Publications
180 results found
Alexander J, Powell N, 2020, Ileocolonic histopathological and microbial alterations in the irritable bowel syndrome: A nested community case-control study, Clinical and Translational Gastroenterology, Vol: 12, Pages: e00296-e00296, ISSN: 2155-384X
IntroductionHistopathological alterations in the ileum and colon in irritable bowel syndrome (IBS) are controversial, and normal values are poorly established. We hypothesized that changes in mucosal immune cells characterize IBS and key changes in immune composition are associated with the mucosa-associated microbiota (MaM).MethodsA nested case-control study (48 IBS and 106 controls included) from 745 colonoscopy participants in a random population sample. Intraepithelial lymphocytes (IELs)/100 enterocytes and eosinophils/5 nonoverlapping high-power fields counted; mast cells identified by immunocytochemistry (CD117)/5 high-power fields. Paneth cells quantified per 5 crypts. 16S rRNA gene amplicon sequencing performed on available sigmoid MaM, n = 55 and fecal microbiota, n = 20. Microbiota profiles compared between samples with high and low IEL counts.ResultsIBS had increased IELs in the terminal ileum (relative risk ratio = 1.70, 95% confidence interval 1.08-2.76, P = 0.022 adjusted for age, sex, and smoking). Cecal IELs were increased in IBS-diarrhea (relative risk ratio = 2.03, 95% confidence interval 1.13-3.63, P = 0.017). No difference was observed in alpha diversity of MaM or fecal microbiota based on IEL count. There was no difference in beta diversity of the MaM according to IEL count in the terminal ileal (TI) (P = 0.079). High TI IEL counts associated with a significant expansion of the genus Blautia (P = 0.024) and unclassified Clostridiales (P = 0.036) in colon MaM.DiscussionA modest but significant increase in IELs was observed in IBS vs. controls in a population-based setting. Subtle TI and cecal inflammation may play a pathogenic role in IBS but needs confirmation. Modest but discernible differences in the colonic MaM were seen according to TI IEL count but not IBS status.
Ibraheim H, Powell N, 2020, Systematic review with meta-analysis: effectiveness of anti-inflammatory therapy in immune checkpoint inhibitor-induced enterocolitis, Alimentary Pharmacology and Therapeutics, Vol: 52, Pages: 1432-1452, ISSN: 0269-2813
Background: Immune checkpoint inhibitors have revolutionised cancer treatment,but at the cost of off-target immune-mediated organ damage. This includes checkpoint inhibitor-induced enterocolitis which frequently requires hospitalisation andmay be life-threatening. Empirical treatment typically includes corticosteroids andinfliximab, although, no large-scale studies have confirmed their effectiveness.Aim: To investigate the effectiveness of anti-inflammatory therapy in checkpointinhibitor-induced enterocolitis.Methods: We performed a systematic review and meta-analysis of studies reportingclinical outcomes of checkpoint inhibitor-induced enterocolitis in adult cancer patients treated with anti-inflammatory agents. We searched Medline, EMBASE, andthe Cochrane library through April and extracted the proportion of patients responding to anti-inflammatory therapy. Variation in effect size was studied using a randomeffects meta-regression analysis, with checkpoint inhibitor agent and tumour type asthe variables.Results: Data were pooled from 1210 treated patients across 39 studies.Corticosteroids were effective in 59% (95% CI 54- 65) of patients, with response significantly more favourable in patients treated with anti-PD-1/L1 monotherapy, compared with anti-CTLA-4 containing regimens (78%, 95% CI 69-85 vs 56 %, 95% CI49-63, P = 0.003), and more favourable in lung cancer patients compared with melanoma patients (88%, 95% CI 62-97 vs 55%, 95% CI 47-63, P = 0.04). Infliximab waseffective in 81% (95% CI 73-87) of patients, and vedolizumab in 85% (95% CI 60-96).Conclusion: Corticosteroids, infliximab and vedolizumab, are effective in the treatment of checkpoint inhibitor‐induced enterocolitis. Checkpoint inhibitor regimen andcancer type were significant moderators in response to corticosteroid therapy.
Favara DM, Spain L, Au L, et al., 2020, Five-year review of corticosteroid duration and complications in the management of immune checkpoint inhibitor-related diarrhoea and colitis in advanced melanoma, ESMO Open, Vol: 5, Pages: 1-8, ISSN: 2059-7029
BackgroundImmune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined.MethodsAll advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables.Results117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%).ConclusionRates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant n
Powell N, 2020, Adaptation of the British Society of Gastroenterology guidelines on the management of acute severe ulcerative colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel, Gut, Vol: 69, Pages: 1769-1777, ISSN: 0017-5749
ObjectiveManagement of acute severe ulcerative colitis (ASUC) during the novel coronavirus2019 (COVID-19) pandemic presents significant dilemmas. We aimed to provideCOVID-19-specific guidance using current British Society of Gastroenterology (BSG)guidelines as a reference point.DesignWe convened a RAND appropriateness panel comprising 14 gastroenterologists andan IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellistsrated the appropriateness of interventions for ASUC in the context of severe acuterespiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores anddisagreement index (DI) were calculated. Results were discussed at a moderatedmeeting prior to a second survey.ResultsPanellists recommended that patients with ASUC should be isolated throughout theirhospital stay and should have a SARS-CoV-2 swab performed on admission. Patientswith a positive swab should be discussed with COVID-19 specialists.As per BSG guidance, intravenous hydrocortisone was considered appropriate asinitial management; only in patients with COVID-19 pneumonia was their use deemeduncertain. In patients requiring rescue therapy, infliximab with continuing steroidswas recommended. Delaying colectomy because of COVID-19 was deemedinappropriate.Steroid tapering as per BSG guidance, was deemed appropriate for all patients apartfrom those with COVID-19 pneumonia in whom a 4-6-week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general,biologics were more likely to be deemed appropriate than azathioprine or tofacitinib.Panellists deemed prophylactic anticoagulation post-discharge to be appropriate inpatients with a positive SARS-CoV-2 swab.ConclusionWe have suggested COVID-19-specific adaptations to the BSG ASUC guideline using aRAND Panel.
Kennedy NA, Jones G-R, Lamb CA, et al., 2020, British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic, Gut, Vol: 69, Pages: 984-990, ISSN: 0017-5749
he COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government’s advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.
Urwyler P, Earnshaw I, Bermudez M, et al., 2020, Mechanisms of checkpoint inhibition-induced adverse events, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 200, Pages: 141-154, ISSN: 0009-9104
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- Citations: 28
Taylor KM, Hanscombe KB, Prescott NJ, et al., 2020, Genetic and Inflammatory Biomarkers Classify Small Intestine Inflammation in Asymptomatic First-degree Relatives of Patients With Crohn's Disease, CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, Vol: 18, Pages: 908-+, ISSN: 1542-3565
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- Citations: 15
Mora-Ortiz M, Ibraheim H, Hermangild Kottoor S, et al., 2020, Introducing ExHiBITT – Exploring Host microBIome inTeractions in Twins –, a colon multiomic cohort study, Wellcome Open Research, Vol: 5, Pages: 30-30
<ns3:p><ns3:bold>Background: </ns3:bold>The colon is populated by approximately 10<ns3:sup>12</ns3:sup> microorganisms, but the relationships between this microbiome and the host health status are still not completely understood. Here, our objective is to present the cohort characteristics of ExHiBITT – Exploring Host microBIome inTeractions in Twins – including i) biomedical phenotypes, ii) environmental factors and ii) colonoscopic findings.</ns3:p><ns3:p> <ns3:bold>Methods:</ns3:bold> Participants from the TwinsUK cohort were recruited to study the interactions between the microbiome and host adaptive immunity. In total, 205 monozygotic twins were recruited from the wider TwinsUK cohort. They completed health questionnaires, and provided saliva, blood, colon biopsies from three different locations, caecal fluid, and two faecal samples.</ns3:p><ns3:p> <ns3:bold>Results:</ns3:bold> A significant proportion of this apparently normal cohort had colonic polyps (28%), which are of interest as potential precursors of colorectal cancer, and, as expected, the number of polyps found was significantly correlated with BMI and age. Hitherto undiagnosed diverticulosis was also not infrequently found during colonoscopy (26%) and was associated with changes in Hybrid Th1-17 cells in the colon. Twin proband co-occurrence rate for diverticulosis (82%) was much higher than for polyps (42%). Familial factors affecting morphology or tolerance may contribute to the ease of endoscopy, as both the time to reach the caecum and pain perceived were highly concordant (proband concordance: 85% and 56%, respectively).</ns3:p><ns3:p> <ns3:bold>Conclusions:</ns3:bold> We found the expected positive relationship between BMI and colonoscopic anomalies such as diverticular disease and polyps in the whole population, but within twin pairs this association was reversed. This suggests tha
Powell N, Pantazi E, Tsamaki A, et al., 2020, Interleukin 22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells, Gut, Vol: 69, Pages: 478-490, ISSN: 0017-5749
Objective - The functional role of interleukin-22 (IL22) in chronic inflammation is controversial and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22- mediated regulation of colonic epithelial cells. Design – To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells we employed a 3-dimentional mini-gut epithelial organoid system,in vivo disease models and transcriptomic datasets in human IBD. Results - As well as inducing transcriptional modules implicated in anti-microbial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional program in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. Conclusions- Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22 regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis
Ibraheim H, Samaan MA, Srinivasan A, et al., 2020, Effectiveness and safety of vedolizumab in inflammatory bowel disease patients aged 60 and over: an observational multicenter UK experience, Annals of Gastroenterology, Vol: 33, Pages: 1-10, ISSN: 1108-7471
Background The GEMINI trials established the efficacy of vedolizumab in moderate-to-severeinflammatory bowel disease (IBD) and demonstrated a favorable safety profile, suggesting it maybe advantageous in older patients at greater risk of treatment-related complications. However,there is a paucity of data exploring the outcomes of vedolizumab in this group. Our objective wasto determine the clinical effectiveness and safety of vedolizumab in older IBD patients within areal-world multicenter UK cohort.Methods A retrospective review of electronic records across 6 UK hospitals was undertaken toevaluate the clinical effectiveness and safety outcomes of vedolizumab in IBD patients aged ≥60at start of therapy. Rates of clinical response, remission and corticosteroid-free remission wereassessed at weeks 14 and 52, using validated clinical indices, and were compared to historicalcontrols from real-world vedolizumab-treated cohorts unstratified by age.Results Of 74 patients aged 60 years or above (median 66 years), 48 were included in oureffectiveness analysis (29 ulcerative colitis, 19 Crohn’s disease). Rates of clinical response, remissionand corticosteroid-free remission at week 14 were 64%, 48% and 30%, respectively. By week 52, therates of clinical response, remission, and corticosteroid-free remission were 52%, 38%, and 32%,respectively. Six (8%) patients experienced adverse effects. Effectiveness and safety outcomes werecomparable to those of age-unstratified vedolizumab-treated cohorts.Conclusion Our 1-year outcome data suggests that vedolizumab is safe and effective in older IBDpatients and broadly comparable to cohorts unselected by age.
Digby-Bell JL, Atreya R, Monteleone G, et al., 2020, Interrogating host immunity to predict treatment response in inflammatory bowel disease, Nature Reviews Gastroenterology and Hepatology, Vol: 17, Pages: 9-20, ISSN: 1759-5045
IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy.
Treveil A, Pavlidis P, Tsakmaki A, et al., 2020, Cytokine responsive transcriptional networks in inflammatory bowel disease, Publisher: OXFORD UNIV PRESS, Pages: S164-S164, ISSN: 1873-9946
Omer OS, Powell N, Lord GM, 2020, Characterizing Innate Lymphoid Cell Phenotype and Function in Human Inflammatory Bowel Disease, INNATE LYMPHOID CELLS, Editors: Amarnath, Publisher: HUMANA PRESS INC, Pages: 199-211, ISBN: 978-1-0716-0337-6
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- Citations: 2
Ibraheim H, Perucha E, Powell N, 2019, Pathology of immune-mediated tissue lesions following treatment with immune checkpoint inhibitors., Rheumatology, Vol: 58, Pages: vii17-vii28, ISSN: 1462-0324
Immune check point inhibitor (CPI) therapy has revolutionized treatment paradigms for several cancers, but at the cost of triggering a diverse spectrum of immune-mediated injury to non-cancer tissues. The complex biology of these toxicities remains incompletely understood, partly because tissue acquisition from affected areas can be challenging to retrieve, thus hindering development of targeted therapy. Here, we review the literature describing pathology of immune-mediated tissue lesions including gastrointestinal, skin, rheumatic, pulmonary, cardiac, renal and hepatic lesions and highlight key immunological insights.
Abu-Sbeih H, Faleck D, Ricciuti B, et al., 2019, Immune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease, Journal for ImmunoTherapy of Cancer, Vol: 7, Pages: 1-12, ISSN: 2051-1426
PURPOSEThe risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors.PATIENTS AND METHODSWe performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events.RESULTSOf the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively).CONCLUSIONPreexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.
Mora-Ortiz M, Ibraheim H, Kottoor SH, et al., 2019, Introducing ExHiBITT – Exploring Host microbiome inTeractions in Twins-, a colon multiomic cohort study
<jats:title>Abstract</jats:title><jats:p>The colon is populated by approximately 10<jats:sup>12</jats:sup> microorganisms, but the relationships between this microbiome and the host health status are still not completely understood. Participants from the TwinsUK cohort were recruited to study the interactions between the microbiome and host adaptive immunity. In total, 205 monozygotic twins were recruited from the wider TwinsUK cohort. They completed health questionnaires, and provided saliva, blood, colon biopsies from three different locations, caecal fluid, and two faecal-samples.</jats:p><jats:p>Here, our objective is to present the cohort characteristics of <jats:bold>ExHiBITT</jats:bold> including i) biomedical phenotypes, ii) environmental factors and ii) colonoscopic findings. A significant proportion of this apparently normal cohort had colonic polyps (28%), which are of interest as potential precursors of colorectal cancer, and as expected, the number of polyps found was significantly correlated with BMI and age. Hitherto undiagnosed diverticulosis was also not infrequently found during colonoscopy (26%) and was associated in changes in Hybrid Th1-17 cells in the colon. Twin proband cooccurrence rate for diverticulosis (82%), was much higher than for polyps (42%). Familial factors affecting morphology or tolerance may contribute to the ease of endoscopy, as both the time to reach the caecum, and pain perceived were highly concordant (proband concordance: 85% and 56% respectively). We found the expected positive relationship between BMI and colonoscopic anomalies such as diverticular disease and polyps in the whole population, but within twin pairs this association was reversed. This suggests that familial factors confound these associations. Host and microbial Next Generation Sequencing and metabolomics of the samples collected are planned in this cohort.</jats:p>
Abu-Sbeih H, Faleck D, Ricciuti B, et al., 2019, Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease, Annual Scientific Meeting of the American-College-of-Gastroenterology (ACG), Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S451-S451, ISSN: 0002-9270
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- Citations: 1
Moulton CD, Pavlidis P, Norton C, et al., 2019, Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation?, Clinical and Experimental Immunology, Vol: 197, Pages: 308-318, ISSN: 0009-9104
Depressive symptoms are reported by more than 20% of people with inflammatory bowel disease (IBD), while sleep difficulties and fatigue are even more common. Co-morbid depressive symptoms predict a poor IBD course, including increased risk of relapse and surgery, which is inconsistently improved by psychological treatments. Rather than being distinct systems, there is compelling evidence for bidirectional communication between gut and brain, driven by neural, metabolic, endocrine and inflammatory mediators. An emerging concept is that depressive symptoms may be mechanistically linked to excess inflammation and dysregulation of the gut-brain axis. Given the close link between the intestinal microbiota and host immune responses, patients prone to shifts in their intestinal microbiome, including smokers, those with poor diet and early life stress, may be exposed to exaggerated immune responses. Excess inflammation is associated with brain changes (depressive symptoms, fatigue, sleep difficulties) and worsening gastrointestinal symptoms, which are exacerbated by psychological distress. Equally, treatments both for depressive symptoms and IBD provide opportunities to break this cycle by reducing the causes and effects of inflammation. As well as addressing potential risk factors such as smoking and diet, treatments to alter the microbiome may reduce depressive symptoms. Observational evidence suggests that anti-inflammatory treatments for IBD may improve co-morbid depressive symptoms correlating with reduction in inflammation. With a growing range of treatments targeting inflammation centrally, peripherally and in the gut, IBD provides a unique model to understand the interplay between brain and gut in the pathogenesis of depressive symptoms, both in IBD and in the whole population.
Moulton CD, Hopkins CWP, Mohamedali Z, et al., 2019, Out of sight, out of mind: the limitations of the hospital anxiety and depression scale in inflammatory bowel disease, Inflammatory Bowel Diseases, Vol: 25, Pages: e100-e100, ISSN: 1078-0998
Samaan MA, Powell N, Irving PM, 2019, Letter: immune checkpoint inhibitor-induced colitis-shouldn't we be checking more often?, Alimentary Pharmacology and Therapeutics, Vol: 50, Pages: 472-473, ISSN: 0269-2813
Pantazi E, Powell N, 2019, Group 3 ILCs: peacekeepers or troublemakers? What's your gut telling you?!, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224
A complex network of interactions exists between the microbiome, the epithelium, and immune cells that reside along the walls of the gastrointestinal tract. The intestinal immune system has been assigned with the difficult task of discriminating between commensal, harmless bacteria, and invading pathogens that translocate across the epithelial monolayer. Importantly, it is trained to maintain tolerance against commensals, and initiate protective immune responses against pathogens to secure intestinal homeostasis. Breakdown of this fine balance between the host and its intestinal microbiota can lead to intestinal inflammation and subsequently to development of inflammatory bowel disease (IBD). A decade since their discovery, innate lymphoid cells (ILCs) are now recognized as important regulators of intestinal homeostasis. ILC3s have emerged as a critical subset in the gut. They are the most phenotypically diverse ILC population and interact directly with numerous different cell types (haematopoietic and non-haematopoeitic), as well as interface with the bacterial flora. In addition to their contribution to intestinal pathogen immunity, they also mitigate against tissue damage occurring following acute injury, by facilitating tissue repair and regeneration, a key function in the maintenance of intestinal homeostasis. However, in chronic inflammation the tables are turned and ILC3s may acquire a pro-inflammatory phenotype in the gut. Chronic ILC activation can lead to persistent inflammation contributing to IBD and/or colorectal cancer. In this review, we discuss current knowledge of group 3 ILCs and their contributions to intestinal homeostasis and disease leading to novel therapeutic targets and clinical approaches that may inform novel treatment strategies for immune-mediated disorders, including IBD.
Ibraheim H, Green M, Papa S, et al., 2019, Topical beclometasone dipropionate in the management of immune checkpoint inhibitor-induced microscopic colitis, BMJ Case Reports, Vol: 12, Pages: 1-4, ISSN: 1757-790X
Immune checkpoint inhibitors (ICPis) have revolutionised survival outcomes for cancer patients by bolstering anti-tumour immunity. However, immune activation also occurs in non-cancer tissue, and a significant proportion of patients develop immune-mediated colitis, which can be fatal if not promptly recognised and managed. Diagnosis is often made by inflammation observed during lower gastrointestinal endoscopy. Little is known about microscopic inflammation (histological findings of inflammation in the absence of overt mucosal injury). Management strategies beyond the use of systemic corticosteroids, which incur a high burden of deleterious side effects, have not been extensively explored. We describe the cases of two cancer patients with ICPi-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects.
Moulton CD, Norton C, Powell N, et al., 2019, Depression in inflammatory bowel disease: risk factor, prodrome or extraintestinal manifestation?, Gut, Vol: 69, Pages: 609-610, ISSN: 0017-5749
Alexander JL, Kohoutova D, Powell N, 2019, Science in focus: the microbiome and cancer therapy, Clinical Oncology, Vol: 31, Pages: 1-4, ISSN: 0936-6555
Garrido-Mesa N, Schroeder J-H, Stolarczyk E, et al., 2019, T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function, Mucosal Immunology, Vol: 12, Pages: 51-63, ISSN: 1933-0219
Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system causes microbiota-dependent colitis to occur due to aberrant ILC3 responses. Thus, T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here, we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL-7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic vs. protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.
Povoleri GAM, Nova-Lamperti E, Scotta C, et al., 2018, Human retinoic acid-regulated CD161(+) regulatory T cells support wound repair in intestinal mucosa, Nature Immunology, Vol: 19, Pages: 1403-1414, ISSN: 1529-2908
Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn’s disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn’s disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.
Arbore G, West EE, Rahman J, et al., 2018, Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism, Nature Communications, Vol: 9, ISSN: 2041-1723
The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.
Arbore G, Le Friec G, West EE, et al., 2018, Complement receptor CD46 is a key co-stimulator for optimal human CD8+T cell effector function, 27th International Complement Workshop (ICW), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 172-172, ISSN: 0161-5890
Samaan MA, Pavlidis P, Digby-Bell J, et al., 2018, Golimumab: early experience and medium-term outcomes from two UK tertiary IBD centres, Frontline Gastroenterology, Vol: 9, Pages: 221-231, ISSN: 2041-4137
Objective To gain an understanding of the effectiveness of golimumab in a ‘real-world’ setting.Design Retrospective cohort study using prospectively maintained clinical records.Setting Two UK tertiary IBD centres.Patients Patients with ulcerative colitis (UC) were given golimumab at Guy’s & St Thomas and King’s College Hospitals between September 2014 and December 2016.Intervention Golimumab, a subcutaneously administered antitumour necrosis factor agent.Main outcome measures Clinical disease activity was assessed at baseline and at the first clinical review following induction therapy using the Simple Clinical Colitis Activity Index (SCCAI). Response was defined as an SCCAI reduction of 3 points or more. Remission was defined as an SCCAI of less than 3.Results Fifty-seven patients with UC completed golimumab induction therapy. Paired preinduction and postinduction SCCAI values were available for 31 patients and fell significantly from 7 (2–19) to 3 (0–11) (p<0.001). To these 31, an additional 13 patients who did not have paired SCCAI data but stopped treatment due to documented ‘non-response’ in the opinion of their supervising clinician, were added. Among this combined cohort, 23/44 (52%) had a clinical response, 15/44 (34%) achieved remission and 13/44 (30%) achieved corticosteroid-free remission.Faecal calprotectin and CRP fell (FC: pre-induction: 1096 (15-4800) μg/g, post-induction: 114 (11-4800) μg/g, p = 0.011; n = 20; CRP: pre-induction: 4 (1-59) mg/L, post-induction: 2 (1-34) mg/L, p = 0.01 for n = 43). Post-induction endoscopy was carried out in 23 patients and a mucosal healing (Mayo 0 or 1) rate of 35% was observed.Conclusions Our experience mirrors previously reported real-world cohorts and demonstrates similar outcomes to those observed in randomised controlled trials. These data demonstrate a meaningful reduction in clinical, biochemical and endoscopic disease activity as well as a steroid-s
Samaan MA, Pavlidis P, Papa S, et al., 2018, Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management, Nature Reviews Gastroenterology and Hepatology, Vol: 15, Pages: 222-234, ISSN: 1759-5045
Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management.
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