Imperial College London

ProfessorJulianMarchesi

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Professor of Digestive Health
 
 
 
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Contact

 

+44 (0)20 3312 6197j.marchesi

 
 
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Location

 

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

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Summary

 

Publications

Publication Type
Year
to

446 results found

Wyatt NJ, Watson H, Anderson CA, Kennedy NA, Raine T, Ahmad T, Allerton D, Bardgett M, Clark E, Clewes D, Cotobal Martin C, Doona M, Doyle JA, Frith K, Hancock HC, Hart AL, Hildreth V, Irving PM, Iqbal S, Kennedy C, King A, Lawrence S, Lees CW, Lees R, Letchford L, Liddle T, Lindsay JO, Maier RH, Mansfield JC, Marchesi JR, McGregor N, McIntyre RE, Ostermayer J, Osunnuyi T, Powell N, Prescott NJ, Satsangi J, Sharma S, Shrestha T, Speight A, Strickland M, Wason JM, Whelan K, Wood R, Young GR, Zhang X, Parkes M, Stewart CJ, Jostins-Dean L, Lamb CAet al., 2024, Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine., BMJ Open, Vol: 14

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was

Journal article

Pinato DJ, D'Alessio A, Fulgenzi CAM, Schlaak AE, Celsa C, Killmer S, Blanco JM, Ward C, Stikas C-V, Openshaw MR, Acuti N, Nteliopoulos G, Balcells C, Keun HC, Goldin RD, Ross PJ, Cortellini A, Thomas R, Young AM, Danckert N, Tait P, Marchesi JR, Bengsch B, Sharma Ret al., 2024, Safety and preliminary efficacy of pembrolizumab following trans-arterial chemoembolization for hepatocellular carcinoma: the PETAL phase Ib study., Clin Cancer Res

BACKGROUND: TACE may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy. METHODS: Patients with liver-confined HCC were planned to receive up to 2 rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30-days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, 21-days dose-limiting toxicities (DLT) from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumour and host determinants of response. RESULTS: Fifteen patients were included in the safety and efficacy population: 73% had non-viral cirrhosis, median age was 72 years. Child-Pugh (CP) class was A in 14 patients. Median tumour size was 4 cm. Ten patients (67%) received pembrolizumab after 1 TACE, 5 patients after 2 (33%). Pembrolizumab yielded no synergistic toxicity nor DLTs post-TACE. Treatment-related adverse events occurred in 93% of patients most commonly skin rash (40%), fatigue and diarrhoea (27%). After a median follow-up of 38.5 months, objective response rate (ORR) 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months (95%CI 7.30-NA). Median duration of response was 7.3 months (95%CI: 6.3-8.3). Median OS was 33.5 months (95%CI: 11.6-NA). Dynamic changes in peripheral T-cell subsets, circulating tumour DNA, serum metabolites and in stool bacterial profiles highlight potential mechanisms of action of multi-modal therapy. CONCLUSIONS: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.

Journal article

Mullish BH, Michael DR, Dabcheva M, Webberley TS, Coates N, John DA, Wang D, Luo Y, Plummer SF, Marchesi JRet al., 2024, A double-blind, randomized, placebo-controlled study assessing the impact of probiotic supplementation on the symptoms of irritable bowel syndrome in females, Neurogastroenterology and Motility, Vol: 36, Pages: 1-13, ISSN: 1350-1925

Background:A previous exploratory study demonstrated the ability of the Lab4 probiotic to alleviate the symptoms of IBS, and post hoc data analysis indicated greatest improvements in the female subgroup. The aim of this study is to confirm the impact of this multistrain probiotic on IBS symptom severity in females.Methods:An 8-week, single-center, randomized, double-blinded, placebo-controlled, superiority study in 70 females with Rome IV-diagnosed irritable bowel syndrome (IBS) receiving the Lab4 probiotic (25 billion colony-forming units) daily or a matched placebo. Changes from baseline in the IBS-symptom severity score (IBS-SSS), daily bowel habits, anxiety, depression, IBS-related control, and avoidance behavior, executive function, and the fecal microbiota composition were assessed. The study was prospectively registered: ISRCTN 14866272 (registration date 20/07/22).Key Results:At the end of the study, there were significant between-group reductions in IBS-SSS (−85.0, p < 0.0001), anxiety and depression scores (−1.9, p = 0.0002 and −2.4, p < 0.0001, respectively), and the IBS-related control and avoidance behavior score (−7.5, p = 0.0002), all favoring the probiotic group. A higher proportion of the participants in the probiotic group had normal stool form (p = 0.0106) and/or fewer defecations with loose stool form (p = 0.0311). There was little impact on the overall diversity of the fecal microbiota but there were significant differences in Roseburia, Holdemanella, Blautia, Agathobacter, Ruminococcus, Prevotella, Bacteroides, and Anaerostipes between the probiotic and placebo groups at the end of the study.Conclusions & Inferences:Daily supplementation with this probiotic may represent an option to be considered in the management of IBS.

Journal article

Routy B, Lenehan JG, Miller WH, Jamal R, Messaoudene M, Daisley BA, Hes C, Al KF, Martinez-Gili L, Punčochář M, Ernst S, Logan D, Belanger K, Esfahani K, Richard C, Ninkov M, Piccinno G, Armanini F, Pinto F, Krishnamoorthy M, Figueredo R, Thebault P, Takis P, Magrill J, Ramsay L, Derosa L, Marchesi JR, Parvathy SN, Elkrief A, Watson IR, Lapointe R, Segata N, Haeryfar SMM, Mullish BH, Silverman MS, Burton JP, Maleki Vareki Set al., 2024, Author Correction: Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial., Nat Med, Vol: 30

Journal article

Kragsnaes MS, Jensen JRB, Nilsson AC, Malik MI, Munk HL, Pedersen JK, Horn HC, Kruhøffer M, Kristiansen K, Mullish BH, Marchesi JR, Kjeldsen J, Röttger R, Ellingsen Tet al., 2024, Dynamics of inflammation-associated plasma proteins following faecal microbiota transplantation in patients with psoriatic arthritis and healthy controls: exploratory findings from the FLORA trial, RMD Open, Vol: 10, ISSN: 2056-5933

Objectives: The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins.Methods: This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel).Results: Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p<0.05), of which 10 proteins were elevated in PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, and IL-2. In the FMT group, levels of 12 proteins changed significantly across all timepoints (tumour necrosis factor (TNF), CDCP1, IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences in protein levels between FMT and sham-treated patients were observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell factor (p=0.024), matrix metalloproteinase-1 (p=0.038), and SLAMF1 (p=0.042). FMT had the largest positive effect on IFN-γ, Axin-1 and CCL25 and the largest negative effect on CCL19 and IL-6.Conclusions: Patients with active PsA have a distinct immunological plasma protein signature compared with HC pre-FMT. FMT affects several of these disease markers, including sustained elevation of IFN-γ.Trial regis

Journal article

Forlano R, Martinez-Gili L, Takis P, Miguens Blanco J, Liu T, Triantafyllou E, Skinner C, Loomba R, Thursz M, Marchesi JR, Mullish BH, Manousou Pet al., 2024, Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus, Gut Microbes, Vol: 16, ISSN: 1949-0976

Aberration of the “gut-liver axis” contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Journal article

Alexander J, Powell N, Marchesi J, Camuzeaux S, Chekmeneva E, Jimenez B, Sands Cet al., 2024, Considerations for peripheral blood transport and storage during large-scale multicentre metabolome research, Gut, Vol: 73, Pages: 379-383, ISSN: 0017-5749

Journal article

Kragsnaes MS, Miguens Blanco J, Mullish BH, Contreras Serrano JI, Kjeldsen J, Horn HC, Pedersen JK, Munk HL, Nilsson AC, Salam A, Lewis MR, Chekmeneva E, Kristiansen K, Marchesi JR, Ellingsen Tet al., 2023, Small intestinal permeability and metabolomic profiles in feces and plasma associate with clinical response in patients with active psoriatic arthritis participating in a fecal microbiota transplantation trial: exploratory findings from the FLORA trial, ACR Open Rheumatology, Vol: 5, Pages: 583-593, ISSN: 2578-5745

ObjectiveWe investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT).MethodsThis exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1H Nuclear Magnetic Resonance.ResultsTrial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = 0.02).ConclusionIntestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.

Journal article

Lo J, Cozzetto D, Alexander J, Danckert N, Madgwick M, Knox N, Sieh J, Olbei M, Liu Z, Ibraheim H, Miguens Blanco J, Kudo H, Castro Seoane R, Possamai L, Goldin R, Marchesi J, Korcsmaros T, Lord G, Powell Net al., 2023, Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and dependent on IL23 and IFNg, Nature Communications, Vol: 14, ISSN: 2041-1723

Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.

Journal article

Biscarini F, Masetti G, Muller I, Verhasselt HL, Covelli D, Colucci G, Zhang L, Draman MS, Okosieme O, Taylor P, Daumerie C, Burlacu M-C, Marino M, Ezra DG, Perros P, Plummer S, Eckstein A, Salvi M, Marchesi JR, Ludgate Met al., 2023, Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study (vol 108, pg 2065, 2023), JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, ISSN: 0021-972X

Journal article

Marchesi J, Alexander J, Balarajah S, Roberts Let al., 2023, Identification of a sub-clinical Salmonella spp. infection in a dairy cow using a commercially available stool storage kit, Animals, Vol: 13, Pages: 1-11, ISSN: 2076-2615

Stool sampling is a useful tool for diagnosing gastrointestinal disease in veterinary medicine. The sub-clinical disease burden of Salmonella spp. in cattle can become significant for farmers. However, current methods of faecal sampling in a rural setting for diagnosis are not consistently sufficient for the preservation of Salmonella spp. in faeces. This study evaluated the use of a commercial stool storage kit for bacterial preservation in cow faecal samples compared to unpreserved stools placed into refrigeration at different time-points. A stool sample was collected per-rectum from one apparently healthy Holstein–Freisen cow. The sample was weighed and aliquoted into two sterile Falcon tubes and into two commercial kit tubes. The aliquots were then placed into refrigeration at 4 °C at 0, 24, and 96 h after processing. One commercial kit tube was not aliquoted and remained at ambient temperature. After 2 weeks, DNA was extracted from the samples and analysed using endpoint PCR, revealing a sub-clinical infection with Salmonella spp. The bacterium was best preserved when the stool was stored in the commercial kit at ambient temperature and re-homogenised immediately prior to DNA extraction. The unpreserved stool did not maintain obvious levels of Salmonella spp. after 24 h at ambient temperature. This commercial kit should be considered for use in the diagnosis of salmonellosis in cattle.

Journal article

Yip AYG, King OG, Omelchenko O, Kurkimat S, Horrocks V, Mostyn P, Danckert N, Ghani R, Satta G, Jauneikaite E, Davies FJ, Clarke TB, Mullish BH, Marchesi JR, McDonald JAKet al., 2023, Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites, Nature Communications, Vol: 14, Pages: 1-20, ISSN: 2041-1723

The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Broad-spectrum antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. Here, we show that antibiotic-induced reduction of gut microbial populations leads to an enrichment of nutrients and depletion of inhibitory metabolites, which enhances CRE growth. Antibiotics decrease the abundance of gut commensals (including Bifidobacteriaceae and Bacteroidales) in ex vivo cultures of human faecal microbiota; this is accompanied by depletion of microbial metabolites and enrichment of nutrients. We measure the nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of several CRE strains. We find that CRE can use the nutrients (enriched after antibiotic treatment) as carbon and nitrogen sources for growth. These nutrients also increase in faeces from antibiotic-treated mice and decrease following intestinal colonisation with carbapenem-resistant Escherichia coli. Furthermore, certain microbial metabolites (depleted upon antibiotic treatment) inhibit CRE growth. Our results show that killing gut commensals with antibiotics facilitates CRE colonisation by enriching nutrients and depleting inhibitory microbial metabolites.

Journal article

Gallacher DJ, Zhang L, Aboklaish AF, Mitchell E, Wach R, Marchesi JR, Kotecha Set al., 2023, Baseline azithromycin resistance in the gut microbiota of preterm born infants, PEDIATRIC RESEARCH, ISSN: 0031-3998

Journal article

Biscarini F, Masetti G, Muller I, Verhasselt HL, Covelli D, Colucci G, Zhang L, Draman MS, Okosieme O, Taylor P, Daumerie C, Burlacu M-C, Marino M, Ezra DG, Perros P, Plummer S, Eckstein A, Salvi M, Marchesi JR, Ludgate Met al., 2023, Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 108, Pages: 2065-2077, ISSN: 0021-972X

Journal article

Routy B, Lenehan JG, Miller WH, Jamal R, Messaoudene M, Daisley BA, Hes C, Al KF, Martinez-Gili L, Punčochář M, Ernst S, Logan D, Belanger K, Esfahani K, Richard C, Ninkov M, Piccinno G, Armanini F, Pinto F, Krishnamoorthy M, Figueredo R, Thebault P, Takis P, Magrill J, Ramsay L, Derosa L, Marchesi JR, Parvathy SN, Elkrief A, Watson IR, Lapointe R, Segata N, Haeryfar SMM, Mullish BH, Silverman MS, Burton JP, Maleki Vareki Set al., 2023, Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial, Nature Medicine, ISSN: 1546-170X

Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899.

Journal article

Garaiova I, Paduchová Z, Nagyová Z, Wang D, Michael DR, Plummer SF, Marchesi JR, Ďuračková Z, Muchová Jet al., 2023, Probiotics with low dose vitamin C reduce antibiotic prescriptions in children: A secondary analysis of a multicentre randomised double-blind placebo-controlled trial, Journal of Functional Foods, Vol: 106, ISSN: 1756-4646

As part of a randomised, double-blind, placebo-controlled study in children looking at the impact of a combination of a multistrain probiotic and vitamin C on upper respiratory tract infection symptoms, we have explored antibiotic prescription during the study. Antibiotic usage in children for acute respiratory tract infections is quite widespread. In this study the incidence rates for oral antibiotic prescriptions were significantly reduced in the Lab4 probiotic/vitamin C group compared to the placebo; children had a lower risk of being prescribed antibiotics (Risk Ratio: 0.60, 95 % CI: 0.39, 0.94, P = 0.0239, per protocol; Risk Ratio: 0.72, 95 % CI: 0.49, 1.05, P = 0.0890, intention to treat, respectively). These data suggest that supplementation with the probiotic/vitamin C may help to reduce antibiotic prescriptions in children.

Journal article

Kragsnaes MS, Kjeldsen J, Horn HC, Munk HL, Pedersen JK, Just SA, Ahlquist P, Davidsen JR, Nilsson AC, Rottger R, Kruhoffer M, Marchesi JR, Kristiansen K, Christensen R, Ellingsen Tet al., 2023, Response to: 'Correspondence on 'Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial'' by McGonagle <i>et al</i>, ANNALS OF THE RHEUMATIC DISEASES, Vol: 82, ISSN: 0003-4967

Journal article

D'Alessio A, Pai M, Spalding D, Goldin RD, Scheiner B, Korolewicz J, Fulgenzi CAM, Ward C, Yip V, Slater S, Akarca A, Sodergren M, Tait P, Habib NA, Thomas R, Cortellini A, Marafioti T, Marchesi JR, Sharma R, Pinato DJJet al., 2023, Neoadjuvant immunotherapy with ipilimumab plus nivolumab and radiologically and pathologically quantifiable responses through modulation of the tumour microenvironment in resectable hepatocellular carcinoma, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Jiwa N, Ford L, Roberts D, Danckert N, Marchesi J, Leff D, Takats Zet al., 2023, Identification of Nipple Biofluid Analytes by Desorption Electrospray Ionization (DESI) Mass Spectrometry and Its Interaction with the Nipple Fluid Microbiota, 24th Annual Meeting of The American Society of Breast Surgeons (ASBrS), Publisher: SPRINGER, Pages: S550-S551, ISSN: 1068-9265

Conference paper

Forlano R, Martinez-Gili L, Blanco JM, Skinner C, Thursz M, Marchesi Jet al., 2023, Altered gut barrier integrity as a mediator of host-microbiome interactions in diabetic patients with advanced Non-alcoholic fatty liver disease, Publisher: ELSEVIER, Pages: S601-S602, ISSN: 0168-8278

Conference paper

Skov Kragsnaes M, Miguens Blanco J, Mullish B, Contreras-Serrano JI, Horn HC, Munk H, Pedersen JK, Nilsson AC, Kristiansen K, Kjeldsen J, Marchesi J, Ellingsen Tet al., 2023, POS0423 PLASMA METABOLOMIC PROFILES OF PATIENTS WITH ACTIVE PERIPHERAL PSORIATIC ARTHRITIS CAN DIFFERENTIATE TREATMENT RESPONDERS FROM FAILURES: EXPLORATORY FINDINGS FROM THE FLORA TRIAL, EULAR 2023 European Congress of Rheumatology, 31 May - 3 June. Milan, Italy, Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism

Conference paper

Alexander J, Danckert N, Patel R, Irwin S, Dimitradis S, Murray S, Forlano R, Roberts L, Miguens-Blanco J, Faustini S, Richter A, Powell N, Thursz M, Manousou P, Barnes E, Marchesi J, Marjot T, Mullish Bet al., 2023, COVID-19 vaccine-induced antibody response is associated with oral microbiota composition in patients with inflammatory bowel disease, cirrhosis, and liver transplantation, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A92-A92, ISSN: 0017-5749

Conference paper

Edwards LA, Woodhouse C, Lee S, Mullish BH, Portlock T, Meoli L, Kronsten V, Marchesi J, Zamalloa A, Tranah T, Patel V, Shoaie S, Goldenberg S, Shawcross DLet al., 2023, Faecal microbiota transplant restores gut barrier function and augments ammonia metabolism in patients with advanced cirrhosis: a randomised single-blind placebo-controlled trial, Publisher: ELSEVIER, Pages: S7-S7, ISSN: 0168-8278

Conference paper

Churchward MA, Michaud ER, Mullish BH, Miguens Blanco J, Garcia Perez I, Marchesi JR, Xu H, Kao D, Todd KGet al., 2023, Short-chain fatty and carboxylic acid changes associated with fecal microbiota transplant communally influence microglial inflammation, Heliyon, Vol: 9, Pages: 1-16, ISSN: 2405-8440

The intestinal microbiota has been proposed to influence human mental health and cognition through the gut-brain axis. Individuals experiencing recurrent Clostridioides difficile infection (rCDI) frequently report depressive symptoms, which are improved after fecal microbiota transplantation (FMT); however, mechanisms underlying this association are poorly understood. Short-chain fatty acids and carboxylic acids (SCCA) produced by the intestinal microbiota cross the blood brain barrier and have been proposed to contribute to gut-brain communication. We hypothesized that changes in serum SCCA measured before and after successful FMT for rCDI influences the inflammatory response of microglia, the resident immune cells of the central nervous system. Serum SCCA were quantified using gas chromatography-mass spectroscopy from 38 patients who participated in a randomized trial comparing oral capsule- vs colonoscopy delivered FMT for rCDI, and quality of life was assessed by SF-36 at baseline, 4, and 12 weeks after FMT treatment. Successful FMT was associated with improvements in mental and physical health, as well as significant changes in a number of circulating SCCA, including increased butyrate, 2-methylbutyrate, valerate, and isovalerate, and decreased 2-hydroxybutyrate. Primary cultured microglia were treated with SCCA and the response to a pro-inflammatory stimulus was measured. Treatment with a combination of SCCA based on the post-FMT serum profile, but not single SCCA species, resulted in significantly reduced inflammatory response including reduced cytokine release, reduced nitric oxide release, and accumulation of intracellular lipid droplets. This suggests that both levels and diversity of SCCA may be an important contributor to gut-brain communication.

Journal article

Dos Santos Correia G, Marchesi J, MacIntyre D, 2023, Moving beyond DNA: towards functional analysis of the vaginal microbiome by non-sequencing-based methods, Current Opinion in Microbiology, Vol: 73, Pages: 1-11, ISSN: 1369-5274

Over the last two decades, sequencing-based methods have revolutionised our understanding of niche-specific microbial complexity. In the lower female reproductive tract, these approaches have enabled identification of bacterial compositional structures associated with health and disease. Application of metagenomics and metatranscriptomics strategies have provided insight into the putative function of these communities but it is increasingly clear that direct measures of microbial and host cell function are required to understand the contribution of microbe–host interactions to pathophysiology. Here we explore and discuss current methods and approaches, many of which rely upon mass-spectrometry, being used to capture functional insight into the vaginal mucosal interface. In addition to improving mechanistic understanding, these methods offer innovative solutions for the development of diagnostic and therapeutic strategies designed to improve women’s health.

Journal article

Payne T, Appleby M, Buckley E, van Gelder LMA, Mullish BH, Sassani M, Dunning MJ, Hernandez D, Scholz S, McNeil A, Libri V, Moll S, Marchesi JR, Taylor R, Su L, Mazzà C, Jenkins TM, Foltynie T, Bandmann Oet al., 2023, A double-blind, randomized, placebo-controlled trial of ursodeoxycholic Acid (UDCA) in Parkinson's disease, Movement Disorders, Vol: 38, Pages: 1493-1502, ISSN: 0885-3185

Background:Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD.Objectives:To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement.Methods:The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment.Results:UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups.Conclusions:High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD.

Journal article

Verhasselt HL, Ramakrishnan E, Schlag M, Marchesi JR, Buer J, Kleinschnitz C, Hagenacker T, Totzeck Aet al., 2023, Fungal gut microbiome in myasthenia gravis: a sub-analysis of the MYBIOM study, Journal of Fungi, Vol: 9, Pages: 1-8, ISSN: 2309-608X

An altered gut microbiota is a possible contributing pathogenic factor in myasthenia gravis (MG), an autoimmune neuromuscular disease. However, the significance of the fungal microbiome is an understudied and neglected part of the intestinal microbiome in MG. We performed a sub-analysis of the MYBIOM study including faecal samples from patients with MG (n = 41), non-inflammatory neurological disorder (NIND, n = 18), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 6) and healthy volunteers (n = 12) by sequencing the internal transcribed spacer 2 (ITS2). Fungal reads were obtained in 51 out of 77 samples. No differences were found in alpha-diversity indices computed between the MG, NIND, CIDP and HV groups, indicating an unaltered fungal diversity and structure. Overall, four mould species (Penicillium aurantiogriseum, Mycosphaerella tassiana, Cladosporium ramonetellum and Alternaria betae-kenyensis) and five yeast species (Candida. albicans, Candida. sake, Candida. dubliniensis, Pichia deserticola and Kregervanrija delftensis) were identified. Besides one MG patient with abundant Ca. albicans, no prominent dysbiosis in the MG group of the mycobiome was found. Not all fungal sequences within all groups were successfully assigned, so further sub-analysis was withdrawn, limiting robust conclusions.

Journal article

Short C-E, 2023, Comparative analysis of vaginal microbiota sampling using menstrual cups and high vaginal swabs in pregnant women living with HIV-1 infection, Frontiers in Cellular and Infection Microbiology, Vol: 13, ISSN: 2235-2988

Background: Menstrual cups (MCs) are increasingly used to collect cervicovaginal secretions to characterise vaginal mucosal immunology, in conjunction with high vaginal swabs (HVS) for metataxonomics, particularly in HIV transmission studies. We hypothesised that both methods of collecting bacterial biomass are equivalent for 16S rRNA gene sequencing.Material and Methods: Cervicovaginal fluid (CVF) samples from 16 pregnant women with HIV-1 (PWWH) were included to represent the major vaginal bacterial community state types (CST I-V). Women underwent sampling during the second trimester by liquid amies HVS followed by a MC (Soft disc™) and samples were stored at -80°C. Bacterial cell pellets obtained from swab elution and MC (500 µL, 1 in 10 dilution) were resuspended in 120 µL PBS for DNA extraction. Bacterial 16S rRNA gene sequencing was performed using V1-V2 primers and were analysed using MOTHUR. Paired total DNA, bacterial load, amplicon read counts, diversity matrices and bacterial taxa were compared by sampling method using MicrobiomeAnalyst, SPSS and R.Results: The total DNA eluted from one aliquot of diluted CVF from an MC was similar to that of a HVS (993ng and 609ng, p=0.18); the mean bacterial loads were also comparable for both methods (MC: 8.0 log10 16S rRNA gene copies versus HVS: 7.9 log10 16S rRNA gene copies, p=0.27). The mean number of sequence reads generated from MC samples was lower than from HVS (MC: 12730; HVS:14830, p=0.05). The α-diversity metrices were similar for both techniques; MC Species Observed: 41 (range 12-96) versus HVS: 47 (range 16-96), p=0.15; MC Inverse Simpson Index: 1.98 (range 1.0-4.0) versus HVS: 0.48 (range 1.0-4.4), p=0.22). The three most abundant species observed were: Lactobacillus iners, Lactobacillus crispatus and Gardnerella vaginalis. Hierarchical clustering of relative abundance data showed that samples obtained using different techniques in an individual clustered in the same CST group.

Journal article

Alexander J, Posma J, Scott A, Poynter L, Mason S, Herendi L, Roberts L, McDonald J, Cameron S, Darzi A, Goldin R, Takats Z, Marchesi J, Teare J, Kinross Jet al., 2023, Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer, Microbiome, Vol: 11, Pages: 1-14, ISSN: 2049-2618

Background and aimsThe gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes.MethodsA multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months.ResultsThirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10−11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR&

Journal article

Michael DR, Kerry-Smith J, Webberley TS, Murphy KR, Plummer SF, Parry L, Marchesi JRet al., 2023, Does flow culture impact upon gut-probiotic interactions: A comparison with static culture, JOURNAL OF FUNCTIONAL FOODS, Vol: 104, ISSN: 1756-4646

Journal article

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