Search

The intestinal barrier dysfunction is intimately associated with inflammatory bowel diseases (IBD) as the gut barrier provides the first line of protection to host from external factors. The pathogenesis of IBD is multifactorial resulting from combinations of genetic polymorphism, environmental factors, diet, altered microbiota and the immune system. Aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor which upon activation can regulate many pathophysiological functions like inflammation and gut barrier homeostasis. Recently, we identified that microbial metabolite Urolithin A (UroA) mitigated colitis in pre-clinical models through activation of AhR-dependent pathways at two distinct levels by preserving the gut barrier function and reducing systemic and acute inflammation. However, the interplay between the enhanced barrier function and reduction in inflammation and the requirement of specific cell types to mediate the UroA activities remains to be established. In the current study, we evaluated the UroA mediated cell specific requirement of AhR by using transgenic mice AhRfx-VillinCre (AhR is deleted in intestinal epithelial cells) and AhRfx-LysMCre (AhR is deleted in myeloid cells) mice. Our studies showed that UroA mediated activation of gut AhR is critical for regulation of intestinal homeostasis in dextran sodium sulphate (DSS) induced colitis. UroA also activated intestinal AhR dependent signaling to induce IL-22 production from type 3 innate lymphoid cells (ILC3). Further, our data from intestinal organoids revealed that AhR dependent-induction of IL-18 from intestinal epithelial cells is responsible for IL-22 production from immune cells. These studies revealed the novel findings that microbial metabolite mediated selective activation of AhR regulates the IL-18/IL-22-axis to maintain gut homeostasis and enhance gut barrier function to attenuate IBD pathogenesis. Current studies are supported by NIH/NIGMS COBRE project P20-GM125504-01 and JHFEREG from University of Louisville. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Stricture formation is a common complication of Crohn's disease, resulting from the disease process, surgery, or drugs. Endoscopic balloon dilation has an important role in the management of strictures, with emerging techniques, such as endoscopic electroincision and stenting, showing promising results. The underlying disease process, altered bowel anatomy from disease or surgery, and concurrent use of immunosuppressive drugs can make endoscopic procedures more challenging. There is an urgent need for the standardisation of endoscopic procedures and peri-procedural management strategies. On the basis of an extensive literature review and the clinical experience of the consensus group, which consisted of representatives from the Interventional Inflammatory Bowel Disease Group, we propose detailed guidance on all aspects of the principles and techniques for endoscopic procedures in the treatment of inflammatory bowel disease-associated strictures.

Bark protects the tree against environmental insults. Here, we analyzed whether this defensive strategy could be utilized to broadly enhance protection against colitis. As a proof of concept, we show that exosome-like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)-mediated activation of the AhR signaling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium-specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti-microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter-kingdom communication in the mammalian intestine through an AhR-COPS8-mediated anti-inflammatory pathway. These data suggest that inflammatory pathways in a microbiota-enriched intestinal environment are regulated by COPS8 and that edible plant-derived ELNs may hold the potential as new agents for the prevention and treatment of gut-related inflammatory disease.

The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases., Urolithins are microbial metabolites derived from food polyphenols. Here, Singh et al. show that urolithin A and a synthetic analogue enhance gut barrier function via Nrf2-dependent pathways and mitigate inflammation and colitis in mice, highlighting a potential application for inflammatory bowel diseases.

Background Inflammatory bowel disease (IBD) can have autoimmunity and/or intestinal barrier dysfunction as part of pathophysiology and may be refractory to all available treatment options. Serum-derived bovine immunoglobulin (SBI) binds microbial components with postulated downstream effects of normalized gut immune and barrier function, which may be useful for managing IBD. The purpose of our study was to evaluate the effectiveness of SBI in the management of refractory IBD, particularly symptoms of chronic diarrhea and loose stools. Methods We retrospectively analyzed charts for patients diagnosed with IBD (n = 40) who were refractory to standard treatment. Patients received oral SBI 5 g daily for a period of at least 6 weeks. Twelve patients with IBD fulfilled study inclusion criteria. Each patient graded the severity and frequency of gastrointestinal symptoms before starting SBI and at 6 weeks of treatment using a standardized patient assessment form. Means and standard deviations for all symptom scores at baseline and week 6 of treatment were analyzed. Results Mean symptom scores decreased significantly for nausea (P = 0.02 for severity and P = 0.03 for mean symptom score) and diarrhea (P = 0.0006, P = 0.0001 and P = 0.0001 for severity, frequency and mean symptom score, respectively). Conclusions Therapy with SBI alleviated some refractory gastrointestinal symptoms in patients with IBD, including nausea and diarrhea. Increased duration, dosage and/or frequency of SBI might provide additional symptom improvement and could be tested through controlled clinical trials with larger sample sizes and longer follow-up.

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets., High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.

Diet influences brain function via inflammatory pathways. However, the molecular mechanisms by which diet intake modulates neuroinflammation are poorly understood. Here we show that garlic exosome-like nanoparticles (GaELNs) inhibited systemic as well as brain inflammatory activity and reverses the insulin resistance in a high-fat diet (HFD) induced mouse obesity model. Oral administration of GaELNs and outer membrane vesicles (OMVs) released from GaELNs manipulated Akkermansia muciniphila are selectively taken up by microglial cells and inhibits its activation. Mechanistically, GaELNphosphatidic acid (PA) (36:4) is required for the uptake of GaELNs via binding microglial brain acid‐soluble protein 1 (BASP1). Formation of the GaELNs/BASP1 complex is required for inhibition of c-Myc mediated expression of STING. Inhibition of STING activity leads to reducing the expression of an array of inflammatory cytokines including IFN-g. IFN-g induces the expression of IDO-1, which in turn IDO-1 mediated metabolites activate the AhR pathway that contributes to insulin resistance. Oral administration of GaELNs decreases the level of IDO-1 metabolites, kynurenine (KYN) which promotes insulin resistance via the AhR pathway in HFD mice. The significance in increased fecal KYN was further demonstrated in the fecal samples of type 2 diabetes patients. Our results further show that the OMVs released from GaELNs treated Akkermansia muciniphila inhibits the expression of microglial IFN-g and prevents KYN mediated IRS-1 and 2 expression in microglial cells. Collectively, these results demonstrate how nanoparticles from a healthy diet can reverse high-fat diet induced brain inflammation and reveal a link between brain microglia/gut microbiota to brain inflammatory disease outcomes via diet-derived exosome-like nanoparticles.

Background: Diet manipulation is the basis for prevention of obesity and diabetes. The molecular mechanisms that mediate the diet-based prevention of insulin resistance are not well understood. Here, as proof-of-concept, ginger-derived nanoparticles (GDNP) were used for studying molecular mechanisms underlying GDNP mediated prevention of high-fat diet induced insulin resistance. Methods: Ginger-derived nanoparticles (GDNP) were isolated from ginger roots and administered orally to C57BL/6 high-fat diet mice. Fecal exosomes released from intestinal epithelial cells (IECs) of PBS or GDNP treated high-fat diet (HFD) fed mice were isolated by differential centrifugation. A micro-RNA (miRNA) polymerase chain reaction (PCR) array was used to profile the exosomal miRs and miRs of interest were further analyzed by quantitative real time (RT) PCR. miR-375 or antisense-miR375 was packed into nanoparticles made from the lipids extracted from GDNP. Nanoparticles was fluorescent labeled for monitoring their in vivo trafficking route after oral administration. The effect of these nanoparticles on glucose and insulin response of mice was determined by glucose and insulin tolerance tests. Results: We report that HFD feeding increased the expression of AhR and inhibited the expression of miR-375 and VAMP7. Treatment with orally administered ginger-derived nanoparticles (GDNP) resulted in reversing HFD mediated inhibition of the expression of miR-375 and VAMP7. miR-375 knockout mice exhibited impaired glucose homeostasis and insulin resistance. Induction of intracellular miR-375 led to inhibition of the expression of AhR and VAMP7 mediated exporting of miR-375 into intestinal epithelial exosomes where they were taken up by gut bacteria and inhibited the production of the AhR ligand indole. Intestinal exosomes can also traffic to the liver and be taken up by hepatocytes, leading to miR-375 mediated inhibition of hepatic AhR over-expression and inducing the expression of genes associated with the hepatic insulin response. Altogether, GDNP prevents high-fat diet-induced insulin resistance by miR-375 mediated inhibition of the aryl hydrocarbon receptor mediated pathways over activated by HFD feeding. Conclusion: Collectively our findings reveal that oral administration of GDNP to HFD mice improves host glucose tolerance and insulin response via regulating AhR expression by GDNP induced miR-375 and VAMP7.

Background Anorectal fistulas (ARFs) are a common, devastating, event in the life of a patient with Crohn's disease. ARFs occur in up to 50% of patients with Crohn's disease. Treatment begins with surgical drainage of the initial abscess, followed by antibiotic therapy, then anti-inflammatory medications. If medical therapy fails to close the fistula tract, surgical intervention is often pursued. Surgery incurs risk of incontinence because of sphincter injury. Increasingly, the role of cell-based therapy is being investigated in ARFs. We evaluated the role a bioabsorbable scaffold plays in delivering cell-based therapy using a porcine model of AFR. Methods ARFs were mechanically created and matured by setons. After 28 days, setons were removed; periaortic fat was harvested and processed for stromal vascular fraction (SVF). The cells were labeled with a membrane stain for later identification, then injected into the fistula or implanted through scaffold. Fistulas not treated with cells were injected with fibrin glue. Animals were monitored visually for healing at weeks 2 and 4, then euthanized to evaluate fistulas for histologic healing. Results All fistulas (6/6) treated with SVF + scaffolds healed by week 2, compared with only 4/6 with just SVF and 0/5 treated with fibrin glue. Scaffolds retained SVF within the fistula tract more readily than injection method and SVF+scaffold treatment accelerated the healing process. Robust neovascularization was also seen in fistulas treated with SVF+scaffold. No adverse events occurred. Conclusions Scaffold technology may improve cell-based therapy healing rates for Crohn's ARFs. This advance should be investigated by human trials.

AIM To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy. METHODS This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria). RESULTS 121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs. CONCLUSION The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

Aims. Nutrient deficiencies are common in patients with inflammatory bowel disease (IBD). Adipose tissue plays a critical role in regulating energy balance. Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator with emerging beneficial roles in lipid homeostasis. We investigated the impact of FGF21 in experimental colitis-induced epididymal white adipose tissue (eWAT) lipolysis. Methods. Mice were given 2.5% dextran sulfate sodium (DSS) ad libitum for 7 days to induce colitis. The role of FGF21 was investigated using antibody neutralization or knockout (KO) mice. Lipolysis index and adipose lipolytic enzymes were determined. In addition, 3T3-L1 cells were pretreated with IL-6, followed by recombinant human FGF21 (rhFGF21) treatment; lipolysis was assessed. Results. DSS markedly decreased eWAT/body weight ratio and increased serum concentrations of free fatty acid (FFA) and glycerol, indicating increased adipose tissue lipolysis. eWAT intracellular lipolytic enzyme expression/activation was significantly increased. These alterations were significantly attenuated in FGF21 KO mice and by circulating FGF21 neutralization. Moreover, DSS treatment markedly increased serum IL-6 and FGF21 levels. IL-6 pretreatment was necessary for the stimulatory effect of FGF21 on adipose lipolysis in 3T3-L1 cells. Conclusions. Our results demonstrate that experimental colitis induces eWAT lipolysis via an IL-6/FGF21-mediated signaling pathway.

Currently, several noninvasive modalities, including MRI and PET, are being investigated to identify early intestinal inflammation, longitudinally monitor disease status, or detect dysplastic changes in patients with inflammatory bowel disease. Here, we assess the applicability and utility of multispectral optoacoustic tomography (MSOT) in evaluating the presence and severity of colitis. Methods: C57B/6 mice were untreated or treated with Bacteroides fragilis and antibiotic-mediated depletion of intestinal flora to initiate colitis. Mice were imaged using MSOT to detect intestinal inflammation. Intestinal inflammation identified with MSOT was also confirmed using both colonoscopy and histology. Results: Mice with bacterial colitis demonstrated a temporally associated increase in mesenteric and colonic vascularity with an increase in mean signal intensity of oxygenated hemoglobin (P = 0.004) by MSOT 2 d after inoculation. These findings were significantly more prominent 7 d after inoculation, with increased mean signal intensity of oxygenated hemoglobin (P = 0.0002) and the development of punctate vascular lesions on the colonic surface, which corresponded to changes observed on colonoscopy as well as histology. Conclusion: With improvements in depth of tissue penetration, MSOT may hold potential as a sensitive, accurate, noninvasive imaging tool in the evaluation of patients with inflammatory bowel disease.

INTRODUCTION Crohn's Disease (CD) results from chronic inflammation of the gastrointestinal (GI) tract involving TNF-α release. Gastrointestinal electrical stimulation (GES), a form of neuromodulation used to treat upper GI motility symptoms (UGI Sx), exerts an anti-inflammatory effect via TNF-α suppression. We hypothesized patients with CD symptoms in patients with gastroparesis (GP) may respond to GES. METHODS We retrospectively examined 284 patients with symptomatic gastroparesis (Gp Sx), who underwent GES placement. Patients with Gp Sx were evaluated by validated GI Sx patient reported outcome. Scores were obtained at baseline, after temporary GES placement and after permanent GES placement. Eleven patients from this cohort with coexisting CD were analyzed for improvements in their CD symptomatology using the Harvey Bradshaw Index (HBI). HBI scores were compared from before GES to after two sequential applications of electrical stimulation (temporary then permanent). A 3-point decrease in HBI indicated a clinical response and an HBI

Inflammatory bowel disease (IBD) embraces Crohn’s disease (CD), ulcerative colitis (UC) and the less common indeterminate colitis, all chronic inflammatory processes of the gastrointestinal (GI) tract. Together, they cause significant morbidity for a million and a half Americans [1]. Symptoms include diarrhea, nausea, abdominal pain, weight loss, which can occasionally prove fatal (i.e., toxic megacolon, perforated bowel) [2]. Patients are also at increased risk for colorectal cancer [3]. First line treatments, including various anti-inflammatory agents and antibiotics, are variably effective against active disease [4]. Remissions can be short-lived and uncontrolled activity is associated with significant side-effects [3]. Gut fibrosis will require most patients (80% and 45% of CD and UC patients, respectively) to undergo surgery [4]. Over the last decade, the so-called biological response modifiers or ‘biologics’, macromolecules that target inflammatory lymphocytes or the cytokines they produce, have emerged as effective therapeutic agents [5]. For example, infliximab, a chimeric anti-human tumor necrosis factor (TNF)-α antibody earned FDA approval almost 20 years ago, based on a high response rate, significant mucosal and fistula healing and long-term remissions in both CD and UC. Additional targets of biologics, either marketed or in various stages of development, include anti-p40, anti-p19, anti-interleukin (IL)-12/23, and anti-alpha 4/beta 7 integrin antibodies [5, 6]. However, an estimated 30% of patients will not respond to such treatments, and of those who initially respond, 50% will relapse within a year risking significant, often serious side effects including infections and increased risk of cancer. So far, biologics have had only a modest impact on surgery rates [7]. The need for novel therapies remains acute. Literature reports indicate that All trans retinoic acid (ATRA) provides benefit in various rodent models of IBD, including potential anti-fibrotic activity [8, 9]. Retinoic acid can exist in the body as any of five different chemical isomers (all-trans-RA, 9-cisRA, 13-cisRA, 11-cisRA and 9, 13-dicisRA). ATRA is the biologically active isomer and the primary enzymatic product of retinaldehyde oxidation. The retinoic acid family regulates a wide range of biological processes, including embryonic development, reproduction, vision, cell growth and differentiation, as well as, apoptosis and inflammation [10]. Topical ATRA is known as tretinoin, and is currently marketed under several trade names such as Retin-A®, Retin-A Micro®, Atralin®, Renova®, and Avita® as FDA approved topical treatment for acne and skin wrinkles. Oral formulations, called isotretinoin (Accutane®, Claravis®, Sotret® and Amnesteem® and Vesanoid®) can cure severe acne and treat acute promyelocytic leukemia (APL), but oral dosing induces more severe side effects. Isotretinoin has not been tested in IBD clinical trials, perhaps due to the serious side effects associated with oral administration, including teratogenicity, suicidality, headache, dizziness, fever, weakness, tiredness, dry mouth, dry skin, other skin changes, thinning hair, nausea, vomiting, itching, bone pain, mouth sores, increased sweating, earaches, and perhaps even colitis. Black-box warnings for oral formulations have been issued by the FDA because of these serious side effects, including retinoic acid syndrome in APL patients. Retinoic acid syndrome may manifest as life threatening upper respiratory tract disturbances (dyspnea, respiratory insufficiency, pleural effusion, expiratory wheezing and increased susceptibility to pneumonia). Its frequency, mechanism and treatment have recently been reviewed [11]. Efforts to circumvent toxicities by tissue targeted administration have included encapsulation in liposomes and aerosolization, although none of these have progressed further in development or resulted in marketed products [12,13]. This review begins with an analysis of published studies bearing on the efficacy of ATRA as an anti-inflammatory treatment for IBD, including in vitro and in vivo work in rodents, as well as ex vivo studies using human tissues. Clinical reports about ATRA attenuation or induction of IBD will also be reviewed. Efforts to deliver ATRA directly to gut tissue to improve activity and reduce side effects will then be discussed. Finally, the potential of ATRA to treat fibrosis will be considered. If successful, oral delivery of ATRA directly to the immune structures of the gut could represent a novel IBD therapy with a potential to reduce fibrosis and the subsequent need for surgery.

Background Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn’s disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn’s colitis (CC) from ulcerative colitis. Methods Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. Results Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7–92.9). Conclusions We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA–based assay to distinguish between these 2 conditions.

This study revisits a visualisation technique for virtual colonoscopy, known as virtual fly-over (FO). The method views the entire colon anatomy from above the centreline. It assigns two cameras located on opposite sides of the centreline, each of which is responsible for viewing one half of the colon. This approach has several advantages over related colon visualisation methods with regards to visibility coverage and polyp detection rate. However, the traditional FO implementation created a few drawbacks that hinder complete visualisation. For example, it could overlook polyps located on the line between the two halves, and it has no data-specific initialisation for cutting planes. The authors enhance the FO method in a number of respects in this study: resolve the cutting issue and improve the virtual camera setup in order to better visualise both the colon surface's hidden structures and polyps that are difficult to locate. Quantitative validation of the revamped FO on 30 actual clinical datasets with complicated shapes and large volumes demonstrated that the average surface visualisation rate is equal to 99.5 ± 0.2%. Also, true and synthetic polyps with various shapes and sizes were used to clinically validate the proposed method. Detection rate is up to 100% on the tested sets.

Ulcerative colitis (UC) is a common, chronic, inflammatory process limited to the colon. UC affects up to 1 million individuals in the USA alone and requires resection in up to 30% of patients. Resection is often followed by creation of a pouch. Pouchitis is the most common complication of ileal pouch-anal anastomosis (IPAA) following total proctocolectomy, affecting up to 50% of patients. Symptoms include increased stool frequency, urgency, cramping, and bleeding. Management of pouchitis is complex in antibiotic refractory cases. Plant-based polyphenolic compounds have shown protective effects against UC. We conducted a retrospective review of pouchitis patients treated with EGCG 200–400 mg twice daily. Seven of nine (78%) patients experienced significant improvement based on reduced frequency of bowel movements and bleeding, while five of nine (56%) experienced complete relief. One patient experienced no improvement with EGCG, and one had progression of pouchitis symptoms while taking EGCG. No significant adverse events were noted by patients while taking EGCG. The green tea-derived molecule EGCG exhibits an efficacy signal in the IBD-related condition of pouchitis. Impressively, 78% of patients experienced noticeable improvement in pouchitis symptoms after initiation of EGCG, while 56% of treated patients entered complete remission. These positive responses to EGCG in patients with pouchitis suggests the need to confirm these findings in a formal, controlled trial. Based on recent findings documenting its effects on epithelial permeability and mucosal inflammation, combined with its favorable safety profile, a possible preventative role could also be explored.

Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic or relapsing immune activation and corresponding inflammation within the gastrointestinal (GI) tract. Diverse genetic mutations, encoding important aspects of innate immunity and mucosal homeostasis, combine with environmental triggers to create inappropriate, sustained inflammatory responses. Recently, significant advances have been made in understanding the interplay of the intestinal epithelium, mucosal immune system, and commensal bacteria as a foundation of the pathogenesis of inflammatory bowel disease. Complex interactions between specialized intestinal epithelial cells and mucosal immune cells determine different outcomes based on the environmental input: the development of tolerance in the presence of commensal bacterial or the promotion of inflammation upon recognition of pathogenic organisms. This article reviews key genetic abnormalities involved in inflammatory and homeostatic pathways that enhance susceptibility to immune dysregulation and combine with environmental triggers to trigger the development of chronic intestinal inflammation and IBD.

This dissertation explores the role of epigallocatechin-3-gallate (EGCG), as a potential treatment for patients with inflammatory bowel disease (IBD). IBD is a common disorder that causes a great deal of suffering. Our understanding of the etiologies, pathogenic mechanisms, and treatment targets continues to evolve. Many new therapeutic targets are making their way through the pharmaceutical pipelines. However, not all patients benefit from these therapies. EGCG has long been studied as an anti-cancer agent. Most of our understanding of this compound comes from the oncologic literature. As the pathways of oncology and inflammation converge, new lessons can be taken from the cross discipline. EGCG’s effects on intracellular signaling bridges cancer to inflammation. Many of the same cytokines, chemokines, and molecular signals influencing cancer cells to grow also stimulate immune cells. Chapter 3 first explores the role of EGCG as both a preventative as well as a therapeutic agent and its effect on the dextran sulfate sodium (DSS) mouse model of colitis. The influence of EGCG on immune cell function is then explored in chapter 4. One novel approach in chapter 4 has to do with a focus on intestinal epithelial cells as agents of an immune response, and how EGCG impacts their function in that role. Chapter 5 explores the impact of EGCG on bolstering barrier function, as this is an important aspect of inflammatory bowel disease that is often neglected when considering new approaches to treating IBD. Finally, chapter 6 ends this dissertation with the first clinical trial in the world’s literature to evaluate EGCG as a therapeutic for IBD.

Background & Aims The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. Methods We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P −8 in meta-analysis with a nominal evidence ( P Results We detected SNPs at HLA-DRB1 , and African-specific SNPs at ZNF649 and LSAMP , with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication ( P −6 ): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B, PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2 ) for CD; and KCNQ2 (near TNFRSF6B ) for UC. Several of these genes, such as TNC (near TNFSF15 ), CXCR6 , and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. Conclusions We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Background and Aims: Interferon-γ-inducible protein-10 [IP-10] mediates immune cell trafficking from the circulation to the inflamed colon and decreases gut epithelial cell survival. IP-10 expression is increased in patients with ulcerative colitis [UC]. We report efficacy and safety results from a dose-ranging induction study of eldelumab, a fully human monoclonal antibody to IP-10, in moderately to severely active UC. Methods: A total of 252 adults with UC [Mayo score ≥ 6 and endoscopic subscore ≥ 2] were randomised 1:1:1 to placebo or eldelumab 15 or 25 mg/kg administered intravenously on Days 1 and 8 and every other week thereafter. The primary endpoint was clinical remission [Mayo score ≤ 2; no individual subscale score > 1] at Week 11. Key secondary endpoints included Mayo score clinical response and mucosal healing at Week 11. Results: Neither eldelumab 15 or 25 mg/kg resulted in significant increases vs placebo in the proportion of patients achieving Week 11 clinical remission. Remission and response rates were 17.6% and 47.1% with eldelumab 25mg/kg, 13.1% and 44.0% with eldelumab 15mg/kg, and 9.6% and 31.3% with placebo. Clinical remission and response rates were higher in anti-tumour necrosis factor [TNF]-naive patients treated with eldelumab compared with placebo. Eldelumab treatment was well tolerated and no immunogenicity was observed. Conclusions: The primary endpoint was not achieved with induction treatment with eldelumab 15 or 25 mg/kg in patients with UC. Trends towards clinical remission and response were observed in the overall population and were more pronounced in anti-TNF naive patients. Eldelumab safety signals were consistent with those reported previously [ClinicalTrials.gov number, [NCT01294410][1]]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01294410&atom=%2Feccojc%2Fearly%2F2016%2F01%2F10%2Fecco-jcc.jjv224.atom

Cholera toxin B subunit (CTB) is a component of a licensed oral cholera vaccine. However, CTB has pleiotropic immunomodulatory effects whose impacts on the gut are not fully understood. Here, we found that oral administration in mice of a plant-made recombinant CTB (CTBp) significantly increased several immune cell populations in the colon lamina propria. Global gene expression analysis revealed that CTBp had more pronounced impacts on the colon than the small intestine, with significant activation of TGFβ-mediated pathways in the colon epithelium. The clinical relevance of CTBp-induced impacts on colonic mucosa was examined. In a human colon epithelial model using Caco2 cells, CTBp, but not the non-GM1-binding mutant G33D-CTBp, induced TGFβ-mediated wound healing. In a dextran sodium sulfate (DSS) acute colitis mouse model, oral administration of CTBp protected against colon mucosal damage as manifested by mitigated body weight loss, decreased histopathological scores, and blunted escalation of inflammatory cytokine levels while inducing wound healing-related genes. Furthermore, biweekly oral administration of CTBp significantly reduced disease severity and tumorigenesis in the azoxymethane/DSS model of ulcerative colitis and colon cancer. Altogether, these results demonstrate CTBp's ability to enhance mucosal healing in the colon, highlighting its potential application in ulcerative colitis therapy besides cholera vaccination.

Background: Crohn's disease (CD) therapy is rapidly evolving. Recent and ongoing clinical trials using immunologically active stem cells (SC) for the treatment of CD demonstrate the potential for this novel therapy to induce complete and long-lasting remission of symptoms in settings where ‘standard’ therapies have been unsuccessful. Objective/methods: This review of SC, including mesenchymal stem cell (MSC) therapy for CD discusses how the immunological effects of MSC may correct some of the pathophysiological defects underpinning CD, and examines the latest clinical trial data providing evidence of their efficacy in the treatment of Crohn's disease. Results/conclusions: Given the beneficial effects on mucosal healing seen in animal models of inflammation and results from early clinical trials, MSC may serve as a candidate therapy for patients who have failed to respond to biological therapy.

Background:Vedolizumab (VDZ) is a gut-selective α4β7 integrin antagonist with demonstrated efficacy and safety in patients with moderately to severely active Crohn's disease (CD).1 In post hoc analyses of data from the double-blind (DB) placebo (PBO)-controlled GEMINI 2 study (NCT00783692), we inves