Imperial College London

DrHoraceWilliams

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Clinical Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3312 1208h.williams

 
 
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Location

 

GI UnitClarence WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

98 results found

Alexander J, Liu Z, Munoz Sandoval D, Reynolds C, Ibraheim H, Saifuddin M, Constable L, Altmann D, Balarajah S, Hicks L, Williams H, Teare J, Hart A, Boyton R, Powell Net al., 2022, COVID-19 vaccine-induced antibody and T cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose: a multicentre, prospective, case-control study, The Lancet Gastroenterology & Hepatology, ISSN: 2468-1253

Background:COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to determine whether immunosuppressive treatments were associated with reduced antibody and T cell responses after a third vaccine dose.Methods:352 adults (72 healthy controls and 280 IBD) were sampled 28-49 days after a third dose of SARS-CoV-2 vaccine. IBD medications studied included thiopurines (n=65), infliximab (n=46), thiopurine/infliximab combination therapy (n=49), ustekinumab (n=44), vedolizumab (n=50) or tofacitinib (n=26). SARS-CoV-2 spike antibody binding and T cell responses were measured. Findings:Geometric mean [geometric SD] anti-S1 RBD antibody concentrations increased in all groups following a third dose, but were significantly lower in patients treated with infliximab (2736.8 U/mL [4.3]; P<0.0001), infliximab and thiopurine combination (1818.3 U/mL [6.7]; P<0.0001) and tofacitinib (8071.5 U/mL [3.1]; P=0.0018) compared to controls (16774.2 U/ml [2.6]). There were no significant differences in anti-S1 RBD antibody concentrations between control subjects and thiopurine (12019.7 U/mL [2.2]; P=0.099), ustekinumab (11089.3 U/mL [2.8]; P=0.060), nor vedolizumab treated patients (13564.9 U/mL [2.4]; P=0.27). In multivariable modelling, lower anti-S1 RBD antibody concentrations were independently associated with infliximab (Geometric mean ratio 0.15, 95% CI 0.11-0.21, P<0.0001), tofacitinib (0.52, 95% CI 0.31-0.87, P=0.012) and thiopurine (0.69, 95% CI 0.51-0.95, P=0.021), but not with ustekinumab (0.64, 95% CI 0.39-1.06, P=0.083), or vedolizumab (0.84, 95% CI 0.54-1.30, P=0.43). Previous SARS-CoV-2 infection (1.58, 95% CI 1.22-2.05, P=0.00056) and older age (0.88, 95% CI 0.80-0.97, P=0.0073) were independently associated with higher and lower anti-S1 antibody concentrations respectively. Antigen specific T cell responses were similar in all groups, except for reci

Journal article

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, Vol: 22, Pages: 1-9, ISSN: 1471-230X

BackgroundUrinary and faecal metabolic profiling have been extensively studied in gastrointestinal diseases as potential diagnostic markers, and to enhance our understanding of the intestinal microbiome in the pathogenesis these conditions. The impact of bowel cleansing on the microbiome has been investigated in several studies, but limited to just one study on the faecal metabolome.AimTo compare the effects of bowel cleansing on the composition of the faecal microbiome, and the urine and faecal metabolome.MethodsUrine and faecal samples were obtained from eleven patients undergoing colonoscopy at baseline, and then at day 3 and week 6 after colonoscopy. 16S rRNA gene sequencing was used to analyse changes in the microbiome, and metabonomic analysis was performed using proton nuclear magnetic resonance (1H NMR) spectroscopy.ResultsMicrobiomic analysis demonstrated a reduction in alpha diversity (Shannon index) between samples taken at baseline and three days following bowel cleansing (p = 0.002), and there was no significant difference between samples at baseline and six weeks post colonoscopy. Targeted and non-targeted analysis of urinary and faecal bacterial associated metabolites showed no significant impact following bowel cleansing.ConclusionsBowel cleansing causes a temporary disturbance in bacterial alpha diversity measured in faeces, but no significant changes in the faecal and urine metabolic profiles, suggesting that overall the faecal microbiome and its associated metabolome is resistant to the effects of an induced osmotic diarrhoea.

Journal article

Alexander JL, Kennedy N, Ibraheim H, Anandabaskaran S, Saifuddin A, Seoane RC, Liu Z, Nice R, Bewshea CM, D'Mello A, Constable LE, Jones G-R, Balarajah S, Fiorentino F, Sebastian S, Irving PM, Hicks LC, Williams HR, Kent AJ, Parkes M, Kok K, Patel KV, Altmann D, Boyton R, Goodhand J, Hart A, Lees CW, Ahmad T, Powell Net al., 2022, COVID-19 VACCINE-INDUCED ANTIBODY RESPONSES ARE IMPAIRED IN IBD PATIENTS TREATED WITH INFLIXIMAB, USTEKINUMAB OR TOFACITINIB, BUT NOT THIOPURINES OR VEDOLIZUMAB, Publisher: W B SAUNDERS CO-ELSEVIER INC

Working paper

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

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

Moore-Gillon C, Suleiman S, Mullish BH, Williams HRTet al., 2021, Faecal microbiota transplant in the treatment of Clostridioides difficile infection: an update, European Medical Journal Gastroenterology, Vol: 10, Pages: 60-68, ISSN: 2054-6203

Clostridioides difficile infection (CDI) presents a major global healthcare challenge. Recurrent/refractory disease is particularly hard to manage, and novel therapeutic strategies have recently been adopted. In particular, within the past decade, faecal microbiota transplant (FMT) has rapidly progressed from a “potential” treatment option of fringe interest to one of the mainstays of therapy for recurrent/refractory C. difficile infection (rCDI). The first randomised study of its use for this indication was published as recently as 2013, but the emergence of subsequent randomised studies has led to its rapid adoption into guidelines and treatment algorithms. Very rare but serious reports of infection transmission from donor to recipient have resulted in ongoing refinements to donor screening, including the adoption of routine screening for intestinal carriage of multi-drug resistant bacteria and SARS-CoV-2 status. Developments in the evidence base have given new insights into optimal recipient selection and preparation. Upper and lower gastrointestinal administration of FMT slurry are both safe and effective in treating rCDI, although the newer option of capsulised FMT has recently grown in popularity; ‘next generation’ FMT products of defined microbial communities derived from donor stool are in late phase clinical trials, and may become licensed for use in the near future. While different regulatory structures for FMT use have been adopted in different countries, the development of international networks of FMT-interested specialists has helped to harmonise best practice.

Journal article

Baunwall SMD, Terveer EM, Dahlerup JF, Erikstrup C, Vehreschild MJGT, Ianiro G, Gasbarrini A, Sokol H, Kump PK, Satokari R, De Looze D, Vermeire S, Nakov R, Brezina J, Helms M, Kjeldsen J, Rode AA, Kousgaard SJ, Alric L, Trang-Poisson C, Scanzi J, Link A, Stallmach A, Kupcinskas J, Johnsen PH, Garborg K, Sánchez-Rodríguez E, Serrander L, Brummer RJ, Galpérine KT, Goldenberg SD, Mullish BH, Williams HRT, Iqbal TH, Ponsioen C, Kuijper EJ, Cammarota G, Keller JJ, Hvas CLet al., 2021, The use of faecal microbiota transplantation (FMT) in Europe: a Europe-wide survey, The Lancet Regional Health - Europe, Vol: 9, ISSN: 2666-7762

BackgroundFaecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe.MethodsWe invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT.FindingsIn 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10–64) FMT procedures; 1,077 (57%) with Clostridioides difficile infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0•3%) unaccounted for. Adjusted to population size, 0•257 per 100,000 population received FMT for CDI and 0•189 per 100,000 population for experimental indications. With estimated 12,400 (6,100–28,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres.InterpretationFMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need.FundingNordForsk under the Nordic Council and Innovation Fund Denmark (j.no. 8056–00006B).

Journal article

Innes AJ, Mullish BH, Ghani R, Szydlo RM, Apperley JF, Olavarria E, Palanicawandar R, Kanfer EJ, Milojkovic D, McDonald JAK, Brannigan ET, Thursz MR, Williams HRT, Davies FJ, Marchesi JR, Pavlu Jet al., 2021, Fecal microbiota transplant mitigates adverse outcomes in patients colonized with multidrug-resistant organisms undergoing allogeneic hematopoietic cell transplantation, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-8, ISSN: 2235-2988

The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT).This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. Weperformed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy forMDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDROgroup), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival wassignificantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensivecare (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant difference and statistically comparablepatient/transplant characteristics, as the sample size was small, a matched-pair analysis to non-MDRO colonized control cohorts(2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4%versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than theirpaired non-colonized cohort. There was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2%respectively, p=0.24) between the FMT-MDRO group and their paired cohort. Negative outcomes, including mortality associatedwith MDRO colonization, may be ameliorated by pre-HCT FMT, despite lack of intestinal decolonization. Further work is needed toexplore the observed benefit.

Journal article

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

Mullish BH, Innes AJ, Ghani R, Szydlo R, Williams HR, Thursz MR, Marchesi J, Davies F, Pavlu Jet al., 2021, FECAL MICROBIOTA TRANSPLANT PRIOR TO ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN PATIENTS COLONIZED WITH MULTI-DRUG RESISTANT ORGANISMS IS ASSOCIATED WITH IMPROVED SURVIVAL, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S168-S169, ISSN: 0016-5085

Conference paper

Radhakrishnan ST, Vasireddy A, Gallagher KI, Hicks LC, Powles ST, Chong L, Peake ST, Orchard TR, Williams HRTet al., 2021, Long-term follow up in IBD: 10-year observational study of a UK IBD cohort, Publisher: OXFORD UNIV PRESS, Pages: S588-S588, ISSN: 1873-9946

Conference paper

Gallagher K, Catesson A, Griffin JL, Holmes E, Williams HRTet al., 2021, Metabolomic analysis in inflammatory bowel disease: a systematic review, Journal of Crohns & Colitis, Vol: 15, Pages: 813-826, ISSN: 1873-9946

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are chronic, idiopathic gastrointestinal (GI) diseases. Whilst their precise etiology is unknown, it is thought to involve a complex interaction between genetic predisposition and an abnormal host immune response to environmental exposures, likely microbial. Microbial dysbiosis has frequently been documented in IBD. Metabolomics (the study of small molecular intermediates and end products of metabolism in biological samples) provides a unique opportunity to characterize disease-associated metabolic changes and may be of particular use in quantifying gut microbial metabolism. Numerous metabolomic studies have been undertaken in inflammatory bowel disease populations, identifying consistent alterations in a range of molecules across several biological matrices. This systematic review aims to summarize these findings. METHODS: A comprehensive, systematic search was carried out using Medline and EMBASE. All studies were reviewed by two authors independently using predefined exclusion criteria. A total of sixty-four relevant papers were quality assessed and included in the review. RESULTS: Consistent metabolic perturbations were identified, including increases in levels of branched chain amino acids and lipid classes across stool, serum, plasma and tissue biopsy samples, and reduced levels of microbially modified metabolites in both urine (such as hippurate) and stool (such as secondary bile acids). CONCLUSIONS: This review provides a summary of metabolomic research in IBD to date, highlighting underlying themes of perturbed gut microbial metabolism and mammalian-microbial co-metabolism associated with disease status.

Journal article

Ghani R, Mullish BH, McDonald JAK, Ghazy A, Williams HRT, Brannigan ET, Mookerjee S, Satta G, Gilchrist M, Duncan N, Corbett R, Innes AJ, Pavlu J, Thursz MR, Davies F, Marchesi JRet al., 2021, Disease prevention not decolonization – a model for fecal microbiota transplantation in patients colonized with multidrug-resistant organisms, Clinical Infectious Diseases, Vol: 72, Pages: 1444-1447, ISSN: 1058-4838

Fecal microbiota transplantation (FMT) yields variable intestinal decolonization results for multidrug-resistant organisms (MDROs). This study showed significant reductions in antibiotic duration, bacteremia and length of stay in 20 patients colonized/ infected with MDRO receiving FMT (compared to pre-FMT history, and a matched group not receiving FMT), despite modest decolonization rates.

Journal article

Keller JJ, Ooijevaar RE, Hvas CL, Terveer EM, Lieberknecht SC, Hogenauer C, Arkkila P, Sokol H, Gridnyev O, Megraud F, Kump PK, Nakov R, Goldenberg SD, Satokari R, Tkatch S, Sanguinetti M, Cammarota G, Dorofeev A, Gubska O, Laniro G, Mattila E, Arasaradnam RP, Sarin SK, Sood A, Putignani L, Alric L, Baunwall SMD, Kupcinskas J, Link A, Goorhuis AG, Verspaget HW, Ponsioen C, Hold GL, Tilg H, Kassam Z, Kuijper EJ, Gasbarrini A, Mulder CJJ, Williams HRT, Vehreschild MJGTet al., 2021, A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group, UNITED EUROPEAN GASTROENTEROLOGY JOURNAL, Vol: 9, Pages: 229-247, ISSN: 2050-6406

Journal article

Ghani R, Mullish B, Innes A, Szydlo RM, Apperley JF, Olavarria E, Palanicawandar R, Kanfer E, Milojkovic D, McDonald JAK, Brannigan E, Thursz MR, Williams HRT, Davies FJ, Pavlu J, Marchesi Jet al., 2021, Faecal microbiota transplant (FMT) prior to allogeneic haematopoietic cell transplantation (HCT) in patients colonised with multidrug-resistant organisms (MDRO) results in improved survival, ECCMID

Conference paper

Jaggard MKJ, Boulange CL, Graca G, Akhbari P, Vaghela U, Bhattacharya R, Williams HRT, Lindon JC, Gupte CMet al., 2021, The influence of sample collection, handling and low temperature storage upon NMR metabolic profiling analysis in human synovial fluid, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 197, ISSN: 0731-7085

Journal article

NICE, 2021, Faecal microbiota transplant for recurrent or refractory Clostridioides difficile infection, Medtech innovation briefing [MIB247]

Report

Akhbari P, Jaggard MK, Boulange CL, Vaghela U, Graca G, Bhattacharya R, Lindon JC, Williams HRT, Gupte CMet al., 2021, Differences between infected and noninfected synovial fluid, BONE & JOINT RESEARCH, Vol: 10, Pages: 85-95, ISSN: 2046-3758

Journal article

Gallagher K, Radhakrishnan ST, Li JV, Thurz MR, Holmes E, Williams HRTet al., 2021, DEVELOPMENT OF A TARGETED METABOLOMIC URINE-BASED PANEL FOR INFLAMMATORY BOWEL DISEASE, Publisher: BMJ PUBLISHING GROUP, Pages: A114-A114, ISSN: 0017-5749

Conference paper

Innes AJ, Ghani R, Mullish BH, Szydlo R, Palanicawandar R, Olavarria E, Apperley JF, Thursz MR, Williams HR, Marchesi JR, Davies F, Pavlu Jet al., 2020, O105. Faecal microbiota transplant (FMT) can reduce the high NRM associated with multi-drug resistant organism (MDRO) colonisation prior to allogeneic HCT., The 46th Annual Meeting of the European Society for Blood and Marrow Transplantation, Publisher: Springer Nature [academic journals on nature.com], Pages: 122-122, ISSN: 0268-3369

Conference paper

Martinez-Gili L, McDonald JAK, Liu Z, Kao D, Allegretti JR, Monaghan TM, Barker GF, Miguens Blanco J, Williams HRT, Holmes E, Thursz MR, Marchesi JR, Mullish BHet al., 2020, Understanding the mechanisms of efficacy of fecal microbiota transplant in treating recurrent Clostridioides difficile infection and beyond: the contribution of gut microbial derived metabolites, Gut Microbes, Vol: 12, ISSN: 1949-0976

Fecal microbiota transplant (FMT) is a highly-effective therapy for recurrent Clostridioides difficile infection (rCDI), and shows promise for certain non-CDI indications. However, at present, its mechanisms of efficacy have remained poorly understood. Recent studies by our laboratory have noted the particular key importance of restoration of gut microbe-metabolite interactions in the ability of FMT to treat rCDI, including the impact of FMT upon short chain fatty acid (SCFAs) and bile acid metabolism. This includes a significant impact of these metabolites upon the life cycle of C. difficile directly, along with potential postulated additional benefits, including effects upon host immune response. In this Addendum, we first present an overview of these recent advancements in this field, and then describe additional novel data from our laboratory on the impact of FMT for rCDI upon several gut microbial-derived metabolites which had not previously been implicated as being of relevance.

Journal article

Jaggard MKJ, Boulange CL, Graca G, Vaghela U, Akhbari P, Bhattacharya R, Williams HRT, Lindon JC, Gupte CMet al., 2020, Can metabolic profiling provide a new description of osteoarthritis and enable a personalised medicine approach?, CLINICAL RHEUMATOLOGY, Vol: 39, Pages: 3875-3882, ISSN: 0770-3198

Journal article

Ghani R, Mullish BH, McDonald JA, Ghazy A, Williams HR, Brannigan E, Satta G, Gilchrist M, Duncan N, Corbett R, Pavlu J, Innes AJ, Thursz MR, Davies F, Marchesi Jet al., 2020, 1144 FECAL MICROBIOTA TRANSPLANT FOR MULTI-DRUG RESISTANT ORGANISMS: IMPROVED CLINICAL OUTCOMES BEYOND INTESTINAL DECOLONISATION, Publisher: Elsevier BV, ISSN: 0016-5085

Conference paper

Akhbari P, Karamchandani U, Jaggard MKJ, Graca G, Bhattacharya R, Lindon JC, Williams HRT, Gupte CMet al., 2020, Can joint fluid metabolic profiling (or "metabonomics") reveal biomarkers for osteoarthritis and inflammatory joint disease? A SYSTEMATIC REVIEW, BONE & JOINT RESEARCH, Vol: 9, Pages: 108-119, ISSN: 2046-3758

Journal article

Ghani R, Mullish BH, McDonald J, Ghazy A, Williams H, Satta G, Eimear B, Gilchrist M, Duncan N, Corbett R, Pavlu J, Innes A, Thursz M, Marchesi J, Davies Fet al., 2020, Disease prevention not decolonisation: a cohort study for faecal microbiota transplantation for patients colonised with multidrug-resistant organisms, ECCMID 2020

Conference paper

Barry R, Ruano-Gallego D, Radhakrishnan ST, Lovell S, Yu L, Kotik O, Glegola-Madejska I, Tate EW, Choudhary JS, Williams HRT, Frankel Get al., 2020, Faecal neutrophil elastase-antiprotease balance reflects colitis severity, Mucosal Immunology, Vol: 13, Pages: 322-333, ISSN: 1933-0219

Given the global burden of diarrheal diseases on healthcare it is surprising how little is known about the drivers of disease severity. Colitis caused by infection and inflammatory bowel disease (IBD) is characterised by neutrophil infiltration into the intestinal mucosa and yet our understanding of neutrophil responses during colitis is incomplete. Using infectious (Citrobacter rodentium) and chemical (dextran sulphate sodium; DSS) murine colitis models, as well as human IBD samples, we find that faecal neutrophil elastase (NE) activity reflects disease severity. During C. rodentium infection intestinal epithelial cells secrete the serine protease inhibitor SerpinA3N to inhibit and mitigate tissue damage caused by extracellular NE. Mice suffering from severe infection produce insufficient SerpinA3N to control excessive NE activity. This activity contributes to colitis severity as infection of these mice with a recombinant C. rodentium strain producing and secreting SerpinA3N reduces tissue damage. Thus, uncontrolled luminal NE activity is involved in severe colitis. Taken together, our findings suggest that NE activity could be a useful faecal biomarker for assessing disease severity as well as therapeutic target for both infectious and chronic inflammatory colitis.

Journal article

Akhbari P, Jaggard MK, Boulange CL, Vaghela U, Graca G, Bhattacharya R, Lindon JC, Williams HRT, Gupte CMet al., 2019, Differences in the composition of hip and knee synovial fluid in osteoarthritis: a nuclear magnetic resonance (NMR) spectroscopy study of metabolic profiles, OSTEOARTHRITIS AND CARTILAGE, Vol: 27, Pages: 1768-1777, ISSN: 1063-4584

Journal article

Mullish BH, McDonald JAK, Pechlivanis A, Allegretti JR, Kao D, Barker GF, Kapila D, Petrof EO, Joyce SA, Gahan CGM, Glegola-Madejska I, Williams HRT, Holmes E, Clarke TB, Thursz MR, Marchesi JRet al., 2019, Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection, Gut, Vol: 68, Pages: 1791-1800, ISSN: 0017-5749

Objective Faecal microbiota transplant (FMT) effectively treats recurrent Clostridioides difficile infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect C. difficile germination or vegetative growth. We hypothesised that loss of gut microbiota-derived bile salt hydrolases (BSHs) predisposes to CDI by perturbing gut bile metabolism, and that BSH restitution is a key mediator of FMT’s efficacy in treating the condition.Design Using stool collected from patients and donors pre-FMT/post-FMT for rCDI, we performed 16S rRNA gene sequencing, ultra performance liquid chromatography mass spectrometry (UPLC-MS) bile acid profiling, BSH activity measurement, and qPCR of bsh/baiCD genes involved in bile metabolism. Human data were validated in C. difficile batch cultures and a C57BL/6 mouse model of rCDI.Results From metataxonomics, pre-FMT stool demonstrated a reduced proportion of BSH-producing bacterial species compared with donors/post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA, a potent C. difficile germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and bsh/baiCD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered bsh-expressing E. coli and naturally BSH-producing organisms (Bacteroides ovatus, Collinsella aerofaciens, Bacteroides vulgatus and Blautia obeum) reduced TCA-mediated C. difficile germination relative to culture supernatant of wild-type (BSH-negative) E. coli. C. difficile total viable counts were ~70% reduced in an rCDI mouse model after administration of E. coli expressing highly active BSH relative to mice administered BSH-negative E. coli (p<0.05).Conclusion Restoration of gut BSH functionality contributes to the efficacy of FMT in treating rCDI.

Journal article

Mullish BH, 2019, The role of bile-metabolising enzymes in the pathogenesis of Clostridioides difficile infection, and the impact of faecal microbiota transplantation

Thesis dissertation

Powles STR, Gallagher K, Hicks LC, Chong LW, Swann JR, Holmes E, Williams HRT, Orchard TRet al., 2019, EFFECT OF CO-MORBIDITIES IN CROHN'S DISEASE ASSOCIATED URINARY METABOLIC PROFILES, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A89-A90, ISSN: 0017-5749

Conference paper

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