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  • 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
    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
    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.

  • 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
    Habboub N, Mullish BH, Moore C, Lanoria M, Challis B, Forlano R, Thursz M, Dumas M-E, Manousou Pet 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 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
    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
    Mullish BH, Danckert NP, Patel R, Irwin SL, Dimitriadis S, Murray SM, Forlano R, Roberts L, Blanco JM, Faustini S, Richter AG, Powell N, Thursz MR, Manousou P, Barnes E, Marchesi J, Marjot T, Alexander JLet 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
  • Journal article
    Mullish BH, Michael DR, Webberley TS, John D, Ramanathan G, Plummer SF, Wang D, Marchesi JRet al., 2023,

    The gastrointestinal status of healthy adults: a post hoc assessment of the impact of three distinct probiotics.

    , Benef Microbes, Pages: 1-14

    There is a growing awareness that supplementation with probiotic bacteria can impart beneficial effects during gastrointestinal disease, but less is known about the impact of probiotics on healthy subjects. Here, we report the outcomes of a post hoc analysis of recorded daily gastrointestinal events and bowel habits completed by healthy adults participating in a placebo-controlled, single-centre, randomised, double-blind, quadruple-arm probiotic tolerability study. Extensive screening ensured the healthy status of subjects entering the study and during a 2-week pre-intervention run-in period, a burden of gastrointestinal events (stomach pains, indigestion, acid reflux, stomach tightening, nausea and vomiting, stomach rumbling, bloating, belching and flatulence) was identified suggesting GI discomfort within the population. In the subsequent 12-week intervention period with 3 distinct probiotic formulations and a matched-placebo, reductions in the incidence rates of bloating, borborygmus, stomach pains, slow faecal transit and incomplete defecations were observed in the probiotic groups compared to the placebo. These results highlighted differing responses among the probiotic formulations tested and indicated potential anti-constipation effects. Product specific modulations in circulating interleukin-6 levels and in the composition of the gut microbiota were also detected. Together, these data suggest a role for probiotic supplementation to exert beneficial effects on the gastrointestinal functioning of healthy subjects and highlight the need for further longer-term studies in healthy populations to gain a greater understanding of the impact of probiotics.

  • Journal article
    Alexander JL, Mullish BH, Danckert NP, Liu Z, Olbei ML, Saifuddin A, Tokizadeh M, Ibraheim H, Miguens Blanco J, Roberts LA, Bewshea CM, Nice R, Lin S, Prabhudev H, Sands C, Horneffer van der Sluis V, Lewis M, Sebastian S, Lees CW, Teare JP, Hart A, Goodhand J, Kennedy NA, Korcsmaros T, Marchesi JR, Ahmad T, Powell Net al., 2023,

    The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients

    , EBioMedicine, Vol: 88, ISSN: 2352-3964

    Background:Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients.Methods:Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination.Findings:Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithoc

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