Publications by authors named "Peter M Irving"

127 Publications

Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients.

J Crohns Colitis 2021 Sep 2. Epub 2021 Sep 2.

Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

Background And Aims: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-TNF level influences serological responses, remains unknown.

Methods: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11422 (53.3% (6084) male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between 29 th January and 30 th September 2020. Data were linked to nationally-held SARS-CoV-2 PCR results to 4 th May 2021.

Results: Rates of PCR confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% (178/5893), adalimumab: 3.0% (152/5074), vedolizumab: 6.7% (25/375), p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index (COI) (1.94 - 9.96) vs 5.02 (2.18 - 18.70), p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI (4.39 - 68.10, p< 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels (<0.8 mg/L) were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were anti-TNF treated. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% (12/152) patients after a median time of 183.5 days (129.8 - 235.3), without differences between drugs.

Conclusion: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels supports a causal relationship, although confounding factors, such as combination therapy with immunomodulator, may have influenced the results.
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http://dx.doi.org/10.1093/ecco-jcc/jjab153DOI Listing
September 2021

Long-term personalized low FODMAP diet improves symptoms and maintains luminal Bifidobacteria abundance in irritable bowel syndrome.

Neurogastroenterol Motil 2021 Aug 24:e14241. Epub 2021 Aug 24.

Department of Nutritional Sciences, King's College London, London, UK.

Background: Short-term trials demonstrate the low FODMAP diet improves symptoms of irritable bowel syndrome (IBS) but impacts nutrient intake and the gastrointestinal microbiota. The aim of this study was to investigate clinical symptoms, nutrient intake, and microbiota of patients with IBS 12 months after starting a low FODMAP diet.

Methods: Participants enrolled in a previous short-term clinical trial and who had been through structured FODMAP restriction, reintroduction, and personalization were invited to participate in a follow-up study at one time point at 12 months. Gastrointestinal symptoms, stool output, dietary intake, and quality of life were recorded. Stool samples were collected and analyzed for microbiota (qPCR) and short-chain fatty acids (SCFA). Data were compared with baseline (prior to any intervention in the original clinical trial) using non-parametric statistics.

Key Results: Eighteen participants were included in the study. Adequate relief of symptoms occurred in 5/18 (28%) at baseline and increased to 12/18 (67%) following long-term personalized low FODMAP diet (p = 0.039). There was a reduction in IBS-SSS total score between baseline (median 227, IQR 99) and long term (154, 89; p < 0.001). Bifidobacteria abundance was not different between baseline (median 9.29 log10 rRNA genes/g, IQR 1.45) and long term (9.20 log10 rRNA genes/g, 1.41; p = 0.766, q = 0.906); however, there were lower concentrations of total SCFA, acetate, propionate, and butyrate.

Conclusions: In this long-term analysis, two thirds of patients reported adequate relief of symptoms after 12 months of personalized low FODMAP diet that did not result in differences from baseline in Bifidobacteria. FODMAP reintroduction and personalization may normalize some of the effects of short-term FODMAP restriction.
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http://dx.doi.org/10.1111/nmo.14241DOI Listing
August 2021

Editorial: is tofacitinib another rescue option for acute severe ulcerative colitis?

Aliment Pharmacol Ther 2021 08;54(3):341-342

IBD Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/apt.16482DOI Listing
August 2021

An observational study of switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with first or second switch.

Aliment Pharmacol Ther 2021 09 5;54(5):678-688. Epub 2021 Jul 5.

Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: Biologics account for a significant cost in inflammatory bowel disease (IBD) management; however, switching from infliximab originator to its biosimilars has enabled cost saving without compromising disease control. The effects on IBD activity and infliximab trough levels of a second switch to another biosimilar are, however, uncertain.

Aims: To assess the effects on disease activity and infliximab trough levels associated with switching from infliximab biosimilar CT-P13 to another biosimilar SB2 and compare outcomes in those switching for the first and second time.

Methods: IBD patients on CT-P13, including some previously switched from originator, were prospectively followed during a switch to SB2. C-reactive protein (CRP), trough infliximab level and clinical disease activity indices were collected at baseline, Infusion 3 or 4 ('early' after switch), and 1 year.

Results: One hundred eighty-six patients (n = 99 second switch) on stable infliximab dosing underwent switching. Compared with baseline, there was no significant change in CRP, clinical disease activity scores or median trough infliximab level at the early time point among first-switch (baseline vs early: 5.7 vs 6.6 µg/mL, P = 0.05) and second-switch (4.3 vs 4.9 µg/mL, P = 0.07) patients nor at 1 year (median infliximab trough levels, baseline vs 1 year, in first-switch [5.7 vs 5.7 µg/mL, P = 0.37] and second-switch [4.3 vs 4.7 µg/mL, P = 0.06] patients). The proportion of patients in clinical remission did not significantly change at the early (92% vs 91% at baseline, P = 0.75) or 1 year (95% vs 91% at baseline, P = 0.16) time points. There was no significant difference in time to loss of response between patients switching for the first or second time (P = 0.69).

Conclusions: Switching from one infliximab biosimilar to another had no adverse impact on infliximab trough levels, and clinical and biochemical disease activity, regardless of whether switching for the first or second time.
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http://dx.doi.org/10.1111/apt.16497DOI Listing
September 2021

Nutrient, fibre and FODMAP intakes and food-related quality of life in patients with inflammatory bowel disease and their relationship with gastrointestinal symptoms of differing aetiologies.

J Crohns Colitis 2021 Jul 3. Epub 2021 Jul 3.

King's College London, Faculty of Life Sciences and Medicine, Department of Nutritional Sciences, London, United Kingdom.

Background And Aims: Certain foods are reported as gut symptom triggers in IBD, and fructans are shown to worsen non-inflammatory symptoms in inactive IBD, which may result in self-imposed dietary restrictions. The aim of this case-control study was therefore to investigate nutrient and FODMAP intakes, and the relationship between gut symptoms and dietary intake, in IBD.

Methods: Nutrient, fibre and FODMAP intakes were estimated using 7-day food records in patients with active IBD (Active IBD), inactive IBD with non-inflammatory gut symptoms (Inactive IBD-GI), inactive IBD without gut symptoms (Inactive IBD) and healthy controls. Nutrient, fibre and FODMAP intakes, numbers of participants achieving national nutrient recommendations, and food-related quality of life (FR-QoL) were compared across and between study groups, where appropriate.

Results: Food diaries were obtained from 232 patients with IBD (65 Active IBD, 86 Inactive IBD-GI, 81 Inactive IBD) and 84 healthy controls. Patients with Active IBD consumed significantly lower intakes of numerous micronutrients, including iron, folate, vitamin C, compared with healthy controls. All IBD groups consumed less total fibre (between 4.5 to 5.8 g/d) than healthy controls (P<0.001), while total FODMAP and fructan intakes were significantly lower in Active IBD compared with healthy controls. Strikingly, FR-QoL was significantly lower in all IBD groups compared with healthy controls (all P<0.001).

Conclusions: This study revealed significantly lower intakes of fibre, FODMAPs and micronutrients, in addition to poorer FR-QoL, in Active IBD and Inactive IBD-GI with gut symptoms compared with healthy controls. Future research should address dietary restrictions responsible for these differences.
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http://dx.doi.org/10.1093/ecco-jcc/jjab116DOI Listing
July 2021

Response to 'Clinical Efficacy of Tofacitinib in Moderate to Severe Ulcerative Colitis'.

J Crohns Colitis 2021 Jun 14. Epub 2021 Jun 14.

Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK.

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http://dx.doi.org/10.1093/ecco-jcc/jjab080DOI Listing
June 2021

A Crohn's disease-associated IL2RA enhancer variant determines the balance of T cell immunity by regulating responsiveness to IL-2 signaling.

J Crohns Colitis 2021 Jun 12. Epub 2021 Jun 12.

School of Immunology and Microbial Sciences, King's College London, Great Maze Pond, London SE1 9RT, UK.

Background And Aims: Differential responsiveness to interleukin (IL)-2 between effector CD4¬+ T cells (Teff) and regulatory T cells (Treg) is a fundamental mechanism of immunoregulation. The single nucleotide polymorphism rs61839660, located within IL2RA (CD25), has been associated with the development of Crohn's disease. We sought to identify the T cell immune phenotype of IBD patients who carry this SNP.

Methods: Teff and Treg were isolated from individuals homozygous (TT), heterozygous (CT) or wild type (CC) for the minor allele at rs61839660, and used for phenotyping (flow cytometry, Cytometry Time Of Flight) functional assays or T cell receptor (TCR) sequencing. Phosphorylation of signal transducer and activator of transcription 5 (STAT5) was assessed in response to IL-2, IL-7 and in the presence of basiliximab, a monoclonal antibody directed against CD25. Teff proinflammatory cytokine expression levels were assessed by reverse transcription quantitative polymerase chain reaction after IL-2 and/or TCR stimulation.

Results: Presence of the minor T allele enhances CD25 expression leading to increased STAT5 phosphorylation and proinflammatory cytokine transcript expression by Teff in response to IL-2 stimulation in vitro. Teff from TT individuals demonstrate a more activated gut homing phenotype. TCR sequencing analysis suggests that TT patients may have a reduced clonal capacity to mount an optimal regulatory T cell response.

Conclusions: rs61839660 regulates the responsiveness of T cells to IL-2 signaling by modulating CD25 expression. As low dose IL-2 is being trialed as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.
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http://dx.doi.org/10.1093/ecco-jcc/jjab103DOI Listing
June 2021

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

Thorax 2021 May 27. Epub 2021 May 27.

Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template.

Methods: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again.

Results: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease.

Conclusion: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.
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http://dx.doi.org/10.1136/thoraxjnl-2021-216904DOI Listing
May 2021

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.

Gut 2021 10 26;70(10):1884-1893. Epub 2021 Apr 26.

Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

Objective: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.

Design: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.

Results: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine.

Conclusion: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.

Trial Registration Number: ISRCTN45176516.
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http://dx.doi.org/10.1136/gutjnl-2021-324789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076631PMC
October 2021

Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.

Gut 2021 05 22;70(5):865-875. Epub 2021 Mar 22.

Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK.

Objective: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections.

Design: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020.

Results: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001).

Conclusions: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy.

Trial Registration Number: ISRCTN45176516.
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http://dx.doi.org/10.1136/gutjnl-2021-324388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992387PMC
May 2021

Effectiveness and Safety of Ustekinumab in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Dig Dis Sci 2021 Mar 16. Epub 2021 Mar 16.

IBD Centre, 1st Floor IBD Centre, Westminster Bridge Road, St Thomas Hospital, Guys and St Thomas NHS Foundation Trust, London, SE1 7EH, UK.

Introduction: Ustekinumab, an interleukin-12 and interleukin-23 antagonist, is licensed for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) after the phase III trial programs demonstrated efficacy over placebo. However, these findings may not be directly transferable to the real-world due to the stringent inclusion criteria of clinical trials.

Methods: We conducted a systematic review and meta-analysis of the safety and effectiveness of ustekinumab in inflammatory bowel disease (IBD). A systematic literature search was conducted via Medline and Embase from inception to April 21, 2020. Observational studies assessing ustekinumab's safety and effectiveness by reporting response, remission and/or adverse events (AE) in either CD or UC were included. Two reviewers independently assessed risk of bias and extracted study data. Random-effects meta-analysis was performed to pool rates of clinical response, remission, and safety data.

Results: Following deduplication, 2147 records were identified of which 41 studies (38 CD, 3 UC) comprising 4400 patients were included for quantitative analysis. Pooled clinical remission rates for CD were 34% (95% CI, 26%-42%) following induction and 31% (95% CI, 25%-38%) at one year. For UC, post-induction clinical remission rates were 39% (95% CI, 23%-56%). Serious AEs were reported in 5.6% of patients. Pregnancy outcomes were similar to the general population. One-third of patients with active baseline perianal disease responded or had fistula healing with ustekinumab.

Conclusions: In the most comprehensive systematic review and meta-analysis to date, and the first to include UC, ustekinumab was shown to be effective and safe in the real-world treatment of IBD.
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http://dx.doi.org/10.1007/s10620-021-06932-4DOI Listing
March 2021

Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

BioDrugs 2021 Mar 26;35(2):187-199. Epub 2021 Feb 26.

The Dermatology Centre, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK.

Background: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions.

Objectives: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources.

Methods: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS).

Results: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices.

Conclusions: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS.
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http://dx.doi.org/10.1007/s40259-020-00464-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952361PMC
March 2021

Risk of common infections in people with inflammatory bowel disease in primary care: a population-based cohort study.

BMJ Open Gastroenterol 2021 02;8(1)

New Road Surgery, Croxley Green, Hertfordshire, UK.

Objective: To evaluate the risk of common infections in individuals with inflammatory bowel disease (IBD) [ulcerative colitis and Crohn's disease] compared with matched controls in a contemporary UK primary care population.

Design: Matched cohort analysis (2014-2019) using the Royal College of General Practitioners Research and Surveillance Centre primary care database. Risk of common infections, viral infections and gastrointestinal infections (including a subset of culture-confirmed infections), and predictors of common infections, were evaluated using multivariable Cox proportional hazards models.

Results: 18 829 people with IBD were matched to 73 316 controls. People with IBD were more likely to present to primary care with a common infection over the study period (46% vs 37% of controls). Risks of common infections, viral infections and gastrointestinal infections (including stool culture-confirmed infections) were increased for people with ulcerative colitis and Crohn's disease compared with matched controls (HR range 1.12-1.83, all p<0.001). Treatment with oral glucocorticoid therapy, immunotherapies and biologic therapy, but not with aminosalicylates, was associated with increased infection risk in people with IBD. Despite mild lymphopenia and neutropenia being more common in people with IBD (18.4% and 1.9%, respectively) than in controls (6.5% and 1.5%, respectively), these factors were not associated with significantly increased infection risk in people with IBD.

Conclusion: People with IBD are more likely to present with a wide range of common infections. Health professionals and people with IBD should remain vigilant for infections, particularly when using systemic corticosteroids, immunotherapies or biologic agents.

Trial Registration Number: Clinicaltrials.gov (NCT03835780).
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http://dx.doi.org/10.1136/bmjgast-2020-000573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893652PMC
February 2021

The effects of COVID-19 on IBD prescribing and service provision in a UK tertiary centre.

GastroHep 2020 Nov 5;2(6):318-326. Epub 2020 Dec 5.

Inflammatory Bowel Disease Unit Guy's and St Thomas' Hospital London UK.

Background: To quantify the effects of COVID-19 on our inflammatory bowel disease (IBD) unit, including service provision, prescribing practices and use of therapeutic drug monitoring (TDM).

Methods: We performed a single centre retrospective observational cohort study. Data was extracted from our IBD database, electronic patient records and radiology/endoscopy reporting systems between 16/3/20-17/4/20 and the corresponding period in 2019.

Results: A similar number of patients commenced biologic therapy before COVID-19 (n = 37) and during the pandemic (n = 36). Patients in the pre-COVID-19 cohort were older (median 36 vs 29 years,  = 0.009) with a longer median disease duration (9.3 vs 5.2 years,  = 0.02). During COVID-19 there was a nonsignificant increase in prescribing of vedolizumab (8/37, 22% vs 14/36, 39%,  = 0.13) and a higher proportion of patients were anti-TNF-naïve (3/17, 18% vs 18/24, 74%,  = 0.0004). There was a reduction in use of concomitant immunomodulators (22/29, 76% vs 4/34, 12%,  < 0.0001) and increased biologic use in thiopurine-naïve patients (3/37, 8% vs 15/36, 42%,  = 0.001). Use of TDM fell by 75% (240 vs 59 tests). Outpatient appointments fell by 68% and were conducted via telemedicine. MRI scanning, endoscopy, luminal surgery and inpatient numbers fell by 87%, 85%, 100% and 82% respectively. IBD Clinical Nurse Specialist and Pharmacist helpline contacts increased by 76% and 228% respectively.

Conclusions: We observed prescribing differences during COVID-19, bypassing the initiation of immunomodulators and/or anti-TNF therapy in favour of vedolizumab with a reduction in immunomodulator prescribing. We also observed a rapid reorganisation of service provision, including a shift towards telemedicine and online solutions.
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http://dx.doi.org/10.1002/ygh2.433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753474PMC
November 2020

COVID-19 and IBD drugs: should we change anything at the moment?

Gut 2021 04 19;70(4):632-634. Epub 2020 Nov 19.

Sorbonne Université, Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, F75012, Paris, France.

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http://dx.doi.org/10.1136/gutjnl-2020-323247DOI Listing
April 2021

Gut microbiota associations with diet in irritable bowel syndrome and the effect of low FODMAP diet and probiotics.

Clin Nutr 2021 04 23;40(4):1861-1870. Epub 2020 Oct 23.

King's College London, Department of Nutritional Sciences, London, United Kingdom. Electronic address:

Background And Aims: Diet is both a modulator of the gastrointestinal microbiota and an important therapy in irritable bowel syndrome (IBS). We aimed to comprehensively (i) identify diet-microbiota associations in adults with IBS consuming habitual diet; (ii) assess the impact of two nutritional interventions on the microbiota; and (iii) determine whether baseline microbiota can predict clinical response to diet or probiotic intervention.

Methods: Data were analyzed from 95 individuals with IBS participating in a previously published 4-week 2x2 factorial design randomized controlled trial investigating the impact of the low FODMAP diet (LFD) and co-administration of a probiotic. Diet was assessed at four hierarchical levels and partial 16S rRNA gene sequencing was used to profile the microbiota.

Results: There were numerous diet-microbiota associations especially at the nutrient level, including a negative association between protein and Bifidobacterium abundance (r = -0.358, p < 0.001). After correction for multiple testing, the significance for this association (q = 0.237) and all others was lost. Low FODMAP diet led to changes in abundance of major saccharolytic genera compared with sham diet, including higher Bacteroides (LFD 34.1% (15.7%) vs sham 23.3% (15.2%), q = 0.01) and lower Bifidobacterium (0.9% (1.0%) vs 2.1%, (2.5%) q = 0.029). Compared with placebo, probiotic supplementation led to higher Lactobacillus (probiotic 0.08% (0.1%) vs placebo 0.03% (0.2%), q < 0.001), and Streptococcus abundance (2.0% (2.2%) vs 0.6% (1.2%), q = 0.001). The probiotic treatment buffered the impact of the low FODMAP diet on Bifidobacterium. Baseline microbiota did not predict clinical response to either intervention.

Conclusions: Although diet modifies the gut microbiota, bivariate correlation analysis may only provide a limited explanation of the complex diet interactions with individual gut bacteria in IBS. Some diet interventions modify the microbiota in IBS.

Trial Registry: ISRCTN (http://www.isrctn.com) Registered under ISRCTN registry identifier no.ISRCTN02275221.
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http://dx.doi.org/10.1016/j.clnu.2020.10.013DOI Listing
April 2021

Vedolizumab-Associated Drug-Induced Liver Injury: A Case Series.

Inflamm Bowel Dis 2021 02;27(3):e32-e34

Department of Hepatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1093/ibd/izaa286DOI Listing
February 2021

Tofacitinib for the Treatment of Ulcerative Colitis, Alopecia Universalis, and Atopic Dermatitis: One Drug, Three Diseases.

Inflamm Bowel Dis 2021 01;27(2):e13-e14

IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1093/ibd/izaa243DOI Listing
January 2021

Organisational changes and challenges for inflammatory bowel disease services in the UK during the COVID-19 pandemic.

Frontline Gastroenterol 2020 16;11(5):343-350. Epub 2020 Jun 16.

IBD Unit, Hull University Teaching Hospitals NHS Trust, Hull, UK.

Objective: To determine the challenges in diagnosis, monitoring, support provision in the management of inflammatory bowel disease (IBD) patients and explore the adaptations of IBD services.

Methods: Internet-based survey by invitation of IBD services across the UK from 8 to 14 April 2020.

Results: Respondents from 125 IBD services completed the survey. The number of whole-time equivalent gastroenterologists and IBD nurses providing elective outpatient care decreased significantly between baseline (median 4, IQR 4-7.5 and median 3, IQR 2-4) to the point of survey (median 2, IQR 1-4.8 and median 2, IQR 1-3) in the 6-week period following the onset of the COVID-19 pandemic (p<0.001 for both comparisons). Almost all (94%; 112/119) services reported an increase in IBD helpline activity. Face-to-face clinics were substituted for telephone consultation by 86% and video consultation by 11% of services. A variation in the provision of laboratory faecal calprotectin testing was noted with 27% of services reporting no access to faecal calprotectin, and a further 32% reduced access. There was also significant curtailment of IBD-specific endoscopy and elective surgery.

Conclusions: IBD services in the UK have implemented several adaptive strategies in order to continue to provide safe and high-quality care for patients. National Health Service organisations will need to consider the impact of these changes in current service delivery models and staffing levels when planning exit strategies for post-pandemic IBD care. Careful planning to manage the increased workload and to maintain IBD services is essential to ensure patient safety.
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http://dx.doi.org/10.1136/flgastro-2020-101520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335699PMC
June 2020

Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

Gut 2021 06 1;70(6):1044-1052. Epub 2020 Sep 1.

Department of Paediatric Gastroenterology, Evelina London Children's Hospital, London, UK

Objective: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison.

Design: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey.

Results: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19.

Conclusion: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.
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http://dx.doi.org/10.1136/gutjnl-2020-322449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470179PMC
June 2021

Vedolizumab Dose Escalation: In for a Penny, in for a Pound?

Dig Dis Sci 2021 06;66(6):1772-1774

Department of Gastroenterology, St Thomas' Hospital, Guy's & St Thomas', First Floor College House, North Wing, Westminster Bridge Road, London, SE1 7EH, UK.

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http://dx.doi.org/10.1007/s10620-020-06565-zDOI Listing
June 2021

Clinical Practice of Adalimumab and Infliximab Biosimilar Treatment in Adult Patients With Crohn's Disease.

Inflamm Bowel Dis 2021 01;27(1):106-122

IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy.

The introduction of tumor necrosis factor (TNF) inhibitors has significantly changed the treatment landscape in Crohn's disease (CD). The overall therapeutic achievements with TNF inhibitors such as infliximab, adalimumab, and certolizumab pegol paved the way to push the boundaries of treatment goals beyond symptomatic relief and toward cessation of objective signs of inflammation, including endoscopic remission. Even though these agents are widely used for the treatment of moderate to severe CD, heterogeneity still exists in translating evidence-based guidelines on the use of anti-TNF agents into actual treatment algorithms in CD. This might be due to several reasons including disparities in health expenditure policies; lack of harmonization between countries; and variations in assessment of disease severity, use of disease monitoring tools, or application of treatment targets by physicians. With the advent of biosimilars, patent-free versions of reference biologics are now available to minimize health inequalities in drug availability. In this context, this article aims to provide practical clinical guidance for the use of infliximab and adalimumab biosimilars in patients with moderate to severe CD by outlining different clinical scenarios that patients may encounter during their treatment journey.
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http://dx.doi.org/10.1093/ibd/izaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737159PMC
January 2021

Clinical trials (and tribulations): the immediate effects of COVID-19 on IBD clinical research activity in the United Kingdom.

J Crohns Colitis 2020 Jun 29. Epub 2020 Jun 29.

Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom.

There have been immediate and profound impacts of SARS-CoV-2 and COVID-19 on healthcare services worldwide with major consequences for non-COVID-19 related healthcare. Alongside efforts to reconfigure services and enable continued delivery of safe clinical care for patients with IBD, consideration must also be given to management of IBD research activity. In many centres there has been an effective shutdown of IBD clinical trial activity as research sites have switched focus to either COVID-19 related research or clinical care only. As a result, the early termination of trial programmes and loss of potentially effective therapeutic options for IBD, has become a real and worrying prospect. Moreover, in many countries research activity has become embedded into clinical care - with clinical trials often providing access to new therapies or strategies - which would otherwise not have been available in standard clinical pathways. This pandemic has significant implications for the design, conduct, analysis and reporting of clinical trials in IBD. In this Viewpoint, we share our experiences from a clinical and academic perspective in the United Kingdom, highlighting the early challenges encountered and consider implications for patients and staff at research sites, sponsors, research ethics committees, funders and regulators. We also offer potential solutions both for now and for when we enter a recovery phase from the pandemic.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337665PMC
June 2020

Managing an IBD Infusion Unit During the COVID-19 Pandemic: Service Modifications and the Patient Perspective.

Inflamm Bowel Dis 2020 09;26(10):e125-e126

Gastroenterology Department, Guy's and St. Thomas's National Health service (NHS) Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1093/ibd/izaa171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337736PMC
September 2020

Tofacitinib in Acute Severe Ulcerative Colitis-A Real-World Tertiary Center Experience.

Inflamm Bowel Dis 2020 10;26(11):e147-e149

IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London,United Kingdom.

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http://dx.doi.org/10.1093/ibd/izaa157DOI Listing
October 2020

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel.

Gut 2020 10 8;69(10):1769-1777. Epub 2020 Jun 8.

IBD Unit, St Mark's Hospital, London, UK.

Objective: Management of acute severe UC (ASUC) during the novel 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.

Design: We 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.

Results: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from 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 postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab.

Conclusion: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.
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http://dx.doi.org/10.1136/gutjnl-2020-321927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299646PMC
October 2020

Therapeutic thresholds for golimumab serum concentrations during induction and maintenance therapy in ulcerative colitis: results from the GO-LEVEL study.

Aliment Pharmacol Ther 2020 07 7;52(2):292-302. Epub 2020 Jun 7.

Gastroenterology, Guy's & St Thomas' Hospital, London, UK.

Background: Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited.

Aims: To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab.

Methods: GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59μg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250μg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag).

Results: Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 μg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 μg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 μg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 μg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66).

Conclusions: GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 μg/mL at week 6 and 2.4 μg/mL during maintenance.
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http://dx.doi.org/10.1111/apt.15808DOI Listing
July 2020

Clinical features and genetic risk of demyelination following anti-TNF treatment.

J Crohns Colitis 2020 Jun 4. Epub 2020 Jun 4.

IBD Pharmacogenetics Group, University of Exeter, Exeter, UK.

Background: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and test whether affected patients were genetically predisposed to multiple sclerosis (MS).

Methods: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF. We compared genetic risk scores (GRS), calculated using carriage of 43 susceptibility loci for MS, in 48 cases to 1219 patients exposed to anti-TNF who did not develop demyelination.

Results: Overall, 39 (74%) cases were female. The median age (range) of patients at time of demyelination was 41.5 years (20.7 - 63.2). The median duration of anti-TNF treatment was 21.3 months (0.5 - 99.4) and 19 (36%) patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord or both. Complete recovery was reported in 12 (23%) patients after a median time of 6.8 months (0.1 - 28.7). After 33.0 months of follow-up partial recovery was observed in 29 (55%) patients, relapsing and remitting episodes in 9 (17%), progressive symptoms in 3 (6%): 2 (4%) patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 x 10-4, SD 0.0039) and controls (mean -1.1×10-3, SD 0.0042) (p=0.23).

Conclusions: Patients who experienced demyelination events following anti-TNF were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa104DOI Listing
June 2020

β-Galactooligosaccharide in Conjunction With Low FODMAP Diet Improves Irritable Bowel Syndrome Symptoms but Reduces Fecal Bifidobacteria.

Am J Gastroenterol 2020 06;115(6):906-915

Department of Nutritional Sciences, King's College London, London, United Kingdom.

Introduction: The low FODMAP diet (LFD) reduces symptoms and bifidobacteria in irritable bowel syndrome (IBS). β-galactooligosaccharides (B-GOS) may reduce the symptoms and increase bifidobacteria in IBS. We investigated whether B-GOS supplementation alongside the LFD improves IBS symptoms while preventing the decline in bifidobacteria.

Methods: We performed a randomized, placebo-controlled, 3-arm trial of 69 Rome III adult patients with IBS from secondary care in the United Kingdom. Patients were randomized to a sham diet with placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.4 g/d B-GOS (LFD/B-GOS) for 4 weeks. Gastrointestinal symptoms, fecal microbiota (fluorescent in situ hybridization and 16S rRNA sequencing), fecal short-chain fatty acids (gas-liquid chromatography) and pH (probe), and urine metabolites (H NMR) were analyzed.

Results: At 4 weeks, adequate symptom relief was higher in the LFD/B-GOS group (16/24, 67%) than in the control group (7/23, 30%) (odds ratio 4.6, 95% confidence interval: 1.3-15.6; P = 0.015); Bifidobacterium concentrations (log10 cells/g dry weight) were not different between LFD and LFD/B-GOS but were lower in the LFD/B-GOS (9.49 [0.73]) than in the control (9.77 [0.41], P = 0.018). A proportion of Actinobacteria was lower in LFD (1.9%, P = 0.003) and LFD/B-GOS (1.8%, P < 0.001) groups than in the control group (4.2%). Fecal butyrate was lower in the LFD (387.3, P = 0.028) and LFD/B-GOS (346.0, P = 0.007) groups than in the control group (609.2).

Discussion: The LFD combined with B-GOS prebiotic produced a greater symptom response than the sham diet plus placebo, but addition of 1.4 g/d B-GOS did not prevent the reduction of bifidobacteria. The LFD reduces fecal Actinobacteria and butyrate thus strict long-term use should not be advised.
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http://dx.doi.org/10.14309/ajg.0000000000000641DOI Listing
June 2020
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