. At ECCO we will present an updated version of this analysis, including genetic mapping of gene-regulation across cell types to identify IBD effector genes and causal variants.

Metastatic Head and Neck Squamous Cell Carcinoma Masquerading as Crohn's Disease

ABSTRACT Metastasis from head and neck tumors to the small intestine is an extremely rare occurrence with a dismal prognosis. We present a 67-year-old man with metastatic head and neck squamous cell carcinoma that initially presented as recurrent small bowel obstruction and was misdiagnosed as Crohn's disease. On colonoscopy, terminal ileum biopsies of lymphoid-appearing subcentimeter nodules were positive for metastatic squamous cell cancer. Our case highlights the importance of having a high index of suspicion for metastasis in patients with a recent history of head and neck cancers.

S2431 Ulcerative Colitis Flare-Ups Following mRNA COVID-19 Vaccination

Introduction: Ulcerative colitis (UC) is an autoimmune disease commonly managed with immunosuppressants. However, its put UC patients at a higher risk for infections. Therefore, vaccination is an important part of management. Messenger RNA (mRNA) vaccine is a new type of vaccine only widely used against COVID-19. The effect of mRNA vaccines on UC patients on immunomodulatory treatement is relatively unknown. Here, we present the first case of UC flare-up after receiving the SARS-CoV-2 mRNA vaccine. Case description/methods: A 36-year-old female with past medical history of ulcerative colitis, autoimmune pancreatitis presented with intermittent lower abdominal pain and diarrhea for 2 weeks with fever for 1 day. Her last flare-up was 3 years ago before she was put on Tofacitinib. She never required hospitalization. Her symptoms started the second day after she received the second dose of Pfizer COVID-19 vaccine. She had daily 5-10 times of non-bloody diarrhea and abdominal cramps. Her symptoms subsided after 7 days of initial onset. On day 11, she started to have daily up to 15 times bloody bowel movements, along with nausea, vomiting, unable to maintain oral intake. Day 17 after vaccination, patient went to ED after fever of 100.5F. On presentation, she is afebrile, WBC 11.9, CRP 61.8, calprotectin 1840, Clostridioides difficile negative, GI Panel negative. CT showed severe colitis involving the left colon from splenic flexure to rectum. Colonoscopy showed erythematous, granular, hemorrhagic, and ulcerated mucosa in the entire examined colon. Terminal ileum, cecum, ascending, transverse, descending, sigmoid and rectum biopsies were negative for CMV, showed chronic active colitis. Patient received intravenous Methylprednisolone, then transited to oral Prednisone taper and resumed her Tofacitinib. Her symptoms gradually improved. Discussion: To our best knowledge, no report has shown the association of mRNA vaccine and UC flare-up. In general, non-live vaccines are safe for UC patients regardless of immunosuppressants usage. Live vaccines are also contraindicated Tofacitinib users like our patient. In the Pfizer COVID-19 vaccine trial, patients on immunosuppressive therapy were excluded. Given the temporal relationship between the vaccine and her flare-up in the setting of long-term remission history, we are concerned that the stress induced by the mRNA vaccine may increase the risk of flare-up. More studies need to be done to evaluate the safety profile of mRNA vaccine for UC patients on immunosuppressants.Figure 1.: A: Nodular mucosa in second portion of duodenum. B: Multiple ulcers in terminal ileum. C and D: 1.7 cm segment of terminal ileum circumferential bowel wall thickening with mucosal hyperenhancement and submucosal edema.

Terminal ileum is the most sensitive site for the histologic diagnosis of grade 4 graft-versus-host disease (GvHD) in the lower GI tract and is a harbinger of poor outcome.

The site of the gastrointestinal (GI) tract where biopsies are most likely to be diagnostic of graft-versus-host disease (GvHD) remains controversial. Recent reports have indicated that biopsies from the rectosigmoid have sufficient sensitivity and specificity for diagnosing GI GvHD and can be obtained via a less invasive flexible sigmoidoscopy procedure. While GvHD histologic grades 1-3 have little correlation with patients' symptoms and overall clinical grade, histologic grade 4 GvHD does correlate with severe clinical presentation and a poor prognosis. We examined cases of lower GI biopsies obtained via a complete colonoscopy with ileal intubation for the evaluation of GvHD within a 2-year period from patients who underwent stem cell transplantation. In our study cohort, grade 4 GvHD was significantly more likely to be identified in a terminal ileum biopsy than in a biopsy from another site in the lower GI tract. Significantly, 5 of 6 patients with histologic grade 4 GvHD diagnosed on ileal biopsies died from complication of severe GI GvHD. Given the poor prognosis of histologic grade 4 GvHD in the terminal ileum, the detection of this finding may serve to inform clinicians that escalation or modification of treatment may need to be considered. Furthermore, our findings suggest that terminal ileal biopsies may help to increase sensitivity for identifying patients at high risk for poor outcome of GvHD.

Folate Transporters Are Found Throughout the Colon of Humans and Their mRNA Expression Appears to Be Unaffected by Low Dose Folic Acid Supplementation

ObjectivesA large depot of folate resides in the colon and can exceed dietary intake. Little is known about the capacity of the colon to absorb folate. We aimed to determine the expression of key folate transporters, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT), throughout the colon of healthy adults and the impact of low dose folic acid (FA) supplementation. MethodsIn this 16 wk open-labelled randomized control trial, healthy adults (n = 25) from a colonoscopy waiting list were randomized to receive daily a multivitamin plus a 400 μg FA (400FA, n = 12) or no FA supplement (0FA, n = 13). Subjects were provided with low FA bread and pasta and instructions how to follow a low FA containing diet. Six 24-hr diet recalls were administered throughout the study and blood samples were collected at baseline, 8 and 16 wk. At colonoscopy (16 wk), 4 tissue biopsies were collected from the terminal ileum, cecum, ascending and descending colon. Blood folates were determined by microbial assay; mRNA levels of folate transporters were assessed using qPCR. ResultsOne subject was removed from analysis due to missing data (0FA). No group differences in age, sex, BMI, dietary intake, vitamin B12, red blood cell (RBC) and plasma folate levels at baseline were observed. Mean ± SD FA supplement adherence was 92 ± 12% and 96 ± 9% at 8 and 16 wk, respectively. Subjects in the 400FA group had higher total folate intake (P < 0.05) and higher RBC and plasma folate levels (P < 0.01) at 8 and 16 wk compared to 0FA subjects. RBC values at 16 wk were 1764 ± 636 and 865 ± 190 nmol/L in the 400FA and 0FA group, respectively. RFC and PCFT were detected in terminal ileum and colon biopsies (n = 96) and their mRNA levels in each section did not differ between groups. However, expression of RFC was markedly higher than PCFT across all biopsy sections (P < 0.05) and highest in the terminal ileum, compared to the cecum, ascending and descending colon in both groups (P < 0.05). ConclusionsWe demonstrated expression of folate transporters, RFC and PCFT, throughout the human colon suggesting their potential contribution to overall folate absorption. mRNA expressions were not affected by a low dose FA supplement. A deeper understanding of how FA and folate status affect colonic transporter regulation may inform future revisions of folate intake recommendations. Funding SourcesNatural Sciences and Engineering Research Council.

A189 ELUCIDATING THE MECHANISTIC ROLE OF GLP-1R IN THE INFLAMMATORY RESPONSE OF MACROPHAGES AND B CELLS TO DIETARY FIBRES

Abstract Background Both diet and the microbiome have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Fibre is not digested; it is fermented by microbes in the large bowel. High fibre intake is related to lower risk for the development of IBD, and a high fibre diet is usually recommended for individuals with IBD. However, work in our lab suggests that select dietary fibres may be pro-inflammatory in a pediatric IBD cohort. Importantly, large bowel dysbiosis in IBD could limit the fermentation of dietary fibres, leading to reduced production of beneficial microbiome metabolites as well as an accumulation of intact fibre in the large bowel. These intact fibres may then interact with immune cells residing in the large bowel, through specific receptors, and perpetuate the inflammatory state seen in IBD. Aims Based on preliminary findings, we hypothesize that the dietary fibre oligofructose acts through GLP-1R on macrophages and B-cells to regulate the inflammatory environment. We expect to find changes in the expression of cytokines and chemokines, and their receptors. Methods Changes in immune cell secretions (ELISA) and the expression of selected inflammatory markers (RT-qPCR) were measured to determine potential pathways involved in response to dietary fibres in vitro. Knockdown of proteins of interest (siRNA) was performed to validate the involvement of these pathways in the inflammatory response to dietary fibres. Cells were treated with oligofructose, oligofructose pre-fermented by bacteria, or no fibre. The involvement of the fibre receptor, GLP-1R, was investigated to understand its connection to pathways identified. Results Qiagen RT2 profiler array (human inflammatory cytokines and receptors) and cytokine secretion (ELISA) indicated that in response to oligofructose macrophages have a predominantly pro-inflammatory response while B cells have an anti-inflammatory response. Presence of GLP-1R in large bowel and terminal ileum biopsies collected during endoscopy was higher in IBD (Crohn disease n=7; Ulcerative colitis n=7) than non-IBD patients (n=7), and expression was confirmed on both B-cells and macrophages. Knockdown of GLP-1R (siRNA) significantly reduced the pro-inflammatory response (IL-1β ELISA) with oligofructose application in THP-1 macrophage cells Conclusions Improving our understanding of the mechanistic link between dietary fibres and immune response will aid us in developing a model for the interactions of oligofructose with the GLP-1R in B cells and macrophages. Findings from this study may be able to inform dietary interventions, prebiotic/probiotic administration, and drug development for treatment of IBDs. Funding Agencies CIHRWeston Foundation

Pathological diagnostic considerations of terminal ileum biopsies in routine practice

Pathological diagnostic considerations of terminal ileum biopsies in routine practice

Effect of Crohn's Disease on Villous Length and CYP3A4 Expression in the Pediatric Small Intestine.

Changes in absorptive capacity and first‐pass metabolism in the small intestine affect oral drug bioavailability. Characterization of such changes as a consequence of inflammation is important for developing physiologically‐based pharmacokinetic (PBPK) models for inflammatory bowel disease. We sought to elucidate the impact of small intestinal Crohn’s disease (CD) on villous length and CYP3A4 expression in children. Freshly frozen duodenal and terminal ileum (TI) biopsies from 107 children (1–19 years) with and without CD were evaluated for active inflammation. Villous length and CYP3A4 mRNA/protein expression were compared among regions of active and inactive inflammation in CD and controls. A twofold reduction in villous length was observed in inflamed duodena and ilia of children with CD, but in the absence of regional inflammation, villi in CD were comparable in length to controls. Expression of CYP3A4 mRNA correlated significantly with villous length in the TI (P = 0.0003), with a trend observed in the duodenum that did not reach statistical significance. In the presence of active inflammation, a significant decrease in CYP3A protein expression was confirmed in the duodenum, where protein expression also correlated significantly with villous length across diagnoses (P < 0.0001). Our findings suggest that previous observations of decreased CYP3A4 expression and function in inflamed intestine may not be due solely to downregulation by inflammatory cytokines, but also to villous blunting and subsequent loss of surface area for protein expression. This information is relevant for PBPK model development and could aid with dose adjustment decisions for oral CYP3A4 substrates administered during CD flare (e.g., budesonide).

Giardia Is Often Overlooked on Histopathologic Examination: A High-Volume, Single-Institution Experience.

is sometimes missed by the pathologist, and we sought to determine how often this occurs at our institution-a large tertiary care center with a subspecialty gastrointestinal pathology service and what certain clinical and histologic clues can be used to flag cases with a higher likelihood of infection, targeting them for greater scrutiny. We identified a set of patients who tested positive for Giardia with a stool-based test, and who also received a small bowel biopsy at a similar time-point. These biopsies were retrospectively reviewed for Giardia, finding 8 positive cases. The organism was prospectively detected in 4 cases (50%) but overlooked in the remaining 4 cases (50%). Three of the 4 cases missed cases showed only rare organisms. The detected cases tended to more frequently have prominent lymphoid aggregates (3 detected cases, 0 overlooked cases) and intraepithelial lymphocytosis (3 detected cases, 0 overlooked cases). Certain clinical and histologic clues can be used to flag cases with a higher likelihood of infection. Specifically, we found abnormalities of the mucosa (active inflammation, intraepithelial lymphocytosis, villous expansion, prominent lymphoid aggregates) in each case, and 4 of 8 cases were from immunocompromised patients. Finally, 2 of 8 cases were terminal ileum biopsies. Biopsies with a histologic abnormality or those from immunocompromised patients should receive greater attention. Routinely looking for Giardia at that terminal ileum is necessary.