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Journal articleRadhakrishnan ST, Alexander JL, Mullish BH, et al., 2022,
Systematic review: the association between the gut microbiota and medical therapies in inflammatory bowel disease
, Alimentary Pharmacology & Therapeutics, Vol: 55, Pages: 26-48, ISSN: 0269-2813<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The gut microbiota has been implicated in the pathogenesis of inflammatory bowel disease (IBD), with <jats:italic>Faecalibacterium prausnitizii</jats:italic> associated with protection, and certain genera (including <jats:italic>Shigella</jats:italic> and <jats:italic>Escherichia</jats:italic>) 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.</jats:p></jats:sec><jats:sec><jats:title>Aims</jats:title><jats:p>To evaluate the bidirectional relationship between IBD medical therapies and the gut microbiota.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We conducted a systematic search of MEDLINE and EMBASE. All original studies analysing interactions between the gut microbiota and established IBD medical therapies were included.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We 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 <jats:italic>Faecalibacterium</jats:italic> predicted response to infliximab and ustekinumab. A post‐treatment increase in <jats:italic>Faecalibacterium prausnitzii</jats:italic> was noted in responders to aminosalicylates, anti‐TNF medications and ustekinumab; conversely, this speci
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Journal articleForslund SK, Chakaroun R, Zimmermann-Kogadeeva M, et al., 2021,
Combinatorial, additive and dose-dependent drug-microbiome associations
, Nature, Vol: 600, Pages: 500-505, ISSN: 0028-0836During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1,2,3,4,5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
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Journal articleBiliński J, Jasiński M, Tomaszewska A, et al., 2021,
Fecal microbiota transplantation with ruxolitinib as a treatment modality for steroid‐refractory/dependent acute, gastrointestinal graft‐versus‐host disease: A case series
, American Journal of Hematology, Vol: 96, ISSN: 0361-8609 -
Journal articleMonaghan TM, Duggal NA, Rosati E, et al., 2021,
A multi-factorial observational study on sequential fecal microbiota transplant in patients with medically refractory Clostridioides difficile infection
, Cells, Vol: 10, ISSN: 2073-4409Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI); increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies.
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Journal articleTarazi M, Jamel S, Mullish BH, et al., 2021,
Impact of gastrointestinal surgery upon the gut microbiome: a systematic review
, Surgery, Vol: 171, ISSN: 0039-6060BackgroundThere is evidence from preclinical models that the gut microbiome may impact outcomes from gastrointestinal surgery, and that surgery may alter the gut microbiome. However, the extent to which gastrointestinal surgery modulates the gut microbiome in clinical practice is currently poorly defined. This systematic review aims to evaluate the changes observed in the gut microbiome after gastrointestinal surgery.MethodsA systematic review and meta-analysis were conducted according to the PRISMA guidelines by screening EMBASE, MEDLINE/PubMed, Web of Science, and CENTRAL for comparative studies meeting the predetermined inclusion criteria. The primary outcome was the difference between pre and postoperative bacterial taxonomic composition and diversity metrics among patients receiving gastrointestinal surgery.ResultsIn total, 33 studies were identified including 6 randomized controlled trials and 27 prospective cohort studies reporting a total of 968 patients. Gastrointestinal surgery was associated with an increase in α diversity and a shift in β diversity postoperatively. Multiple bacterial taxa were identified to consistently trend toward an increase or decrease postoperatively. A difference in microbiota across geographic provenance was also observed. There was a distinct lack of studies showing correlation with clinical outcomes or performing microbiome functional analysis. Furthermore, there was a lack of standardization in sampling, analytical methodology, and reporting.ConclusionThis review highlights changes in bacterial taxa associated with gastrointestinal surgery. There is a need for standardization of microbial analysis methods and reporting of results to allow interstudy comparison. Further adequately powered multicenter studies are required to better assess variation in microbial changes and its potential associations with clinical outcomes.
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Journal articleNalpas N, Hoyles L, Anselm V, et al., 2021,
An integrated workflow for enhanced taxonomic and functional coverage of the mouse fecal metaproteome.
, Gut Microbes, Vol: 13, Pages: 1-23, ISSN: 1949-0976Intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behavior. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of fecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of taxa. Furthermore, there is a lack of consensus regarding preparation of fecal samples, as well as downstream bioinformatic analyses following metaproteomics data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse feces in a typical mass spectrometry-based metaproteomic experiment. We show that subtle changes in sample preparation protocols may influence interpretation of biological findings. Two-step database search strategies led to significant underestimation of false positive protein identifications. Unipept software provided the highest sensitivity and specificity in taxonomic annotation of the identified peptides of unknown origin. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.
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Journal articleMonaghan TM, Seekatz AM, Mullish BH, et al., 2021,
Clostridioides difficile: innovations in target discovery and potential for therapeutic success.
, Expert Opin Ther Targets, Vol: 25, Pages: 949-963INTRODUCTION: Clostridioides difficile infection (CDI) remains a worldwide clinical problem. Increased incidence of primary infection, occurrence of hypertoxigenic ribotypes, and more frequent occurrence of drug resistant, recurrent, and non-hospital CDI, emphasizes the urgent unmet need of discovering new therapeutic targets. AREAS COVERED: We searched PubMed and Web of Science databases for articles identifying novel therapeutic targets or treatments for C. difficile from 2001 to 2021. We present an updated review on current preclinical efforts on designing inhibitory compounds against these drug targets and indicate how these could become the focus of future therapeutic approaches. We also evaluate the increasing exploitability of gut microbial-derived metabolites and host-derived therapeutics targeting VEGF-A, immune targets and pathways, ion transporters, and microRNAs as anti-C. difficile therapeutics, which have yet to reach clinical trials. Our review also highlights the therapeutic potential of re-purposing currently available agents . We conclude by considering translational hurdles and possible strategies to mitigate these problems. EXPERT OPINION: Considerable progress has been made in the development of new anti-CDI drug candidates. Nevertheless, a greater comprehension of CDI pathogenesis and host-microbe interactions is beginning to uncover potential novel therapeutic targets, which can be exploited to plug gaps in the CDI drug discovery pipeline.
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Journal articleLythgoe MP, Ghani R, Mullish BH, et al., 2021,
The Potential of Faecal Microbiota Transplantation in Oncology
, Trends in Microbiology, ISSN: 0966-842X -
Journal articleBaunwall SMD, Terveer EM, Dahlerup JF, et al., 2021,
The use of Faecal Microbiota Transplantation (FMT) in Europe: A Europe-wide survey
, The Lancet Regional Health - Europe, Vol: 9, Pages: 100181-100181, ISSN: 2666-7762 -
Journal articleInnes AJ, Mullish BH, Ghani R, et al., 2021,
Fecal Microbiota Transplant Mitigates Adverse Outcomes Seen in Patients Colonized With Multidrug-Resistant Organisms Undergoing Allogeneic Hematopoietic Cell Transplantation
, Frontiers in Cellular and Infection Microbiology, Vol: 11<jats:p>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. We performed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy for MDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDRO group), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival was significantly higher in the FMT-MDRO group (70% <jats:italic>versus</jats:italic> 36% <jats:italic>p</jats:italic> = 0.044). Post-HCT, fewer FMT-MDRO patients required intensive care (0% <jats:italic>versus</jats:italic> 46%, <jats:italic>P</jats:italic> = 0.045) or experienced fever (0.29 <jats:italic>versus</jats:italic> 0.11 days, <jats:italic>P</jats:italic> = 0.027). Intestinal MDRO decolonization occurred in 25% of FMT-MDRO patients <jats:italic>versus</jats:italic> 11% non-FMT MDRO patients. Despite the significant differences and statistically comparable patient/transplant characteristics, as the sample size was small, a matched-pair analysis between both groups 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% <jats:italic>versus</jats:italic> 61.9% respectively, <jats:italic>p</jats:italic>=0.012), and higher non relapse mortality (NRM; 60.2% <jats:italic>versus</jats:italic> 16.7% respectively, <jats:italic>p</jats:italic>=0.009) than their paired non-MDRO-colonized cohort. Conversely, there was no difference in survival (70% <jats:italic>versus</jats:italic> 43.4%, <jats:ita
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