Publications

Journal article

Talmor-Barkan Y, Bar N, Shaul AA, Shahaf N, Godneva A, Bussi Y, Lotan-Pompan M, Weinberger A, Shechter A, Chezar-Azerrad C, Arow Z, Hammer Y, Chechi K, Forslund SK, Fromentin S, Dumas M-E, Ehrlich SD, Pedersen O, Kornowski R, Segal Eet al., 2022,

Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease

, NATURE MEDICINE, Vol: 28, Pages: 295-+, ISSN: 1078-8956

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Citations: 40

Journal article

Forlano R, Mullish BH, Roberts LA, Thursz MR, Manousou Pet al., 2022,

The intestinal barrier and its dysfunction in patients with metabolic diseases and non-alcoholic fatty liver disease

, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067

Non-alcoholic fatty liver disease (NAFLD) represents an increasing cause of liver disease worldwide, mirroring the epidemics of obesity and metabolic syndrome. As there are still no licensed medications for treating the disease, there is an ongoing effort to elucidate the pathophysiology and to discover new treatment pathways. An increasing body of evidence has demonstrated a crosstalk between the gut and the liver, which plays a crucial role in the development and progression of liver disease. Among other intestinal factors, gut permeability represents an interesting factor at the interface of the gut–liver axis. In this narrative review, we summarise the evidence from human studies showing the association between increased gut permeability and NAFLD, as well as with type-2 diabetes and obesity. We also discuss the manipulation of the gut permeability as a potential therapeutical target in patients with NAFLD.

Journal article

Biliński J, Winter K, Jasiński M, Szczęś A, Bilinska N, Mullish BH, Małecka-Panas E, Basak GWet al., 2022,

Rapid resolution of COVID-19 after faecal microbiota transplantation.

, Gut, Vol: 71, Pages: 230-232

Journal article

Radhakrishnan ST, Alexander JL, Mullish BH, Gallagher KI, Powell N, Hicks LC, Hart AL, Li JV, Marchesi JR, Williams HRTet 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

Journal article

Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, Marko L, Aron-Wisnewsky J, Nielsen T, Moitinho-Silva L, Schmidt TSB, Falony G, Vieira-Silva S, Adriouch S, Alves RJ, Assmann K, Bastard J-P, Birkner T, Caesar R, Chilloux J, Coelho LP, Fezeu L, Galleron N, Helft G, Isnard R, Ji B, Kuhn M, Le Chatelier E, Myridakis A, Olsson L, Pons N, Prifti E, Quinquis B, Roume H, Salem J-E, Sokolovska N, Tremaroli V, Valles-Colomer M, Lewinter C, Sondertoft NB, Pedersen HK, Hansen TH, Gotze JP, Kober L, Vestergaard H, Hansen T, Zucker J-D, Hercberg S, Oppert J-M, Letunic I, Nielsen J, Backhed F, Ehrlich SD, Dumas M-E, Raes J, Pedersen O, Clement K, Stumvoll M, Bork Pet al., 2021,

Combinatorial, additive and dose-dependent drug-microbiome associations

, Nature, Vol: 600, Pages: 500-505, ISSN: 0028-0836

During 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.

Journal article

Biliński J, Jasiński M, Tomaszewska A, Lis K, Kacprzyk P, Chmielewska L, KarakulskaPrystupiuk E, Mullish BH, Basak GWet 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 article

Monaghan TM, Duggal NA, Rosati E, Griffin R, Hughes J, Roach B, Yang DY, Wang C, Wong K, Saxinger L, Pučić-Baković M, Vučković F, Klicek F, Lauc G, Tighe P, Mullish BH, Miguens Blanco J, McDonald JAK, Marchesi JR, Xue N, Dottorini T, Acharjee A, Franke A, Wong GK-S, Polytarchou C, Yau TO, Christodoulou N, Hatziapostoulou M, Wang M, Russell LA, Kao DHet al., 2021,

A multi-factorial observational study on sequential fecal microbiota transplant in patients with medically refractory Clostridioides difficile infection

, Cells, Vol: 10, ISSN: 2073-4409

Fecal 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.

Journal article

Tarazi M, Jamel S, Mullish BH, Markar SR, Hanna GBet al., 2021,

Impact of gastrointestinal surgery upon the gut microbiome: a systematic review

, Surgery, Vol: 171, ISSN: 0039-6060

BackgroundThere 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.

Journal article

Nalpas N, Hoyles L, Anselm V, Ganief T, Martinez-Gili L, Grau C, Droste-Borel I, Davidovic L, Altafaj X, Dumas M-E, Macek Bet al., 2021,

An integrated workflow for enhanced taxonomic and functional coverage of the mouse fecal metaproteome.

, Gut Microbes, Vol: 13, Pages: 1-23, ISSN: 1949-0976

Intestinal 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.

Journal article

Monaghan TM, Seekatz AM, Mullish BH, Moore-Gillon CCER, Dawson LF, Ahmed A, Kao D, Chan WCet al., 2021,

Clostridioides difficile: innovations in target discovery and potential for therapeutic success.

, Expert Opin Ther Targets, Vol: 25, Pages: 949-963

INTRODUCTION: 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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