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Journal articleForlano R, Martinez-Gili L, Takis P, et al., 2024,
Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus.
, Gut Microbes, Vol: 16Aberration 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.
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Journal articleGhani R, Chrysostomou D, Roberts LA, et al., 2024,
Faecal (or intestinal) microbiota transplant: a tool for repairing the gut microbiome.
, Gut Microbes, Vol: 16Faecal/intestinal microbiota transplant (FMT/IMT) is an efficacious treatment option for recurrent Clostridioides difficile infection, which has prompted substantial interest in FMT's potential role in the management of a much broader range of diseases associated with the gut microbiome. Despite its promise, the success rates of FMT in these other settings have been variable. This review critically evaluates the current evidence on the impact of clinical, biological, and procedural factors upon the therapeutic efficacy of FMT, and identifies areas that remain nebulous. Due to some of these factors, the optimal therapeutic approach remains unclear; for example, the preferred timing of FMT administration in a heavily antibiotic-exposed hematopoietic cell transplant recipient is not standardized, with arguments that can be made in alternate directions. We explore how these factors may impact upon more informed selection of donors, potential matching of donors to recipients, and aspects of clinical care of FMT recipients. This includes consideration of how gut microbiome composition and functionality may strategically inform donor selection criteria. Furthermore, we review how the most productive advances within the FMT space are those where clinical and translational outcomes are assessed together, and where this model has been used productively in recent years to better understand the contribution of the gut microbiome to human disease, and start the process toward development of more targeted microbiome therapeutics.
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Journal articleBibbò S, Porcari S, Del Vecchio LE, et al., 2023,
Gut microbiota and immunotherapy of renal cell carcinoma
, Human Vaccines & Immunotherapeutics, Vol: 19, ISSN: 2164-5515 -
Journal articleMullish BH, Tohumcu E, Porcari S, et al., 2023,
The role of faecal microbiota transplantation in chronic noncommunicable disorders
, Journal of Autoimmunity, Vol: 141, Pages: 103034-103034, ISSN: 0896-8411 -
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 <i>Enterobacteriaceae</i> by enriching nutrients and depleting microbial metabolites
, NATURE COMMUNICATIONS, Vol: 14- Cite
- Citations: 39
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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, Vol: 29, Pages: 2121-2132, ISSN: 1078-8956Fecal 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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Conference paperForlano R, Martinez-Gili L, Blanco JM, et al., 2023,
TOP-088 - Altered gut barrier integrity as a mediator of host-microbiome interactions in diabetic patients with advanced Non-alcoholic fatty liver disease
, EASL Congress 2023, Publisher: Elsevier, Pages: S601-S602, ISSN: 0168-8278 -
Conference paperKragsnaes MS, Blanco JM, Mullish B, et al., 2023,
PLASMA METABOLOMIC PROFILES OF PATIENTS WITH ACTIVE PERIPHERAL PSORIATIC ARTHRITIS CAN DIFFERENTIATE TREATMENT RESPONDERS FROM FAILURES: EXPLORATORY FINDINGS FROM THE FLORA TRIAL
, European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 467-468, ISSN: 0003-4967
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