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Alexander JL, Kennedy NA, Ibraheim H, et al., 2022, COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study, The Lancet Gastroenterology & Hepatology, Vol: 7, Pages: 342-352, ISSN: 2468-1253
BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·
Pavlidis P, Joshi D, El Sherif Y, et al., 2022, Faecal calprotectin is a surrogate marker of biliary inflammation in primary sclerosing cholangitis associated inflammatory bowel disease, FRONTLINE GASTROENTEROLOGY, ISSN: 2041-4137
Lin S, Kennedy NA, Saifuddin A, et al., 2022, Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab, Nature Communications, Vol: 13, ISSN: 2041-1723
Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 – 27.5] vs 47.6 days [45.5 – 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 – 36.8] vs 58.0 days [55.0 – 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.
Alexander J, Powell N, Liu Z, et al., 2022, A prospective, case-control study of COVID-19 vaccine-induced antibody responses in immunosuppressed patients with IBD, The Lancet Gastroenterology & Hepatology, ISSN: 2468-1253
Background:We sought to determine whether COVID-19 vaccine-induced antibody responses were diminished in patients with IBD on commonly used immunosuppressive drugs.Methods:We prospectively recruited 483 adults (121 healthy controls and 362 IBD) following two doses of either ChAdOx1 nCoV-19 (Oxford/AstraZeneca), BNT162b2 (Pfizer/BioNTech) or mRNA1273 (Moderna) vaccines (doses delivered between six to twelve weeks apart according to scheduling adopted in the United Kingdom). IBD medications studied comprised thiopurines (n=78), infliximab (n=63), thiopurine/infliximab combination therapy (n=72), ustekinumab (n=57), vedolizumab (n=62) or tofacitinib (n=30). The pre-defined primary outcome was anti-SARS-CoV-2 spike (anti-S1 RBD) antibody concentrations, 53-92 days after second vaccine dose, in 370 participants without prior infection, adjusted by age and vaccine type. Findings:Geometric mean [geometric SD] anti-S1 RBD antibody concentrations were significantly lower in patients treated with infliximab (157U/mL [5.7]; P<0.0001), infliximab and thiopurine combination (111U/mL [5.7]; P<0.0001) and tofacitinib (430 U/mL [3.1]; P=0.0012) compared to controls (1578U/ml [3.7]). There were no significant differences in anti-S1 RBD antibody concentrations between control subjects and thiopurine (1020U/mL [4.3]; P=0.74), nor ustekinumab (582U/mL [4.6]; P=0.11), nor vedolizumab treated patients (954U/mL [4.1]; P=0.50). In multivariable modelling, lower anti-S1 RBD antibody concentrations were independently associated with infliximab (Geometric mean ratio 0.12, 95% CI 0.08-0.17, P<0.0001) and tofacitinib (0.43, 95% CI 0.23-0.81, P=0.009), but not with ustekinumab (0.69, 95% CI 0.41-1.19, P=0.18), thiopurine (0.89, 95% CI [0.64-1.24], P=0.50) or vedolizumab (1.16, 95% CI 0.74-1.83, P=0.51). mRNA vaccines (3.68 [95% CI 2.80-4.84], P<0.0001) and older age (0.79 [95% CI 0.72-0.87], P<0.0001) were independently associated with higher and lower anti-S1 antibody concentrati
Lo J, Cozzetto D, Madgwick M, et al., 2022, Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis, Publisher: Research Square
Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common and serious complication. To probe the impact of immune checkpoints on intestinal homeostasis, mice were challenged with combination anti-CTLA-4/anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. Colonic immune responses were profiled using bulk and single-cell RNA-sequencing and flow cytometry. CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9), cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7) and the chemokine receptor Cxcr6. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis. This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis likely holds the key to preventing and reversing CPI-colitis.
Radhakrishnan ST, Alexander JL, Mullish BH, et al., 2022, Systematic Review: The association between the gut microbiota and medical therapies in inflammatory bowel disease, Alimentary Pharmacology and Therapeutics, Vol: 55, Pages: 26-48, ISSN: 0269-2813
BackgroundThe gut microbiota has been implicated in the pathogenesis of inflammatory bowel disease (IBD), with Faecalibacterium prausnitizii associated with protection, and certain genera (including Shigella and Escherichia) associated with adverse features. The variability of patient response to medical therapies in IBD is incompletely understood. Given the recognised contribution of the microbiota to treatment efficacy in other conditions, there may be interplay between the gut microbiota, IBD medical therapy and IBD phenotype.AimsTo evaluate the bidirectional relationship between IBD medical therapies and the gut microbiota.MethodsWe conducted a systematic search of MEDLINE and EMBASE. All original studies analysing interactions between the gut microbiota and established IBD medical therapies were included.ResultsWe screened 1296 records; 19 studies were eligible. There was heterogeneity in terms of sample analysis, treatment protocols, and outcome reporting. Increased baseline α-diversity was observed in responders versus non-responders treated with exclusive enteral nutrition (EEN), infliximab, ustekinumab or vedolizumab. Higher baseline Faecalibacterium predicted response to infliximab and ustekinumab. A post-treatment increase in Faecalibacterium prausnitzii was noted in responders to aminosalicylates, anti-TNF medications and ustekinumab; conversely, this species decreased in responders to EEN. Escherichia was a consistent marker of unfavourable drug response, and its presence in the gut mucosa correlated with inflammation in aminosalicylate-treated patients.ConclusionsBoth gut microbiota diversity and specific taxonomic features (including high abundance of Faecalibacterium) are associated with the efficacy of a range of IBD therapies. These findings hold promise for a potential role for the gut microbiota in explaining the heterogeneity of patient response to IBD treatments.
Lin S, Kennedy NA, Saifuddin A, et al., 2022, Antibody decay, T cell immunity and breakthrough infections following SARS-CoV-2 vaccination in infliximab- and vedolizumab-treated patients, Publisher: OXFORD UNIV PRESS, Pages: I023-I025, ISSN: 1873-9946
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Alexander J, Selinger CP, Powell N, 2021, Third doses of SARS-CoV-2 vaccines in immunosuppressed patients with inflammatory bowel disease, The Lancet Gastroenterology & Hepatology, Vol: 6, Pages: 987-988, ISSN: 2468-1253
Lo J, Cozzetto D, Sieh JYX, et al., 2021, IMMUNE CHECKPOINT INHIBITOR-INDUCED COLITIS IS MEDIATED BY IL23 RESPONSIVE CD90+CYTOTOXIC LYMPHOCYTES, Publisher: BMJ PUBLISHING GROUP, Pages: A77-A77, ISSN: 0017-5749
Alexander J, Ibraheim H, Sheth B, et al., 2021, A MULTI-CENTRE STUDY OF INFLIXIMAB TREATMENT FOR CORTICOSTEROID-REFRACTORY CHECKPOINT INHIBITOR INDUCED ENTEROCOLITIS, Publisher: BMJ PUBLISHING GROUP, Pages: A22-A22, ISSN: 0017-5749
Torkizadeh M, Ibraheim H, Radhakrishnan S, et al., 2021, HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH CHECKPOINT INHIBITOR ENTEROCOLITIS, Publisher: BMJ PUBLISHING GROUP, Pages: A100-A100, ISSN: 0017-5749
Alexander J, Ibraheim H, Richards C, et al., 2021, CLIPPER (BECLOMETHASONE DIPROPIONATE) AS A TREATMENT FOR CHECKPOINT INHIBITOR INDUCED ENTEROCOLITIS, Publisher: BMJ PUBLISHING GROUP, Pages: A101-A101, ISSN: 0017-5749
Allegretti JR, Kelly CR, Grinspan A, et al., 2021, Inflammatory bowel disease outcomes following fecal microbiota transplantation for recurrent C. difficile infection, Inflammatory Bowel Diseases, Vol: 27, Pages: 1371-1378, ISSN: 1078-0998
BackgroundRecurrent Clostridioides difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is a clinical challenge. Fecal microbiota transplantation (FMT) has emerged as a recurrent CDI therapy. Anecdotal concerns exist regarding worsening of IBD activity; however, prospective data among IBD patients are limited.MethodsSecondary analysis from an open-label, prospective, multicenter cohort study among IBD patients with 2 or more CDI episodes was performed. Participants underwent a single FMT by colonoscopy (250 mL, healthy universal donor). Secondary IBD-related outcomes included rate of de novo IBD flares, worsening IBD, and IBD improvement—all based on Mayo or Harvey-Bradshaw index (HBI) scores. Stool samples were collected for microbiome and targeted metabolomic profiling.ResultsFifty patients enrolled in the study, among which 15 had Crohn’s disease (mean HBI, 5.8 ± 3.4) and 35 had ulcerative colitis (mean partial Mayo score, 4.2 ± 2.1). Overall, 49 patients received treatment. Among the Crohn’s disease cohort, 73.3% (11 of 15) had IBD improvement, and 4 (26.6%) had no disease activity change. Among the ulcerative colitis cohort, 62% (22 of 34) had IBD improvement, 29.4% (11 of 34) had no change, and 4% (1 of 34) experienced a de novo flare. Alpha diversity significantly increased post-FMT, and ulcerative colitis patients became more similar to the donor than Crohn’s disease patients (P = 0.04).ConclusionThis prospective trial assessing FMT in IBD-CDI patients suggests IBD outcomes are better than reported in retrospective studies.
Alexander J, Johnston B, Smith T, et al., 2021, Low referral rates for genetic assessment of patients with multiple adenomas in United Kingdom Bowel Cancer Screening Programmes, Diseases of the Colon and Rectum, Vol: 64, Pages: 1058-1063, ISSN: 0012-3706
Background:Approximately one in twenty cases of colorectal cancer are caused by monogenic syndromes. Published guidelines recommend that patients with ten or more adenomas be referred for genetic testing, based on evidence that colorectal cancer risk is associated with adenoma multiplicity. Objective:The aim of this study was to determine adherence to guidelines on referral for genetic screening in patients with ten or more adenomas.Design:A cross-sectional study was performed of prospectively collected data from the United Kingdom Bowel Cancer Screening Program between May 2007 & June 2018. Only histologically confirmed adenomas were included. Clinicopathological data were recorded from patient records and referrals to clinical genetics services were ascertained. Setting:Data were obtained from three centres in London, United Kingdom.Patients:A total of 17,450 subjects underwent colonoscopy following an abnormal faecal occult blood test. Main outcome measures:We quantified patients with ten or more adenomas and the proportion referred for genetic screening.Results:The adenoma detection rate was 50.6% amongst 17,450 patients who underwent colonoscopy (8,831 had one or more adenomas). 347 patients (2.0%) had 10 or more adenomas. Patients with 10 or more adenomas were more likely to be male than those with less than 10 adenomas (76.9% vs. 53.4%; p<0.0001). A family history was collected in 37.8% of the multiple adenoma population. Of 347 patients with 10 or more adenomas, 28 (8.1%) were referred for genetic assessment.Limitations:All three screening centres were in a single city. No genetic outcome data were available to permit analysis of actual rates of inherited cancer syndromes in this population.Conclusions:In this study, almost one in fifty patients had ten or more adenomas. Despite guidelines advising genetic testing in this group, referral rates are low. A referral pathway and management strategies should be established to address this patient popula
Mason SE, Manoli E, Alexander JL, et al., 2021, Lipidomic profiling of colorectal lesions for real-time tissue recognition and risk-stratification using rapid evaporative ionisation mass spectrometry., Annals of Surgery, Vol: 00, ISSN: 0003-4932
OBJECTIVE: Rapid Evaporative Ionisation Mass Spectrometry (REIMS) is a metabolomic technique analysing tissue metabolites, which can be applied intra-operatively in real-time. The objective of this study was to profile the lipid composition of colorectal tissues using REIMS, assessing its accuracy for real-time tissue recognition and risk-stratification. SUMMARY BACKGROUND DATA: Metabolic dysregulation is a hallmark feature of carcinogenesis, however it remains unknown if this can be leveraged for real-time clinical applications in colorectal disease. METHODS: Patients undergoing colorectal resection were included, with carcinoma, adenoma and paired-normal mucosa sampled. Ex vivo analysis with REIMS was conducted using monopolar diathermy, with the aerosol aspirated into a Xevo G2S QToF mass spectrometer. Negatively charged ions over 600-1000m/z were used for univariate and multivariate functions including linear discriminant analysis. RESULTS: 161 patients were included, generating 1013 spectra. Unique lipidomic profiles exist for each tissue type, with REIMS differentiating samples of carcinoma, adenoma and normal mucosa with 93 1% accuracy and 96 1% negative predictive value for carcinoma. Neoplasia (carcinoma or adenoma) could be predicted with 96 0% accuracy and 91 8% negative predictive value. Adenomas can be risk-stratified by grade of dysplasia with 93 5% accuracy, but not histological subtype. The structure of 61 lipid metabolites was identified, revealing that during colorectal carcinogenesis there is progressive increase in relative abundance of phosphatidylglycerols, sphingomyelins and mono-unsaturated fatty acid containing phospholipids. CONCLUSIONS: The colorectal lipidome can be sampled by REIMS and leveraged for accurate real-time tissue recognition, in addition to risk-stratification of colorectal adenomas. Unique lipidomic features associated with carcinogenesis are described.
Lo JWP, Cozzetto D, Sieh JYX, et al., 2021, Immune checkpoint inhibitor-induced colitis is mediated by IL23 responsive CD90+cytotoxic lymphocytes, Publisher: WILEY, Pages: 81-81, ISSN: 0014-2980
Alexander J, Ibraheim H, Sheth B, et al., 2021, Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor induced enterocolitis treated with infliximab, Journal for ImmunoTherapy of Cancer, Vol: 9, Pages: 1-9, ISSN: 2051-1426
IntroductionImmune Checkpoint Inhibitors (CPI) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. MethodsWe conducted a multi-centre (six cancer centres), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with CTCAE grade 0 for diarrhoea at 12 weeks after IFX initiation. We also assessed cancer outcomes at one year using RECIST criteria.Results127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhoea CTCAE grade >2 and 115 (90.6%) required hospitalisation for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistical regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04-0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13-8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared to patients with IFX-responsive enterocolitis (37.5%; p=0.013).ConclusionThis is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Utilizing pre-defined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI-therapy.
Alexander JL, Powell N, 2021, SARS-CoV-2 vaccination in immunosuppressed patients with inflammatory bowel disease: should our approach change?, The Lancet Gastroenterology & Hepatology, Vol: 6, Pages: S28-S29, ISSN: 2468-1253
Paizs P, Widlak M, Perdones-Montero A, et al., 2021, High-throughput fecal metabolic profiling for the early detection of colorectal cancer using a direct mass spectrometry assay., Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Alexander JL, Kennedy NA, Lees CW, et al., 2021, SARS-CoV-2 vaccination for patients with inflammatory bowel disease reply, LANCET GASTROENTEROLOGY & HEPATOLOGY, Vol: 6, Pages: S23-S24
Miguens Blanco J, Liu Z, Mullish BH, et al., 2021, A Phenomic Characterization of the Gut Microbiota - Associations with Psoriatic Arthritis and Ankylosing Spondylitis, World Microbe Forum
Radhakrishnan ST, Mullish BH, Gallagher K, et al., 2021, RECTAL SWABS AS A VIABLE ALTERNATIVE TO FECAL SAMPLING FOR THE ANALYSIS OF GUT MICROBIOME FUNCTIONALITY AS WELL AS COMPOSITION, Society-for-Surgery-of-the-Alimentary-Tract Annual Meeting at Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S733-S733, ISSN: 0016-5085
Alexander JL, Sheth B, Ibraheim H, et al., 2021, INFLIXIMAB TREATMENT FOR CHECKPOINT INHIBITOR INDUCED COLITIS: CLINICAL OUTCOMES FROM A MULTI-CENTRE STUDY, Society-for-Surgery-of-the-Alimentary-Tract Annual Meeting at Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S26-S27, ISSN: 0016-5085
Capece D, D'Andrea D, Begalli F, et al., 2021, Enhanced triacylglycerol catabolism by Carboxylesterase 1 promotes aggressive colorectal carcinoma., Journal of Clinical Investigation, ISSN: 0021-9738
The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cell-autonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.
Mullish BH, Alexander JL, Segal JP, 2021, Microbiota and faecal microbiota transplant, Microbiota in Health and Disease, Vol: 3, ISSN: 2704-8845
As the range of disease states associated with the gut microbiome expands - and the mechanistic links between the gut microbiome and host physiology further deepens – so interest also grows in microbiome manipulation as medical therapy. In particular, bolstered by its established role in recurrent C. difficile infection (and promising results in other conditions), faecal microbiota transplant (FMT) has remained of growing global focus. This article reviews the key FMT-based studies published between April 2020 - March 2021. While the COVID-19 pandemic was the dominant challenge of the year, important FMT trials of interest were published for patients with a range of different conditions. The emergence of ‘next generation’ microbiome therapeutics offers an additional perspective and new opportunities within the field.
Alexander J, Hart A, Segal JP, et al., 2021, SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement, The Lancet Gastroenterology and Hepatology, Vol: 6, Pages: 218-224, ISSN: 2468-1253
SARS-CoV-2 has caused a global health crisis and mass vaccination programmes provide the best opportunity for controlling transmission and protecting populations. Despite the impressive clinical trial results of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines, important unanswered questions remain, especially in patients with pre-existing conditions. In this position statement endorsed by the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) section and IBD Clinical Research Group, we consider SARS-CoV-2 vaccination strategy in patients with IBD. The risks of SARS-CoV-2 vaccination are anticipated to be very low, and we strongly support SARS-CoV-2 vaccination in patients with IBD. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV-2 vaccination may be diminished in some patients with IBD, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in patients treated with anti-TNF drugs, are likely to outweigh these theoretical concerns. Key areas for further research are discussed, including vaccine hesitancy and its effect in the IBD community, the effect of immunosuppression on vaccine efficacy, and the search for predictive biomarkers of vaccine success.
Alexander JL, Andreasson A, Hugerth LW, et al., 2021, AN EXPANDED INTESTINAL INTRAEPITHELIAL LYMPHOCYTE COMPARTMENT IS LINKED TO SHIFTS IN COMPOSITION OF MUCOSAL MICROBIOTA, Publisher: BMJ PUBLISHING GROUP, Pages: A208-A208, ISSN: 0017-5749
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.
Segal JP, Mak JWY, Mullish BH, et al., 2020, The gut microbiome: an under-recognised contributor to the Covid-19 pandemic?, Therapeutic Advances in Gastroenterology, Vol: 13, Pages: 1-14, ISSN: 1756-2848
The novel Coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus, Covid-19 has rapidly spread across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ for propensity to and severity of Covid-19 infection. Furthermore, the gut microbiome has been linked to a variety of diseases and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While the data profiling the gut microbiome in Covid-19 infection to date are limited, they support the possibility of several routes of interaction between Covid-19, the gut microbiome, ACE2 expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of Covid-19 and speculate about the gut microbiome’s capability as a therapeutic avenue against Covid-19.
Miguens Blanco J, Selvarajah U, Liu Z, et al., 2020, Identification of New Associations Between Psoriatic Arthritis and the Gut Microbiota. the Mi-PART, a Phenomic Study, ACR Convergence 2020, Publisher: Wiley, ISSN: 2326-5205
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