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Journal articleHvas CL, Keller J, Baunwall SMD, et al., 2023,
European academic faecal microbiota transplantation (EURFMT) network: improving the safety and quality of microbiome therapies in Europe
, Microbiota in Health and Disease, Vol: 5, ISSN: 2704-8845Faecal microbiota transplantation (FMT) has evolved from an anecdotally reported last resort for the critically ill to a well-established first-line treatment for patients with recurrent Clostridioides difficile infection (CDI), supported by grade 1a evidence. Given our improved understanding of the intestinal microbiota and how it impacts human health, FMT is now being explored for a range of emerging indications beyond CDI. In light of the rapid emergence of FMT as a novel treatment strategy in medicine, a need for international harmonisation has arisen. Addressing this need, the recently published 5th edition of the Guide to the quality and safety of tissues and cells for human application, issued by the European Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM), harbours complete descriptions of the collection, procurement and application of donor faeces as a substance of human origin (SoHO). The proposed revision of the Blood Tissue and Cell Regulation of the European Union (EU) incorporates stool for FMT as a SoHO. This revised regulation will provide a regulatory framework for the future development of donor-derived microbiome therapies. To implement and underpin the safety and quality requirements for FMT in this newly designed legal context, and to facilitate clinical use, collaboration and research, we established the European Academic FMT Network (EurFMT network). The European FMT Registry plays a pivotal role within this network, facilitating its clinical activities and monitoring safety. In this document, we summarise the basis for using donor faeces-derived microbiome therapies as well as the aim and main scope for the EurFMT network.
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Journal articleKragsnaes MS, Miguens Blanco J, Mullish BH, et 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: 2578-5745ObjectiveWe 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.
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Journal articleYip AYG, King OG, Omelchenko O, et 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: 2041-1723The 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.
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Journal articleRouty B, Lenehan JG, Miller WH, et al., 2023,
Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
, Nature Medicine, ISSN: 1546-170XFecal 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.
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Journal articleChurchward MA, Michaud ER, Mullish BH, et 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: 2405-8440The 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.
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Conference paperSkov Kragsnaes M, Miguens Blanco J, Mullish B, et 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 paperHabboub N, Mullish BH, Moore C, et al., 2023,
Investigating the correlation of a poly-metabolic risk score to clinical features in non-alcoholic fatty liver disease patients throughout a faecal microbiota transplant clinical trial
, Publisher: ELSEVIER, Pages: S344-S345, ISSN: 0168-8278 -
Conference paperEdwards LA, Woodhouse C, Lee S, et 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 paperForlano R, Martinez-Gili L, Blanco JM, et 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 paperMullish BH, Danckert NP, Patel R, et al., 2023,
Tu1866 SALIVARY MICROBIOTA COMPOSITION IS ASSOCIATED WITH ANTIBODY RESPONSE FOLLOWING COVID-19 VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE, CIRRHOSIS AND LIVER TRANSPLANTATION
, Publisher: Elsevier BV, ISSN: 0016-5085
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