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1. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial

Author

Noor, Nurulamin, Lee, James, Bond, Simon, Dowling, Francis, Brezina, Biljana, Patel, Kamal, Ahmad, Tariq, Banim, Paul, Berrill, James, Cooney, Rachel, De La Revilla Negro, Juan, de Silva, Shanika, Din, Shahida, Durai, Dharmaraj, Gordon, John, Irving, Peter, Johnson, Matthew, Kent, Alexandra, Kok, Klaartje Bel, Moran, Gordon, Mowat, Craig, Patel, Pritash, Probert, Chris, Raine, Tim, Saich, Rebecca, Seward, Abigail, Sharpstone, Dan, Smith, Melissa, Subramanian, Sreedhar, Upponi, Sara, Wiles, Alan, Williams, Horace, van Den Brink, Gijs, Vermeire, Severine, Jairath, Vipul, D'Haens, Geert, McKinney, Eoin, Lyons, Paul, Lindsay, James, Kennedy, Nicholas, Smith, Kenneth, Parkes, Miles, Allcock, Clare, Bhatti, Suhaylah, Blackwell, Jonathan, Boulton-Jones, Robert, Brookes, Matthew, Butcher, Rhys, Butterworth, Jeffrey, Champion, Karlena, Chaudhary, Rakesh, Cole, Andy, Derikx, Lauranne, Dhar, Anjan, Flowerdew, Mary, Goel, Rishi, Hart, Ailsa, Hughes, Rory, Javaid, Babur, Knight, Paul, Lee, Jacinta, Lees, Charlie, Levell, Emma, Li, Andy, Murray, Charles, O'Brien, Leisha, Parkes, Gareth, Pollok, Richard, Powles, Sam, Ramdas, Arvind, Smith, Philip, Speight, Richard Ally, Travis, Simon, Weaver, Sean, Wesley, Emma, Noor, Nurulamin M, Lee, James C, Patel, Kamal V, Banim, Paul J, Berrill, James W, Gordon, John N, Irving, Peter M, Kent, Alexandra J, Kok, Klaartje B, Moran, Gordon W, Probert, Chris S, Smith, Melissa A, Upponi, Sara S, Williams, Horace R T, van den Brink, Gijs R, Vermeire, Séverine, D'Haens, Geert R, McKinney, Eoin F, Lyons, Paul A, Lindsay, James O, Kennedy, Nicholas A, and Smith, Kenneth G C

Published
2024
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7. Gas Chromatography–Sensor System Aids Diagnosis of Inflammatory Bowel Disease, and Separates Crohn's from Ulcerative Colitis, in Children.

Author

Slater, Rachael, Tharmaratnam, Kukatharmini, Belnour, Salma, Auth, Marcus Karl-Heinz, Muhammed, Rafeeq, Spray, Christine, Wang, Duolao, de Lacy Costello, Ben, García-Fiñana, Marta, Allen, Stephen, and Probert, Chris

Subjects
CROHN'S disease, ULCERATIVE colitis, INFLAMMATORY bowel diseases, VOLATILE organic compounds, CALPROTECTIN, PEDIATRICS
Abstract

The diagnosis of inflammatory bowel disease (IBD) in children and the need to distinguish between subtypes (Crohn's disease (CD) and ulcerative colitis (UC)) requires lengthy investigative and invasive procedures. Non-invasive, rapid, and cost-effective tests to support these diagnoses are needed. Faecal volatile organic compounds (VOCs) are distinctive in IBD. VOC profiles can be rapidly determined using a gas chromatography–sensor device (OdoReader©). In an inception-cohort of children presenting with suspected IBD, we directly compared the diagnostic fidelity of faecal calprotectin (FCP, a non-specific protein marker of intestinal inflammation) with OdoReader© VOC profiles of children subsequently diagnosed with IBD with matched controls diagnosed with other gastrointestinal conditions. The OdoReader© was 82% (95% confidence interval 75–89%) sensitive and 71% (61–80%) specific but did not outperform FCP (sensitivity 93% (77–99%) and specificity 86% (67–96%); 250 µg/g FCP cut off) in the diagnosis of IBD from other gastrointestinal conditions when validated in a separate sample from the same cohort. However, unlike FCP and better than other similar technologies, the OdoReader© could distinguish paediatric CD from UC (up to 88% (82–93%) sensitivity and 80% (71–89%) specificity in the validation set) and justifies further validation in larger studies. A non-invasive test based on VOCs could help streamline and limit invasive investigations in children. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Faecal volatile organic compounds differ according to inflammatory bowel disease sub‐type, severity, and response to treatment in paediatric patients

Author

Belnour, Salma, Slater, Rachael, Tharmaratnam, Kukatharmini, Karl‐Heinz Auth, Marcus, Muhammed, Rafeeq, Spray, Christine, Wang, Duolao, Zeeshan Ijaz, Umer, Probert, Chris, and Allen, Stephen

Abstract

Faecal volatile organic compounds (VOCs) differ with disease sub‐type and activity in adults with established inflammatory bowel disease (IBD) taking therapy. To describe patterns of faecal VOCs in children newly presented with IBD according to disease sub‐type, severity, and response to treatment. Children presenting with suspected IBD were recruited from three UK hospitals. Children in whom IBD was diagnosed were matched with a non‐IBD child for age, sex, and recruitment site. Faecal VOCs were characterised by gas chromatography–mass spectrometry at presentation and 3 months later in children with IBD. In 132 case/control pairs, median (inter‐quartile range) age in IBD was 13.3 years (10.2–14.7) and 38.6% were female. Compared with controls, the mean abundance of 27/62 (43.6%) faecal VOCs was statistically significantly decreased in Crohn's disease (CD), ulcerative colitis (UC) or both especially amongst ketones/diketones, fatty acids, and alcohols (p< 0.05). Short‐chain, medium chain, and branched chain fatty acids were markedly reduced in severe colitis (p< 0.05). Despite clinical improvement in many children with IBD, the number and abundance of almost all VOCs did not increase following treatment, suggesting persistent dysbiosis. Oct‐1‐en‐3‐ol was increased in CD (p= 0.001) and UC (p= 0.012) compared with controls and decreased following treatment in UC (p= 0.01). In CD, propan‐1‐ol was significantly greater than controls (p< 0.001) and extensive colitis (p= 0.001) and fell with treatment (p= 0.05). Phenol was significantly greater in CD (p< 0.001) and fell with treatment in both CD (p= 0.02) and UC (p= 0.01). Characterisation of faecal VOCs in an inception cohort of children with IBD reveals patterns associated with diagnosis, disease activity, and extent. Further work should investigate the relationship between VOCs and the microbiome in IBD and their role in diagnosis and disease monitoring.

Published
2024
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13. Towards better models and mechanistic biomarkers for drug-induced gastrointestinal injury

Author

Carr, Daniel F., Ayehunie, Seyoum, Davies, Andrea, Duckworth, Carrie A., French, Stephanie, Hall, Neil, Hussain, Syed, Mellor, Howard R., Norris, Alan, Park, B. Kevin, Penrose, Alexander, Pritchard, D. Mark, Probert, Chris S., Ramaiah, Shashi, Sadler, Claire, Schmitt, Michael, Shaw, Alison, Sidaway, James E., Vries, Robert G., Wagoner, Matthew, and Pirmohamed, Munir

Published
2017
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17. GC-MS Techniques Investigating Potential Biomarkers of Dying in the Last Weeks with Lung Cancer

Author

Chapman, Elinor, Baker, James, Aggarwal, Prashant, Hughes, David, Nwosu, Amara, Boyd, Mark, Mayland, Catriona, Mason, Stephen, Ellershaw, John E, Probert, Chris, Coyle, Seamus, Chapman, Elinor, Baker, James, Aggarwal, Prashant, Hughes, David, Nwosu, Amara, Boyd, Mark, Mayland, Catriona, Mason, Stephen, Ellershaw, John E, Probert, Chris, and Coyle, Seamus

Abstract

Predicting when a patient with advanced cancer is dying is a challenge and currently no prognostic test is available. We hypothesised that a dying process from cancer is associated with metabolic changes and specifically with changes in volatile organic compounds (VOCs). We analysed urine from patients with lung cancer in the last weeks of life by headspace gas chromatography mass spectrometry. Urine was acidified or alkalinised before analysis. VOC changes in the last weeks of life were identified using univariate, multivariate and linear regression analysis; 12 VOCs increased (11 from the acid dataset, 2 from the alkali dataset) and 25 VOCs decreased (23 from the acid dataset and 3 from the alkali dataset). A Cox Lasso prediction model using 8 VOCs predicted dying with an AUC of 0.77, 0.78 and 0.85 at 30, 20 and 10 days and stratified patients into a low (median 10 days), medium (median 50 days) or high risk of survival. Our data supports the hypothesis there are specific metabolic changes associated with the dying. The VOCs identified are potential biomarkers of dying in lung cancer and could be used as a tool to provide additional prognostic information to inform expert clinician judgement and subsequent decision making.

Published
2023

18. Faecal and urine metabolites, but not gut microbiota, may predict response to low FODMAP diet in irritable bowel syndrome

Author

Wilson, Bridgette, Kanno, Tokuwa, Slater, Rachael, Rossi, Megan, Irving, Peter M., Lomer, Miranda, Probert, Chris, Mason, James, and Whelan, Kevin

Abstract

BackgroundThe low FODMAP diet (LFD) leads to clinical response in 50%–80% of patients with irritable bowel syndrome (IBS). It is unclear why only some patients respond.AimsTo determine if differences in baseline faecal microbiota or faecal and urine metabolite profiles may separate clinical responders to the diet from non-responders allowing predictive algorithms to be proposed.MethodsWe recruited adults fulfilling Rome III criteria for IBS to a blinded randomised controlled trial. Patients were randomised to sham diet with a placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.8 g/d B-galactooligosaccharide (LFD/B-GOS), for 4 weeks. Clinical response was defined as adequate symptom relief at 4 weeks after the intervention (global symptom question). Differences between responders and non-responders in faecal microbiota (FISH, 16S rRNA sequencing) and faecal (gas–liquid chromatography, gas-chromatography mass-spectrometry) and urine (1H NMR) metabolites were analysed.ResultsAt 4 weeks, clinical response differed across the 3groups with adequate symptom relief of 30% (7/23) in controls, 50% (11/22) in the LFD group and 67% (16/24) in the LFD/B-GOS group (p = 0.048). In the control and the LFD/B-GOS groups, microbiota and metabolites did not separate responders from non-responders. In the LFD group, higher baseline faecal propionate (sensitivity 91%, specificity 89%) and cyclohexanecarboxylic acid esters (sensitivity 80%, specificity 78%), and urine metabolite profile (Q2 0.296 vs. randomised −0.175) predicted clinical response.ConclusionsBaseline faecal and urine metabolites may predict response to the LFD.

Published
2023
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22. Predicting Dying: Metabolomic Changes, a Model and the Dying Process in Patients with Lung Cancer

Author

Coyle, Seamus, primary, Chapman, Elinor, additional, Hughes, David Michael, additional, Baker, James, additional, Slater, Rachael, additional, Davison, Andrew S., additional, Norman, Brendan, additional, Roberts, Ivayla, additional, Nwosu, Amara C., additional, Boyd, Mark T., additional, Mayland, Catriona R., additional, Kell, Douglas, additional, Mason, Stephen, additional, Ellershaw, John, additional, and Probert, Chris, additional

Published
2023
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24. Mechanisms affecting the gut of preterm infants in enteral feeding trials: a nested cohort within a randomised controlled trial of lactoferrin

Author

Young, Greg, primary, Berrington, Janet E, additional, Cummings, Stephen, additional, Dorling, Jon, additional, Ewer, Andrew K, additional, Frau, Alessandra, additional, Lett, Lauren, additional, Probert, Chris, additional, Juszczak, Ed, additional, Kirby, John, additional, Beck, Lauren C, additional, Renwick, Victoria L, additional, Lamb, Christopher, additional, Lanyon, Clare V, additional, McGuire, William, additional, Stewart, Christopher, additional, and Embleton, Nicholas, additional

Published
2022
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25. Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa

Author

Papoutsopoulou, Stamatia, primary, Tang, Joseph, additional, Elramli, Ahmed H., additional, Williams, Jonathan M., additional, Gupta, Nitika, additional, Ikuomola, Felix I., additional, Sheibani-Tezerji, Raheleh, additional, Alam, Mohammad T., additional, Hernández-Fernaud, Juan R., additional, Caamaño, Jorge H., additional, Probert, Chris S., additional, Muller, Werner, additional, Duckworth, Carrie A., additional, and Pritchard, D. Mark, additional

Published
2022
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30. Mechanisms affecting the gut of preterm infants in enteral feeding trials: a nested cohort within a randomised controlled trial of lactoferrin.

Author

Young, Greg, Berrington, Janet E., Cummings, Stephen, Dorling, Jon, Ewer, Andrew K., Frau, Alessandra, Lett, Lauren, Probert, Chris, Juszczak, Ed, Kirby, John, Beck, Lauren C., Renwick, Victoria L., Lamb, Christopher, Lanyon, Clare V., McGuire, William, Stewart, Christopher, and Embleton, Nicholas

Subjects
PREMATURE infants, RANDOMIZED controlled trials, LACTOFERRIN, VOLATILE organic compounds, GUT microbiome
Abstract

Objective: To determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants.Design: Cohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation.Setting: Thirteen UK hospitals participating in a RCT of lactoferrin.Patients: 479 infants born <32 weeks' gestation between June 2016 and September 2017.Results: 10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition.Conclusions: This multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Recommendations for the optimal use of mesalazine in the management of patients with mild to moderate ulcerative colitis

Author

Akbar, Ayesha, primary, Arnott, Ian, additional, Kennedy, Nicholas A, additional, Nolan, Jonathan, additional, Peake, Simon, additional, Whiteoak, Simon R, additional, Probert, Chris, additional, Fraser, Aileen, additional, Cheshire, Alex, additional, Lewis, Allyson, additional, Sugrue, Kathleen, additional, Laird, Susan, additional, and Scott, Glyn, additional

Published
2022
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36. Recommendations for the optimal use of mesalazine in the management of patients with mild to moderate ulcerative colitis

Author

Akbar, Ayesha, primary, Arnott, Ian, additional, Kennedy, Nicholas A, additional, Nolan, Jonathan, additional, Peake, Simon, additional, Whiteoak, Simon R, additional, Probert, Chris, additional, Fraser, Aileen, additional, Cheshire, Alex, additional, Lewis, Allyson, additional, Sugrue, Kathleen, additional, Laird, Susan, additional, and Scott, Glyn, additional

Published
2021
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37. A phase II study of laquinimod in Crohnʼs disease

Author

DʼHaens, Geert, Sandborn, William J, Colombel, Jean Frederic, Rutgeerts, Paul, Brown, Kurt, Barkay, Hadas, Sakov, Anat, Haviv, Asi, Feagan, Brian G, Baert, Filip, Dupas, Jean-Louis, Bouhnik, Yoram, Bonaz, Bruno, Hebuterne, Xavier, Allez, Matthieu, Israeli, Eran, Fraser, Gerald, Segol, Ori, Fishman, Sigal, Lahat, Adi, Melzer, Ehud, Pallone, Francesco, Campieri, Massimo, Gasbarrini, Antonio, Kohn, Anna, Vecchi, Maurizo, Ponsioen, Cyriel, Van der Woude, Janneke, Rydzewska, Grazyna, Mach, Tomasz, Paradowski, Leszek, Wright, John Philip, Watermeyer, Gillian Ann, Pettengell, Keith Edward, Mahomed, Adam Dawood, Prins, Maarten Jeroen, Aboo, Nazimuddin, Diaz, Julian Panes, Taxonera, Carlos, Gisbert, Javier, Hinojosa, Joaquin, Garcia, Fernand Gomollon, Sanchez, Valle Garcia, Parkes, Miles, Probert, Chris, Leiper, Keith, Nwokolo, Chuka, Mayberry, John, and Bloom, Stuart

Published
2015
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46. The Stool Volatile Metabolome of Pre-Term Babies

Author

Frau, Alessandra, primary, Lett, Lauren, additional, Slater, Rachael, additional, Young, Gregory R., additional, Stewart, Christopher J., additional, Berrington, Janet, additional, Hughes, David M., additional, Embleton, Nicholas, additional, and Probert, Chris, additional

Published
2021
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49. Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource

Author

Stournaras, Evangelos, Qian, Wendi, Pappas, Apostolos, Hong, You Yi, Shawky, Rasha, UK IBD BioResource Investigators, Raine, Tim, Parkes, Miles, UK IBD Bioresource Investigators, Ahmad, Tariq, Kennedy, Nick, Irving, Peter, Prescott, Natalie, Lees, Charlie, Mansfield, John, Lamb, Chris, Satsangi, Jack, Simmons, Alison, Hart, Alisa, Subramanian, Sreedhar, Probert, Chris, Shenderey, Richard, Gunasekera, Anton, Kok, Klaartje Bel, Javaid, Babur, Sinha, Leena, Singh, Salil, Preston, Cathryn, Jarvis, Mark, Penn, Ruth, Dhar, Anjan, Shenoy, Achuth, Phillis, Kath, Oglesby, Arabis, Tilbury, Jude, Scott, Glyn, Collum, Joseph, Carter, Martyn, Barbour, Jamie, Gordon, John, Ramage, John, Sivagi, Ganesh, Roberts, Phil, Bose, Monica, Sebastian, Shaji, Wilkins, Joy, Banim, Paul, Kent, Alexana, Verma, Ajay, Warren, Dawn, Wiles, Alan, Johnson, Matthew, Koss, Konrad, Oza, Chirag, Elamin, Khalid, Woods, Annette, Baburajan, Bijay, MacDonald, Chris, Theron, Byron, Tremelling, Mark, Shmueli, Udi, Bevan, Roisin, Limdi, Jimmy, Nair, Prakash, Vani, Deven, Lewis, Stephen, Baker-Moffat, Michelle, Moran, Gordon, McLaughlin, Simon, Silva, Aminda De, Beckly, John, Cole, Anew, Murray, Charles, Lobo, Alan, Smith, Melissa, Mathew, Sanju, Saunders, John, Steed, Helen, Brookes, Matthew, Loehry, Juliette, Rahman, Monira, Butterworth, Jeff, Muddu, Ajay, Clark, Katie, Selinger, Christian, Ramadas, Arvind, McLaughlin, John, Pollok, Richard, Rees, Colin, Panter, Simon, Hobday, David, Foley, Stephen, Patel, Vinod, Wesley, Emma, Gavin, Daniel, Edwards, Cathryn, Bloom, Stuart, Nwokolo, Chuka, DeCaestecker, John, Hanna, Mina, Davies, Albert, Hancock, Laura, Cummings, Fraser, Ramakrishnan, Subramaniam, Tindall, Theresa, Landy, Jonathan, Appleby, Richard, Sharpstone, Dan, Li, Andy, Keld, Richard, Mear, Lin, Philips, Anne, Willia, Horace, Ben Warner, Laura Hancock, Durai, Dharmaraj, Brinkworth, Elaine, Mahmood, Zahid, Cooney, Rachel, Stournaras, Evangelos [0000-0002-9885-0673], Parkes, Miles [0000-0002-6467-0631], and Apollo - University of Cambridge Repository

Subjects
azathioprine, tolerance, crohn's disease, 6-mercaptopurine, Inflammatory bowel disease, ulcerative colitis
Abstract

Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p

Published
2020
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50. 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

Author

Din, Shahida, Kent, Alexandra, Pollok, Richard C., Meade, Susanna, Kennedy, Nicholas A, Arnott, Ian, Beattie, Mark R., Chua, Felix, Cooney, Rachel, Dart, Robin, Galloway, James, Gaya, Daniel R, Ghosh, Subrata, Griffiths, Mark, Hancock, Laura, Hansen, Richard, Hart, Ailsa, Lamb, Christopher A., Lees, Charlie W., Limdi, Jimmy K, Lindsay, James O., Murray, Charlie, Patel, Kamal, Powell, Nick, Probert, Chris, Raine, Tim, Selinger, Christian, Sebastian, Shaji, Smith, Philip J., Tozer, Philip J., Ustianowski, Andrew, Younge, Lisa, Samaan, Mark A, and Irving, Peter

Abstract

ObjectiveManagement of acute severe ulcerative colitis (ASUC) during the novel coronavirus 2019 (COVID-19) pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point.DesignWe convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting 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 a RAND Panel.

Published
2020

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