Imperial College London

DrJamesAlexander

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Lecturer
 
 
 
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j.alexander

 
 
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Queen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

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Summary

 

Publications

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44 results found

Powles STR, Gallagher KI, Chong LWL, Alexander JL, Mullish BH, Hicks LC, McDonald JAK, Marchesi JR, Williams HRT, Orchard TRet al., 2022, Effects of bowel preparation on intestinal bacterial associated urine and faecal metabolites and the associated faecal microbiome, BMC Gastroenterology, ISSN: 1471-230X

Journal article

Alexander JL, Kennedy NA, Ibraheim H, Anandabaskaran S, Saifuddin A, Castro Seoane R, Liu Z, Nice R, Bewshea C, D'Mello A, Constable L, Jones GR, Balarajah S, Fiorentino F, Sebastian S, Irving PM, Hicks LC, Williams HRT, Kent AJ, Linger R, Parkes M, Kok K, Patel KV, Teare JP, Altmann DM, Boyton RJ, Goodhand JR, Hart AL, Lees CW, Ahmad T, Powell N, VIP study investigatorset 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·

Journal article

Pavlidis P, Joshi D, El Sherif Y, Warner B, Gulati S, Alexander J, Cross G, Dew T, Abu Arqoub H, Devlin J, Heneghan M, Dubois P, Bjarnason I, Powell N, Hayee Bet al., 2022, Faecal calprotectin is a surrogate marker of biliary inflammation in primary sclerosing cholangitis associated inflammatory bowel disease, FRONTLINE GASTROENTEROLOGY, ISSN: 2041-4137

Journal article

Lin S, Kennedy NA, Saifuddin A, Sandoval DM, Reynolds CJ, Seoane RC, Kottoor SH, Pieper FP, Lin K-M, Butler DK, Chanchlani N, Nice R, Chee D, Bewshea C, Janjua M, McDonald TJ, Sebastian S, Alexander JL, Constable L, Lee JC, Murray CD, Hart AL, Irving PM, Jones G-R, Kok KB, Lamb CA, Lees CW, Altmann DM, Boyton RJ, Goodhand JR, Powell N, Ahmad Tet 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

Journal article

Alexander J, Powell N, Liu Z, Constable L, Ibraheim H, Anandabaskaran S, Saifuddin M, Castro Seoane R, Balarajah S, Hicks L, Williams H, Teare J, Altmann D, Boyton R, Hart Aet 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

Journal article

Radhakrishnan ST, Alexander JL, Mullish BH, Gallagher KI, Powell N, Hicks LC, Hart AL, Li JV, Marchesi JR, Williams HRTet 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.

Journal article

Alexander JL, Selinger CP, Powell N, 2021, Third doses of SARS-CoV-2 vaccines in immunosuppressed patients with inflammatory bowel disease, LANCET GASTROENTEROLOGY & HEPATOLOGY, Vol: 6, Pages: 987-988

Journal article

Alexander J, Selinger CP, Powell N, 2021, Vaccination against SARS-CoV-2 in immunosuppressed IBD patients – third doses, The Lancet Gastroenterology & Hepatology, ISSN: 2468-1253

Journal article

Allegretti JR, Kelly CR, Grinspan A, Mullish BH, Hurtado J, Carrellas M, Marcus J, Marchesi JR, McDonald JAK, Gerardin Y, Silverstein M, Pechlivanis A, Barker GF, Miguens Blanco J, Alexander JL, Gallagher KI, Pettee W, Phelps E, Nemes S, Sagi SV, Bohm M, Kassam Z, Fischer Met 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.

Journal article

Alexander J, Johnston B, Smith T, Yong KK, Marshall S, Fawkes J, Martin J, Seward E, Saunders B, Monahan Ket 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

Journal article

Alexander J, Ibraheim H, Sheth B, Little J, Khan MS, Richards C, Hunter N, Chauhan D, Ratnakumaran R, McHugh K, Pinato DJ, Nathan P, Choy J, Cursz SM, Furness A, Turajlic S, Pickering L, Larkin J, Teare J, Papa S, Speight A, Powell Net 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.

Journal article

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

Journal article

Alexander JL, Kennedy NA, Lees CW, Ahmad T, Powell N, British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Groupet al., 2021, SARS-CoV-2 vaccination for patients with inflammatory bowel disease - Authors' reply., Lancet Gastroenterol Hepatol, Vol: 6, Pages: 523-524

Journal article

Alexander J, Kennedy NA, Lees CW, Ahmad T, Powell Net al., 2021, A response to HM Garcia Garrido et al., The Lancet Gastroenterology and Hepatology, ISSN: 2468-1253

Journal article

Miguens Blanco J, Liu Z, Mullish BH, Danckert NP, Alexander JL, Chrysostomou D, Sengupta R, McHugh N, McDonald JAK, Abraham SM, Marchesi JRet al., 2021, A Phenomic Characterization of the Gut Microbiota - Associations with Psoriatic Arthritis and Ankylosing Spondylitis, World Microbe Forum

Conference paper

Radhakrishnan ST, Mullish BH, Gallagher K, Alexander JL, Danckert NP, Blanco JM, Serrano-Contreras JI, Valdivia-Garcia M, Hopkins BJ, Ghai A, Li JV, Marchesi J, Williams HRet al., 2021, RECTAL SWABS AS A VIABLE ALTERNATIVE TO FECAL SAMPLING FOR THE ANALYSIS OF GUT MICROBIOME FUNCTIONALITY AS WELL AS COMPOSITION, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S733-S733, ISSN: 0016-5085

Conference paper

Capece D, D'Andrea D, Begalli F, Goracci L, Tornatore L, Alexander JL, Di Veroli A, Leow S-C, Vaiyapuri TS, Ellis JK, Verzella D, Bennett J, Savino L, Ma Y, McKenzie JS, Doria ML, Mason SE, Chng KR, Keun HC, Frost G, Tergaonkar V, Broniowska K, Stunkel W, Takats Z, Kinross JM, Cruciani G, Franzoso Get 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.

Journal article

Mullish BH, Alexander JL, Segal JP, 2021, Microbiota and faecal microbiota transplant, Microbiota in Health and Disease, 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.

Journal article

Alexander JL, Moran GW, Gaya DR, Raine T, Hart A, Kennedy NA, Lindsay JO, MacDonald J, Segal JP, Sebastian S, Selinger CP, Parkes M, Smith PJ, Dhar A, Subramanian S, Arasaradnam R, Lamb CA, Ahmad T, Lees CW, Dobson L, Wakeman R, Iqbal TH, Arnott I, Powell Net 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, LANCET GASTROENTEROLOGY & HEPATOLOGY, Vol: 6, Pages: 218-224

Journal article

Alexander J, Hart A, Segal JP, Powell Net al., 2021, British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement on SARS-CoV2 Vaccination, The Lancet Gastroenterology and Hepatology, ISSN: 2468-1253

SARS-CoV2 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 vaccine (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-CoV2 vaccination strategy in patients with IBD. The risks of SARS-CoV2 vaccination are anticipated to be very low, and we strongly support SARS-CoV2 vaccination in IBD patients. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV2 vaccination may be diminished in some IBD patients, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in anti-TNF treated patients, 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 impact of immunosuppression on vaccine efficacy and the search for predictive biomarkers of vaccine success.

Journal article

Alexander JL, Andreasson A, Hugerth LW, Engstrand L, Walker MM, Talley NJ, Powell Net 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

Conference paper

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.

Journal article

Segal JP, Mak JWY, Mullish BH, Alexander JL, Ng SC, Marchesi JRet 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.

Journal article

Miguens Blanco J, Selvarajah U, Liu Z, Mullish BH, Alexander J, McDonald J, Abraham S, Marchesi Jet 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

Conference paper

Allegretti JR, Kelly CR, Grinspan A, Mullish BH, Kassam Z, Fischer Met al., 2020, Outcomes of fecal microbiota transplantation in patients with inflammatory bowel diseases and recurrent Clostridioides difficile infection, Gastroenterology, Vol: 159, Pages: 1982-1984, ISSN: 0016-5085

There has been an increase in the burden of Clostridioides difficile infection (CDI),1 especially in high-risk populations such as patients with inflammatory bowel disease (IBD).2 The prevalence of CDI in the IBD population is up to 8-fold higher than comparable controls, with increased rates of recurrence and CDI-associated mortality.3 In addition, CDI may induce an IBD flare, and worsen disease severity and clinical course.4Fecal microbiota transplantation (FMT) is a guideline recommended therapy for recurrent CDI5; however, supportive randomized trials excluded patients with IBD. In retrospective trials of patients with IBD, FMT failure rates had been reported to be approximately 25% to 30%.6 In addition, Khoruts and colleagues reported that patients with IBD and CDI were more likely to fail FMT,7 leading to further uncertainty regarding the safety and efficacy of FMT in IBD patients with concurrent CDI. Accordingly, we conducted the first prospective study examining the efficacy of FMT among patients with IBD and CDI.MethodsWe conducted an open-label, prospective, single-arm, multicenter cohort study at 4 tertiary care FMT referral centers (Brigham and Women’s Hospital, Indiana University, Brown University, and Mount Sinai Hospital; NCT03106844). Patients with a confirmed diagnosis of IBD and 2 or more confirmed CDI episodes within 12 months, including the most recent episode occurring within 3 months, were enrolled. In keeping with CDI clinical guidelines,5 polymerase chain reaction or glutamate dehydrogenase with toxin enzyme immunoassay were permitted for the qualifying CDI episode. Patients with a total or subtotal colectomy, isolated ileal or small bowel Crohn’s disease, those pregnant or breastfeeding, those treated with vancomycin or metronidazole for more than 60 days, or those who had undergone a prior FMT within 12 months were excluded. Baseline IBD and CDI data were collected. All patients underwent a single FMT via colonoscopy. Four robus

Journal article

Alexander JL, Mullish BH, 2020, The gut microbiome, and its relevance to critical care, British Journal of Nursing, Vol: 29, Pages: 1106-1112, ISSN: 0966-0461

Whilst it is well-established that particular bacteria may cause gastroenteritis and other infections when present in the gut, it is only recently that we have made significant inroads into understanding the huge number of other bacteria and additional microbes that live within the gastrointestinal tract, referred to as the gut microbiome. In particular, we now recognise that bacteria within the gut microbiome have a wide variety of roles in maintaining different aspects of human health, and that disturbances of these bacteria may potentially cause or contribute to a number of different medical conditions, including particular infections, certain cancers, and chronic conditions including inflammatory bowel disease. Moreover, there is increasing awareness that these bacteria help determine how we respond to medication, including antibiotics and chemotherapy. There has been growing interest in different approaches to alter the gut microbiome as a novel approach to medical therapy. In this Review, we give an overview of the importance of the gut microbiome, with a particular focus upon critical care.

Journal article

Qiu S, Nikolaou S, Zhu J, Jeffery P, Goldin R, Kinross J, Alexander J, Rasheed S, Tekkis P, Kontovounisios Cet al., 2020, Characterisation of the expression of neurotensin and its receptors in human colorectal cancer and its clinical implications, Biomolecules, Vol: 10, Pages: 1-15, ISSN: 2218-273X

Introduction: Colorectal Cancer (CRC) accounts for 9% of cancer deaths globally. Hormonal pathways play important roles in some cancers. This study investigated the association of CRC expression of neurotensin (NTS), NTS receptors 1 and 3 (NTSR1 and NTSR3) and clinical outcomes. Methods: A prospective cohort study which quantifies the protein expression of NTS, NTSR1 and NTSR3 in human CRCs using immunohistochemistry. Expression levels were then compared with clinico-pathological outcome including histological grade, overall survival (OS) and disease-free survival (DFS). Results: Sixty-four patients were enrolled with median follow-up of 44.0 months. There was significantly higher expression of NTS in cancer tissue in CRC with higher T stages (p < 0.01), N stages (p = 0.03), and AJCC clinical stages (p = 0.04). There was significantly higher expression of NTS, NTSR1 and NTSR3 in cancer tissue compared to surrounding normal epithelium (median H-score 163.5 vs 97.3, p < 0.01). There was significantly shorter DFS in individuals with CRC with high levels of NTS compared to lower levels of NTS (35.8 months 95% CI 28.7–42.8 months vs 46.4 months 95% CI 42.2–50.5 months, respectively, p = 0.02). Above median NTS expression in cancer tissue was a significant risk factor for disease recurrence (HR 4.10, 95% CI 1.14–14.7, p = 0.03). Discussion: The expression of NTS and its receptors has the potential to be utilised as a predictive and prognostic marker in colorectal cancer for postoperative selection for adjuvant therapy and identify individuals for novel therapies targeting the neurotensinergic pathways. Conclusions: High NTS expression appears to be associated with more advanced CRC and worse DFS.

Journal article

Fessas P, Possamai LA, Clark J, Daniels E, Gudd C, Mullish BH, Alexander JL, Pinato DJet al., 2020, Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms., Immunology, Vol: 159, Pages: 167-177, ISSN: 0019-2805

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and, whilst immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognising potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathologic findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.

Journal article

Cameron SJS, Alexander JL, Bolt F, Burke A, Ashrafian H, Teare J, Marchesi JR, Kinross J, Li JV, Takats Zet al., 2019, Evaluation of direct from sample metabolomics of human feces using rapid evaporative ionization mass spectrometry, Analytical Chemistry, Vol: 91, Pages: 13448-13457, ISSN: 0003-2700

Mass spectrometry is a powerful tool in the investigation of the human fecal metabolome. However, current approaches require time-consuming sample preparation, chromatographic separations, and consequently long analytical run times. Rapid evaporative ionization mass spectrometry (REIMS) is a method of ambient ionization mass spectrometry and has been utilized in the metabolic profiling of a diverse range of biological materials, including human tissue, cell culture lines, and microorganisms. Here, we describe the use of an automated, high-throughput REIMS robotic platform for direct analysis of human feces. Through the analysis of fecal samples from five healthy male participants, REIMS analytical parameters were optimized and used to assess the chemical information obtainable using REIMS. Within the fecal samples analyzed, bile acids, including primary, secondary, and conjugate species, were identified, and phospholipids of possible bacterial origin were detected. In addition, the effect of storage conditions and consecutive freeze/thaw cycles was determined. Within the REIMS mass spectra, the lower molecular weight metabolites, such as fatty acids, were shown to be significantly affected by storage conditions for prolonged periods at temperatures above −80 °C and consecutive freeze/thaw cycles. However, the complex lipid region was shown to be unaffected by these conditions. A further cohort of 50 fecal samples, collected from patients undergoing bariatric surgery, were analyzed using the optimized REIMS parameters and the complex lipid region mass spectra used for multivariate modeling. This analysis showed a predicted separation between pre- and post-surgery specimens, suggesting that REIMS analysis can detect biological differences, such as microbiome-level differences, which have traditionally been reliant upon methods utilizing extensive sample preparations and chromatographic separations and/or DNA sequencing.

Journal article

Mason S, Manoli E, Poynter L, Alexander J, Paizs P, Adebesin A, Goldin R, Darzi A, Takats Z, Kinross Jet al., 2019, Mass spectrometry transanal minimally invasive surgery (MS-TAMIS) to promote organ preservation in rectal cancer, Surgical Endoscopy: surgical and interventional techniques, Vol: 34, Pages: 3618-3625, ISSN: 0930-2794

BACKGROUND: Transanal minimally invasive surgery (TAMIS) is deployed for organ preservation in early rectal cancer and significant rectal polyps. Rapid evaporative ionisation mass spectrometry (REIMS) provides biochemical tissue analysis, which could be applied intraoperatively to give real-time tissue feedback to the surgeon and decrease the risk of an involved margin. However, the accuracy and feasibility of this approach have not been established. METHODS: In this prospective observational study, patients undergoing resection of rectal adenomas or carcinomas were recruited. An electrosurgical handpiece analysed tissues ex vivo using diathermy, with the aerosol aspirated into a Xevo G2-S ToF mass spectrometer. The relative abundance of lipids underwent predictive statistical modelling and leave-one-patient-out cross-validation. The outcomes of interest were the ability of REIMS to differentiate normal, adenomatous and cancerous tissue, or any disease subtype from normal. REIMS was coupled with TAMIS for in vivo sampling, assessing the accuracy of tissue recognition and distinguishing bowel wall layers. RESULTS: Forty-seven patients were included, yielding 266 spectra (121 normal, 109 tumour and 36 adenoma). REIMS differentiates normal, adenomatous and cancerous rectal tissues with 86.8% accuracy, and normal and adenomatous tissue with 92.4% accuracy and 91.4% accuracy when differentiating disease from normal. We have performed the first five in-man mass spectrometry augmented TAMIS (MS-TAMIS). In real time, MS-TAMIS can differentiate rectal mucosa and submucosa based on their relative abundance of triglycerides and glycerophospholipids. The ex vivo accuracy distinguishing diseased and normal tissues is maintained in vivo at 90%, with negative predictive value of 95%. The system identified a deep and lateral involved tumour margin during TAMIS. CONCLUSIONS: REIMS distinguishes rectal tissue types based on underlying lipid biology, and this can be translated in vivo

Journal article

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