Including Inflammatory Bowel Diseases Patients Research Articles

Abnormal Promoter Methylation of Nucleotide-Binding Oligomerization Domain Containing 2 (NOD2) Gene in the Pathogenesis of Crohn’s Disease

Background: Changes in the expression of nucleotide-binding oligomerization domain containing 2 (NOD2) play an important role in the pathogenesis of a variety of autoimmune diseases including inflammatory bowel diseases (IBDs). Epigenetic modifications, including DNA methylation, are considered an important mechanism in the suppression of gene activity. In this study, we investigated the relationship between DNA methylation patterns of the promoter region of the NOD2 gene and the pathogenesis of Crohn’s disease (CD). Methods: Colonic mucosa samples were obtained from 15 Iranian patients with IBD and 15 age- and sexmatched healthy controls with no history of autoimmune disease. After the bisulfite conversion of genomic DNA, the DNA methylation status of three CpG sites in the promoter region of the NOD2 gene was determined by the real-time quantitative multiplex methylation-specific PCR (QM-MSP) assay. Results: Using this approach, we identified that IBD patients showed a decreased level of methylation of the NOD2 promoter in the colonic mucosa than did the healthy controls. (Unmethylated DNA in Crohn's disease vs. healthy controls; 0.128±0.093 vs. 0.025±0.016, P<0.000). Conclusion: According to our findings, promoter hypomethylation of the NOD2 gene in the colonic mucosa might contribute to the development and severity of CD. Furthermore, aberrant DNA methylation levels are expected to serve as a clinically useful risk marker.

A Potential Role for Gut Microbes in Mediating Effects of Omega-3 Fatty Acids in Inflammatory Bowel Diseases: A Comprehensive Review.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with several inflammatory conditions, including inflammatory bowel diseases (IBDs), and found to have an impact on gut microbiota. In fact, some randomized controlled studies suggest benefits to IBD patients, but others do not. Our aim was to review recent evidence on the effects of omega-3 on IBD and establish the contribution of the gut microbiome. Omega-3 mediate anti-inflammatory effects in IBD through various mechanisms, including suppression of NLR family pyrin domain-containing 3 (NLRP3) inflammasome, Toll-like receptor-4 (TLR4), and nucleotide-binding oligomerization domain 2 (NOD2) signaling; this results in the repression of the nuclear factor-kappa B (Nf-kB) pathway and the secretion of pro-inflammatory cytokines. Omega-3 can also affect gut microbiota and revert the bacterial community to patterns associated with healthy status by increasing short-chain fatty acid (SCFA)-producing bacteria and enhancing the mucosal gut barrier, thus promoting homeostasis. The combination of these immunoregulatory effects and anti-inflammation properties with the promotion of a balanced gut microbiome environment could suggest that omega-3 might benefit IBD patients. Considering the microbiota of IBD patients while using omega-3 might predict and improve omega-3 effectiveness. Combining omega-3 with bacteria-altering therapy, such as probiotics and fecal microbiota transplantation, may further enhance its efficacy; however, further studies are required to elucidate mechanisms and potential preventive or treatment roles of omega-3 in IBD.

NAMPT and NAPRT serum levels predict response to anti-TNF therapy in inflammatory bowel disease.

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyl transferase (NAPRT) are key intracellular enzymes that participate in the biosynthesis on NAD but have also been shown to be released as proinflammatory cytokines. A number of reports have shown that circulating NAMPT is increased in serum of patients with inflammatory disorders, including inflammatory bowel diseases (IBD), while nothing is known regarding circulating NAPRT and the presence of both cytokines in IBD patient stools. In the present study, we evaluated eNAMPT and eNAPRT levels in a large cohort of IBD patients not on biological therapy and in a subset that then was prescribed biologics. We conducted a retro-perspective study on 180 patients, of which 111 underwent subsequent biological treatment (adalimumab, vedolizumab, and ustekinumab). We analyzed eNAMPT and eNAPRT concentrations in serum and faces of IBD patients, correlating them with response to biologics. We now report that eNAMPT and eNAPRT are significantly increased in both serum and stools of IBD patients. NAMPT and NAPRT levels correlate with disease severity, with C reactive protein and with serum IL-6 levels. Importantly, levels of NAMPT in patients starting treatment with adalimumab correlate with response failure at three months: patients with levels above 4 ng/ml were significantly less likely to obtain benefit. Serum NAMPT as a biomarker of response yields a sensitivity of 91% and a specificity of 100%. The present work strongly suggests that a prospective trial evaluating eNAMPT and eNAPRT levels in relation to response to biologicals in IBD should be initiated.

P842 SARS-CoV-2 antibody titers analysis in immune mediated inflammatory disease patients after COVID-19 vaccination: a monocentric retrospective study

Abstract Background Immune-mediated inflammatory diseases (IMID) including inflammatory bowel diseases (IBD) and inflammatory arthritides are commonly treated with biological therapies, in particular anti-TNF. Patients on anti-TNF have impaired protective immunity following pneumococcal, influenza and viral hepatitis. However, the serological response to COVID-19 vaccination is still under-studied. Recent studies demonstrated that serologic response is attenuated in IMID patients on immunosuppressive therapy. In this study, the primary outcome is to describe the antibody response in IMID patients according to baseline patient characteristics, type of inflammatory disease, treatment and disease activity. Secondary outcome is to compare antibody response in patients treated with anti-TNF, versus other biologic therapies. Methods This study is a monocentric retrospective study, including 265 IMID patients followed at CHU Saint Pierre, Belgium, between 2021 and 2022. Respective baseline patient characteristics, vaccination status, treatment type, disease activity and SARS-CoV-2 antibody titers (IgG) after first, second and third vaccination were collected and analyzed. Results A total of 265 patients were enrolled (mean age 47 years old, 35% males, 67% IBD patients). Of these, 217 patients (82%) completed the 2 doses of vaccination and 130 patients (49%) the 3 doses, while 40 patients (15%) remained unvaccinated. Antibody titers after 2 doses of vaccination were available for 50 patients. In this group, the median antibody titer was 93 AU/mL [26-421] after first vaccination, raised up to 640 AU/mL [271-800] after the second vaccination (Δ85%, p<0.0001). Similarly, a statistically significant increase was noted in the subgroup of patients with available serologic data after 3 vaccination doses (N=18). The median antibody titer after the first vaccination in anti-TNF subgroup (N=15) was lower than that in other biotherapies subgroup (N=23); 34 AU/mL [6-145] versus 131 AU/mL [34-704] respectively. However, after the second vaccination, higher antibody titers were found in the anti-TNF subgroup, 686 AU/mL [321-800] versus 400 AU/mL [250-800] (p<0.388). Conclusion In our cohort of IMID patients, followed at CHU Saint Pierre, Belgium, there was a statistically significant raise in antibody titers after the second and third dose of COVID-19 vaccination, regardless of the type of inflammatory disease, disease activity, type of treatment and vaccine type. The antibody titers in this particular immunocompromised population were comparable to that found in the literature for the general population. More prospective observational studies are needed with a larger sample size to determine the characteristics of patients with sub-optimal serological response.

Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection

Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protectivereparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.

Inflammatory Bowel Disease: Role of Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of refractory forms of epilepsy and depression. The brain–gut axis is increasingly being studied as a possible etiological factor of chronic inflammatory diseases, including inflammatory bowel diseases (IBD). A significant percentage of IBD patients lose response to treatments or experience side effects. In this perspective, VNS has shown the first efficacy data. The aim of this narrative review is to underline the biological plausibility of the use of VNS in patients affected by IBD, collect all clinical data in the literature, and hypothesize a target IBD population on which to focus the next clinical study.

Modulation of intestinal immune cell responses by eubiotic or dysbiotic microbiota in inflammatory bowel diseases

BackgroundAlterations of the gut microbiota have been linked to aberrant mucosal immune responses, leading to different intestinal and extraintestinal disorders, including inflammatory bowel diseases (IBD) in genetically susceptible hosts. Thus, restoration of immune homeostasis through the manipulation of the gut microbiota is now considered a possible therapeutic approach to treat IBD patients. Management of IBD patients is currently including the customization of microbe-targeted therapies, such as antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation. In this narrative review, we will discuss recent advancements in the understanding of host-microbes interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. MethodsWe interrogated with no limit of publication time, the PubMed and Scopus databases using the following keywords: microbiota, inflammatory bowel diseases, IBD, immune system, microbe-targeted therapies. ResultsTherapeutic restoration of homeostatic immune function in IBD patients currently include the manipulation of the gut microbiota through antibiotics, prebiotics, probiotics, and faecal microbiota transplantation. Nonetheless, differences in efficacy has been reported according to existing microbe-targeted therapies, opening the venue for the search of novel approaches such as phage therapies and combinatorial therapies. ConclusionsAlterations in the composition of the gut microbiota have been implicated in a wide variety of pathologies, including IBD. Microbiome-modulating therapies have proven promising treatments targeting inflammation by modulating the microbiota to correct patients’ dysbiosis, normalize immune system responses and repair epithelial barrier deficiencies.

Diversion proctocolitis and the problem of the forgotten rectum in inflammatory bowel diseases: A systematic review.

Background and aimsDiversion proctocolitis (DP) is a non‐specific mucosal inflammation arising in the defunctionalized colon and/or rectum following faecal diversion (colostomy, ileostomy). Differential diagnosis of DP from the underlying disease in patients with inflammatory bowel diseases (IBD) is often unclear. As a result, it might be difficult to undertake any specific treatment. We aimed to systematically review the literature evidence on DP in IBD patients.MethodsFor this qualitative systematic review, we searched PubMed, EMBASE and Scopus to identify all studies published until July 2021 including IBD patients affected by DP.ResultsOverall, 37 papers published between 1982 and 2021 were included. A total of 1.211 IBD patients were included: 613 UC (50.6%), 524 CD (43.3%), 66 IBD‐unclassified (IBD‐U) (5.4%), 8 unspecified patients (0.7%). Most patients with DP are asymptomatic, although inflammation is detectable in almost all patients with a rectal stump. Reduced short‐chain fatty acids and an altered microbiome, may trigger mucosal inflammation and have been proposed as causing factors. An increased risk of developing cancer on DP has been reported in patients with a history of previous dysplasia/cancer.ConclusionsThe etiopathogenesis of DP is still unknown. The efficacy of mesalamine, corticosteroids or short‐chain fatty acids has not been proven by randomized trials yet. Since the incidence of cancer of the rectal stump can reach 4.5 per 1.000 diverted patients‐year, IBD patients undergoing subtotal colectomy with end‐ileostomy should undergo close endoscopic surveillance, being eventually counseled for surgery with or without the restoration of the intestinal continuity.

MicroRNA expression in inflammatory bowel disease-associated colorectal cancer.

MicroRNAs (miRNAs) are non-coding RNA molecules composed of 19–25 nucleotides that regulate gene expression and play a central role in the regulation of several immune-mediated disorders, including inflammatory bowel diseases (IBD). IBD, represented by ulcerative colitis and Crohn’s disease, is characterized by chronic intestinal inflammation associated with an increased risk of colorectal cancer (CRC). CRC is one of the most prevalent tumors in the world, and its main risk factors are obesity, physical inactivity, smoking, alcoholism, advanced age, and some eating habits, in addition to chronic intestinal inflammatory processes and the use of immunosuppressants administered to IBD patients. Recent studies have identified miRNAs associated with an increased risk of developing CRC in this population. The identification of miRNAs involved in this tumorigenic process could be useful to stratify cancer risk development for patients with IBD and to monitor and assess prognosis. Thus, the present review aimed to summarize the role of miRNAs as biomarkers for the diagnosis and prognosis of IBD-associated CRC. In the future, therapies based on miRNA modulation could be used both in clinical practice to achieve remission of the disease and restore the quality of life for patients with IBD, and to identify the patients with IBD at high risk for tumor development.

Hair EDX Analysis-A Promising Tool for Micronutrient Status Evaluation of Patients with IBD?

Micronutrient deficiencies can arise in various conditions, including inflammatory bowel diseases (IBD), and diagnosing these deficiencies can be challenging in the absence of specific clinical signs. The aim of this study was to evaluate the status of various trace elements hair concentration in IBD patients compared to a healthy control group and to identify potential correlations between the micronutrient status and relevant parameters related to disease activity. The concentrations of iron, magnesium, calcium, zinc, copper, manganese, selenium and sulfur in the hair of 37 IBD patients with prior diagnosed IBD (12 Crohn’s disease and 25 ulcerative colitis) and 31 healthy controls were evaluated by Energy Dispersive X-Ray spectroscopy (EDX). Significant differences in hair concentration profile of studied trace elements were identified for IBD patients compared to healthy controls. A significantly decreased hair concentration of iron, magnesium, calcium and selenium and a significantly increased sulfur hair concentration were observed in IBD patients at the time of evaluation. A decreased hair calcium concentration (r = −0.772, p = 0.003) and an increased sulfur concentration (r = 0.585, p = 0.046) were significantly correlated with disease activity. Conclusion: Hair mineral and trace elements evaluation may contribute to a proper evaluation of their status in IBD patients and improving the management of nutritional status of IBD patients.

Epstein–Barr Virus DNA Exacerbates Colitis Symptoms in a Mouse Model of Inflammatory Bowel Disease

Infection with EBV has been associated with various inflammatory disorders including inflammatory bowel diseases (IBD). Contribution of this virus to intestinal disease processes has not been assessed. We previously detected that EBV DNA triggers proinflammatory responses via the activation of endosomal Toll-like receptor (TLR) signaling. Hence, to examine the colitogenic potential of EBV DNA, we used the dextran sodium sulfate (DSS) mouse colitis model. C57BL/6J mice received either DSS-containing or regular drinking water. Mice were then administered EBV DNA by rectal gavage. Administration of EBV DNA to the DSS-fed mice aggravated colonic disease activity as well as increased the damage to the colon histologic architecture. Moreover, we observed enhanced expression of IL-17A, IFNγ and TNFα in colon tissues from the colitis mice (DSS-treated) given the EBV DNA compared to the other groups. This group also had a marked decrease in expression of the CTLA4 immunoregulatory marker. On the other hand, we observed enhanced expression of endosomal TLRs in colon tissues from the EBV DNA-treated colitis mice. These findings indicate that EBV DNA exacerbates proinflammatory responses in colitis. The ubiquity of EBV in the population indicates that possible similar responses may be of pertinence in a relevant proportion of IBD patients.

P690 Changes of intestinal microbiota in patients with inflammatory bowel diseases

Abstract Background Normal microbiota is one of the main topic controling normal function of human organism. Microbiota changes and dysbiosis are the important factors in the pathogenesis of different digestive diseases, including inflammatory bowel diseases (IBD). The aim: estimation the intestinal microbiota changes in patients with IBD. Methods We investigated fecal samples to determine features of intestinal microbiota in 17 patients with IBD in acute phase of diseases: 10 patients with ulcerative colitis and 7 patient with Crohn’s disease, four patients received therapy with immunodiological agents. For feces analysis we used real-time polymerase chain reaction with fluorescent detection. Statistical processing was performed using the SPSS8.0 software package. Results 100% of patients showed some changes in gut microbiota. These disorders were different in patients but no any significant changes in ulcerative colitis and Crohn’s disease patients. We saw the most frequent and significant changes: 1. decrease of Lactobacillus spp. level was determined in 59% of those examined 2. increase of Bifidobacterium spp. level was determined in 47% of patients 3. changing of the ratio of Bacteroides spp./Faecalibacterium prausnitzii towards increase of Bacteroides - in 24% of patients 4. frequency of occurrence of C. difficile was 24% of patients 5. frequency of occurrence of Candida spp. was in 35% of patients. In a number of patients, increased growth of opportunistic bacteria was detected: Proteus vulgaris/mirabilis - 24%, Citrobacter spp. - 29%, Enterobacter spp. - 12%. Microboal indirect microbial markers of colon oncopathology Fusobacterium nucleatum was identified in 18% and Parvimonas micra - in 24%. F. nucleatum and P. micra have higher frequency in patient who received immimmunodiological agents. Conclusion Patients with IBD show a downward trend in Lactobacillus spp. and increasing Bifidobacterium spp., whereby lacto-containing probiotics may be recommended for such patients and Bifidobacteria-containing probiotic may be not recommended. There is also a relatively high incidence of F. nucleatum and P. micra in IBD patients, which dictates the need for dispensary surveillance of these patients not only for the purpose of controlling the onset and maintenance of remission, but also for the purpose of early detection of colorectal cancer and IBD-associated malignancies.

Fecal Serine Protease Profiling in Inflammatory Bowel Diseases.

Serine proteases are extensively known to play key roles in many physiological processes. However, their dysregulation is often associated to several diseases including inflammatory bowel diseases (IBD). Here, we used specific substrates to monitor fecal protease activities in a large cohort of healthy and IBD patients. Of interest, serine protease activity was 10-fold higher in IBD fecal samples compared to healthy controls. Moreover, functional analysis of these fecal proteolytic activities revealed that the most increased activities are trypsin-like, elastase-like and cathepsin G-like. We also show for the first time, an increase of proteinase 3-like activity in these samples compared to controls. Results presented here will guide further investigations to better understand the relevance of these peptidases in IBD.

P360 Safety and clinical efficacy of double switch from originator infliximab to biosimilars CT-P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicentre study

Abstract Background Since infliximab (IFX) patent expiry in 2015, several IFX biosimilars have been licensed in EU for all indications, including inflammatory bowel diseases (IBD). IFX biosimilars currently available in Italy include CT-P13 and SB2, both of which demonstrated comparable efficacy, safety and immunogenicity with IFX originator in IBD patients. Safety and clinical efficacy of single switch from originator IFX to CT-P13 have also been confirmed in a prospective clinical trial. On the contrary, data regarding multiple therapeutic switching of IFX originator with CT-P13 and SB2 are currently lacking. Methods This study was aimed to evaluate the safety and efficacy of double switch from IFX originator to CT-P13 and subsequently to SB2 in patients with IBD. From November 2018 to May 2019, patients undergoing IFX double switch in 8 Centres in Lombardy were retrospectively analysed. The overall rate of IFX discontinuation, incidence and type of adverse events (AE) and proportion of patients on clinical remission over time were recorded. Data were compared with a control group of 66 IBD patients single switched from IFX originator to CT-P13. Results Fifty-two double-switched IBD patients were enrolled (63% M, mean age 41 years, 75% Crohn’s disease, 25% ulcerative colitis). Main indications for IFX therapy were moderate to severe disease (50%) and steroid-dependent disease (25%). The overall 24- and 48-week IFX discontinuation rates following second switch (CTP13->SB2) were 2% (95% CI 0–6%) and 14% (95% CI 3–25%), respectively. During a median follow-up of 40 weeks (18–48), 4 patients (12%) experienced a total of 6 AE (2 cutaneous, 2 infectious, 1 articular and 1 immunological), leading to IFX discontinuation in 3 cases (6%). No infusion reactions were observed. At week 24 following second switch, 49 (94%) patients were in clinical remission, the remaining 3 patients not being in remission already at the time of second switch. Only one patient lost response after week 24, 48 (92%) of patients being in clinical remission at the end of follow-up. No differences in IFX discontinuation, AE and clinical remission rates were found between double-switched and single-switched patients. No clinical parameters were found to predict safety and efficacy outcomes. Conclusion The study supports both safety and efficacy of the double switch from IFX originator to CT-P13 and SB2 in patients with IBD, and demonstrates its non-inferiority to a single switch strategy, with potential cost implications.

P163 Changes in diagnostic delay in inflammatory bowel diseases over the years: a retrospective single-centre analysis

Abstract Background Delayed diagnosis is common in inflammatory bowel diseases (IBD) and has been reported to be longer for patients with Crohn’s disease (CD) than for those with ulcerative colitis (UC). Aims of study were to assess the median time to diagnosis in IBD patients, to examine whether diagnostic delay (DD) has improved over the years and its impact on biological treatment and need for surgery. Methods A retrospective monocentric study including IBD patients living in the area of Verona (Italy), diagnosed up to 2019 and followed-up for at least 6 months at IRCCS Sacro Cuore—Don Calabria, Negrar, was carried out. DD was defined as the period (months) from symptoms onset to histological diagnosis of IBD and reported as <6 months, 6–12 months and >12 months. Results Six-hundred-six patients (255 CD; 351 UC; 308 males; 298 females) were enrolled. Median DD was 10 (IQR 2–12), 6 (IQR 1–12) and 2 (IQR 1–7) months <2000, between 2001–2010, and >2010, respectively. Median time to diagnosis was not significantly longer in CD than in UC patients (4 vs. 3 months; IQR 1- 12). No sex- or age-related differences in DD were observed. Using the Mann–Whitney test, DD was longer in patients diagnosed <2000 and between 2001–2010, than in those diagnosed >2010 (p = 0.0000 and p = 0.0004). Comparing DD <2000 and >2010, the statistical difference was reported for UC (p = 0.0000) but not for CD (p = 0.2756). Considering the use of biologics over the years, patients diagnosed between 2000–2010, and >2010 were compared (194 CD and 333 UC), reporting a significant increase in their use both for CD (30 vs. 60; p = 0.0008) and UC (28 vs. 43; p = 0.0000). DD did not influence the need for biological treatment in both diseases (p = 0.987 for CD; p = 0.433 for UC). Considering a DD <6, 6–12, and >12 percentages of patients needing biologics were respectively 53.4%, 63.6% and 56.5% for CD and 28.5%, 34.1% and 26.3% for UC. Seventy-two CD and 27 UC patients needed surgery. Analyzing the time to surgery, DD did not influence the rate of resections in CD (p = 0.6559), as well as in UC (p = 0.2792). Conclusion In our cohort, DD has significantly decreased over the last years, more for UC than CD patients. This is probably related to the increased awareness of patients on disease and of general practitioners in sending them to the specialist. Considering the published literature, UC and CD did not differ in DD; moreover age at diagnosis did not affect DD in our patients. DD did not influence the need for biological treatment or surgery rates in both diseases. These results are probably related to the difference in disease extension and severity among the patients enrolled. An analysis on targeted patients at higher risk for bowel damage is presently under way.

Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition.

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.

NAD immunometbolism drives intestinal inflammation and colitis-associated tumorigenesis

Nicotinamide-phosphoribosyl transferase (NAMPT) constitutes the rate-limiting enzyme in the NAD salvage pathway that is essential for the maintenance of cellular NAD levels. Upon inflammation including inflammatory bowel diseases (IBD), NAMPT is strongly induced and thereby impedes an increased cellular NAD-wastage promoted by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD-metabolism. Here, we investigated the efficacy of NAMPT inhibition by the small-molecule inhibitor FK866 in models of acute colitis, colitis-associated cancer and on lamina propria mononuclear cells (LPMNC) from IBD patients. FK866 mitigated colitis and suppressed inflammation-associated tumorigenesis. NAMPT blockade resulted in NAD-depletion that was associated with reduced abundances and activities of PARP1, Sirt6 and CD38, decreased inflammatory monocytes, macrophages and activated T-cells. FK866-treatment effectively supressed cytokine production in human LPMNC and was further associated with an altered monocyte/macrophage biology, skewing macrophages towards an anti-inflammatory M2 phenotype. Our data suggest that targeting the NAD immunometabolism by FK866 constitutes a promising therapeutic approach in acute intestinal inflammation and colitis-associated tumorigenesis.

IgE antibodies and skin tests in immediate hypersensitivity reactions to infliximab in inflammatory bowel disease: impact on infliximab retreatment.

Infliximab (IFX) is used for the treatment of inflammatory bowel diseases (IBD). Immediate hypersensitivity reactions (HR) to IFX are frequently reported. We investigated immunoglobulin E (IgE)-mediated mechanisms underlying immediate HR to IFX. We also evaluated the clinical utility of allergological tests as well as the tolerability of IFX retreatment in these patients. This was a prospective single-center study including IBD patients with previous immediate HR to IFX. Skin tests to IFX, including prick tests and intradermal tests, and measurement of anti-IFX IgE antibodies were performed at least 4 weeks after HR. In case of negative skin tests and absence of IgE antibodies, readministration of IFX was performed with a twice-reduced infusion rate. In case of positive tests or recurrence of HR during readministration of IFX, a 12-step desensitization or induction of tolerance protocol was proposed. A total of 24 IBD patients were included (Crohn's disease: n=20). Prick tests to IFX were all negative. Intradermal test was positive in one patient. Anti-IFX IgE antibodies were not detected in 21 patients and were detected in three patients (significant level in one patient and intermediate level in two patients). No relationship was observed between positive skin tests and the presence of anti-IFX IgE antibodies. Switch to adalimumab was well tolerated in 10/11 patients. The readministration of IFX was well tolerated in 4/11 patients. Desensitization to IFX was successful in three out of four patients. The vast majority of immediate HR to IFX is not IgE-mediated. Allergological tests are of poor clinical utility. Desensitization or induction of tolerance protocol may allow continuation of IFX therapy in IBD patients with a history of immediate HR.

Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation.

Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise.

Anti-inflammatory action of a novel orally available peptide 317 in mouse models of inflammatory bowel diseases

BackgroundThe endogenous opioid system constitutes an attractive target in the treatment of GI disorders, including inflammatory bowel diseases (IBD). The aim of our study was to characterize the anti-inflammatory and antinociceptive effect of P-317, a novel cyclic analog of opioid peptide morphiceptin, in animal models of IBD. MethodsThe anti-inflammatory effect of P-317 after intraperitoneal (ip) and oral (po) administration was assessed in two mouse models of IBD – Crohn's disease, induced by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS) and ulcerative colitis, induced by addition of dextran sodium sulfate (DSS) into drinking water. The antinociceptive action of P-317 was characterized in mice with acute colitis using mustard oil-induced pain test. Real time RT PCR was used to assess semiquantitatively the expression of IL-1β and TNF-α mRNA in mouse colonic samples. To translate our results to clinical conditions, MOP and KOP mRNA were quantified in human colonic biopsies from IBD patients. ResultsP-317 (0.1mg/kg, ip and 1mg/kg, po) alleviated colonic inflammation in TNBS- and DSS-treated mice in the opioid receptor-dependent manner. The anti-inflammatory effect of P-317 was associated with the decrease in mRNA expression of proinflammatory cytokines. The antinociceptive effect of P-317 was observed after ip and po administration in mice with acute colitis. ConclusionOur results show a potent anti-inflammatory and antinociceptive effect of P-317 in mouse models of colitis upon activation of opioid receptors. The unique bioavailability of P-317 after oral administration suggests that it is a promising drug candidate for future treatment of IBD.