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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, 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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Journal articleAllegretti JR, Kelly CR, Grinspan A, et al., 2021,
Inflammatory Bowel Disease Outcomes Following Fecal Microbiota Transplantation for Recurrent <i>C. difficile</i> Infection
, Inflammatory Bowel Diseases, Vol: 27, Pages: 1371-1378, ISSN: 1078-0998<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Recurrent Clostridioides difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is a clinical challenge. Fecal microbiota transplantation (FMT) has emerged as a recurrent CDI therapy. Anecdotal concerns exist regarding worsening of IBD activity; however, prospective data among IBD patients are limited.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Secondary analysis from an open-label, prospective, multicenter cohort study among IBD patients with 2 or more CDI episodes was performed. Participants underwent a single FMT by colonoscopy (250 mL, healthy universal donor). Secondary IBD-related outcomes included rate of de novo IBD flares, worsening IBD, and IBD improvement—all based on Mayo or Harvey-Bradshaw index (HBI) scores. Stool samples were collected for microbiome and targeted metabolomic profiling.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Fifty patients enrolled in the study, among which 15 had Crohn’s disease (mean HBI, 5.8 ± 3.4) and 35 had ulcerative colitis (mean partial Mayo score, 4.2 ± 2.1). Overall, 49 patients received treatment. Among the Crohn’s disease cohort, 73.3% (11 of 15) had IBD improvement, and 4 (26.6%) had no disease activity change. Among the ulcerative colitis cohort, 62% (22 of 34) had IBD improvement, 29.4% (11 of 34) had no change, and 4% (1 of 34) experienced a de novo flare. Alpha diversity significantly increased post-FMT, and ulcerative colitis patients became more similar to the donor than Crohn’s disease patients (P = 0.04).</jats:p>
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Journal articleMonaghan TM, Biswas RN, Nashine RR, et al., 2021,
Multiomics profiling reveals signatures of dysmetabolism in urban populations in central India
, Microorganisms, Vol: 9, Pages: 1-21, ISSN: 2076-2607Background: Non-communicable diseases (NCDs) have become a major cause of morbidity and mortality in India. Perturbation of host–microbiome interactions may be a key mechanism by which lifestyle-related risk factors such as tobacco use, alcohol consumption, and physical inactivity may influence metabolic health. There is an urgent need to identify relevant dysmetabolic traits for predicting risk of metabolic disorders, such as diabetes, among susceptible Asian Indians where NCDs are a growing epidemic. Methods: Here, we report the first in-depth phenotypic study in which we prospectively enrolled 218 adults from urban and rural areas of Central India and used multiomic profiling to identify relationships between microbial taxa and circulating biomarkers of cardiometabolic risk. Assays included fecal microbiota analysis by 16S ribosomal RNA gene amplicon sequencing, quantification of serum short chain fatty acids by gas chromatography-mass spectrometry, and multiplex assaying of serum diabetic proteins, cytokines, chemokines, and multi-isotype antibodies. Sera was also analysed for N-glycans and immunoglobulin G Fc N-glycopeptides. Results: Multiple hallmarks of dysmetabolism were identified in urbanites and young overweight adults, the majority of whom did not have a known diagnosis of diabetes. Association analyses revealed several host–microbe and metabolic associations. Conclusions: Host–microbe and metabolic interactions are differentially shaped by body weight and geographic status in Central Indians. Further exploration of these links may help create a molecular-level map for estimating risk of developing metabolic disorders and designing early interventions.
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