Publications
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Allegretti JR, Kassam Z, Hurtado J, et al., 2020, Tu1909 IMPACT OF FECAL MICROBIOTA TRANSPLANTATION ON PREVENTION OF METABOLIC SYNDROME AMONG PATIENTS WITH OBESITY, Gastroenterology, Vol: 158, ISSN: 0016-5085
Monaghan T, Russell L, Rosati E, et al., 2020, Mo1939 TEMPORAL MODULATION OF TCR REPERTOIRE FOLLOWING SEQUENTIAL FMT TREATMENT IN PATIENTS WITH SEVERE OR FULMINANT CLOSTRIDIOIDES DIFFICILE INFECTION, Gastroenterology, Vol: 158, ISSN: 0016-5085
Blanco JM, Liu Z, Selvarajah U, et al., 2020, Sa1923 IDENTIFICATION OF NEW ASSOCIATIONS BETWEEN PSORIATIC ARTHRITIS AND THE GUT MICROBIOTA, A PHENOMIC STUDY, Gastroenterology, Vol: 158, Pages: S-481, ISSN: 0016-5085
Ianiro G, Mullish BH, Kelly CR, et al., 2020, Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel, The Lancet Gastroenterology & Hepatology, Vol: 5, Pages: 430-432, ISSN: 2468-1253
Smith PJ, 2020, GI highlights from the literature, Gut, Vol: 69, Pages: 963-964, ISSN: 0017-5749
Allegretti JR, Kassam Z, Mullish BH, et al., 2020, Effects of fecal microbiota transplantation with oral capsules in obese patients, Clinical Gastroenterology and Hepatology, Vol: 18, Pages: 855-863.e2, ISSN: 1542-3565
Background & AimsStudies in mice have shown that the intestinal microbiota can contribute to obesity via the anorexigenic gut hormone glucagon-like peptide 1 (GLP1) and bile acids, which affect lipid metabolism. We performed a randomized, placebo-controlled pilot study of the effects of fecal microbiota transplantation (FMT) in obese, metabolically uncompromised patients.MethodsWe performed a double-blind study of 22 obese patients (body mass index [BMI] ≥ 35kg/m2) without a diagnosis of diabetes, non-alcoholic steatohepatitis, or metabolic syndrome. Participants were randomly assigned (1:1) to groups that received FMT by capsules (induction dose of 30 capsules at week 4 and maintenance dose of 12 capsules at week 8) or placebo capsules. FMT capsules were derived from a single, lean donor (BMI, 17.5 kg/m2). Patients were followed through week 26; the primary outcome was safety. Stool and serum samples were collected from patients at baseline and at weeks 1, 4, 6, 8 and 12 after administration of the first dose of FMT or placebo and analyzed by 16S RNA gene sequencing. Stool and serum samples were analyzed for metabolomics by liquid chromatography-mass spectrometry. Additional outcomes were change in area under the curve for GLP1 at week 12.ResultsWe observed no significant differences in adverse events between patients who received FMT vs placebo. There was no increase in the area under the curve of GLP1 in either group. Patients who received FMT had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001). Patients who received FMT had a sustained decrease in stool levels of taurocholic acid (P<.05), compared with baseline; bile acid profiles began to more closely resemble those of the donor. We did not observe significant changes in mean BMI at week 12 in either group.ConclusionsIn a placebo-controlled pilot study, we found that FMT capsules (derived from a lean donor) were safe but did not reduce BMI in obese metabol
Smith PJ, 2020, GI highlights from the literature, Gut, Vol: 69, Pages: 781-782, ISSN: 0017-5749
Michael DR, Jack AA, Masetti G, et al., 2020, A randomised controlled study shows supplementation of overweight and obese adults with lactobacilli and bifidobacteria reduces bodyweight and improves well-being, Scientific Reports, Vol: 10
<jats:title>Abstract</jats:title><jats:p>In an exploratory, block-randomised, parallel, double-blind, single-centre, placebo-controlled superiority study (ISRCTN12562026, funded by Cultech Ltd), 220 Bulgarian participants (30 to 65 years old) with BMI 25–34.9 kg/m<jats:sup>2</jats:sup> received Lab4P probiotic (50 billion/day) or a matched placebo for 6 months. Participants maintained their normal diet and lifestyle. Primary outcomes were changes in body weight, BMI, waist circumference (WC), waist-to-height ratio (WtHR), blood pressure and plasma lipids. Secondary outcomes were changes in plasma C-reactive protein (CRP), the diversity of the faecal microbiota, quality of life (QoL) assessments and the incidence of upper respiratory tract infection (URTI). Significant between group decreases in body weight (1.3 kg, <jats:italic>p</jats:italic> < 0.0001), BMI (0.045 kg/m<jats:sup>2</jats:sup>, <jats:italic>p</jats:italic> < 0.0001), WC (0.94 cm, <jats:italic>p</jats:italic> < 0.0001) and WtHR (0.006, <jats:italic>p</jats:italic> < 0.0001) were in favour of the probiotic. Stratification identified greater body weight reductions in overweight subjects (1.88%, <jats:italic>p</jats:italic> < 0.0001) and in females (1.62%, <jats:italic>p</jats:italic> = 0.0005). Greatest weight losses were among probiotic hypercholesterolaemic participants (−2.5%, <jats:italic>p</jats:italic> < 0.0001) alongside a significant between group reduction in small dense LDL-cholesterol (0.2 mmol/L, <jats:italic>p</jats:italic> = 0.0241). Improvements in QoL and the incidence rate ratio of URTI (0.60, <jats:italic>p</jats:italic> <&thins
Ovadia C, Perdones-Montero A, Fan HM, et al., 2020, Ursodeoxycholic acid enriches intestinal bile salt hydrolase-expressing Bacteroidetes in cholestatic pregnancy, Scientific Reports, Vol: 10
<jats:title>Abstract</jats:title><jats:p>Ursodeoxycholic acid (UDCA) treatment can reduce itch and lower endogenous serum bile acids in intrahepatic cholestasis of pregnancy (ICP). We sought to determine how it could influence the gut environment in ICP to alter enterohepatic signalling. The gut microbiota and bile acid content were determined in faeces from 35 pregnant women (14 with uncomplicated pregnancies and 21 with ICP, 17 receiving UDCA). Faecal bile salt hydrolase activity was measured using a precipitation assay. Serum fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) concentrations were measured following a standardised diet for 21 hours. Women with a high ratio of<jats:italic>Bacteroidetes</jats:italic>to<jats:italic>Firmicutes</jats:italic>were more likely to be treated with UDCA (Fisher’s exact test p = 0.0178) than those with a lower ratio. Bile salt hydrolase activity was reduced in women with low<jats:italic>Bacteroidetes</jats:italic>:<jats:italic>Firmicutes</jats:italic>. Women taking UDCA had higher faecal lithocholic acid (p < 0.0001), with more unconjugated bile acids than women with untreated ICP or uncomplicated pregnancy. UDCA-treatment increased serum FGF19, and reduced C4 (reflecting lower bile acid synthesis). During ICP, UDCA treatment can be associated with enrichment of the gut microbiota with<jats:italic>Bacteroidetes</jats:italic>. These demonstrate high bile salt hydrolase activity, which deconjugates bile acids enabling secondary modification to FXR agonists, enhancing enterohepatic feedback via FGF19.</jats:p>
Ghani R, Mullish B, Thursz M, et al., 2020, Case-control study of recurrent Extended-Spectrum Beta Lactamase Enterobacteriaceae Urinary Tract Infections (ESBL UTIs): the management challenges, Access Microbiology, Vol: 2
<jats:p>Recurrent UTIs are associated with increased hospitalisation and antibiotic use. We investigated patients with recurrent ESBL versus non-ESBL UTIs to identify risk factors and potential treatments.</jats:p> <jats:p>A30 month retrospective case-control study was performed in patients with recurrent EBSL versus non-ESBL UTI. Definition :1) > three in a year (>two weeks apart) or 2) > two in six months (>one week apart) with the same profile. 3) ESBL UTIs were Enterobacteriaceae resistant to cefalexin AND ceftazadime/ceftriaxone.</jats:p> <jats:p>281/1449 “recurrent UTI” patients were ESBLs. Patients were more likely to be older, male, with associated bacteraemia, colonisation with carbapenemase-producing Enterobacteriaceae (CPE) and higher resistance rates to non beta-lactam antibiotics. 75% of renal patients were transplant cases, 81% of urology patients had a tube insertion.</jats:p> <jats:p>Recurrent ESBL UTIRecurrent non-ESBL UTIp value</jats:p> <jats:p>Number (%)Number (%)(Chi-squared test)</jats:p> <jats:p>Patients 281 1168</jats:p> <jats:p>Organism Klebsiella spp (%)42 (14.9) 10 (0.8) <0.001</jats:p> <jats:p>E coli (%)199 (70.8)811 (69.4)0.665</jats:p> <jats:p>Demographics Age (mean, SD)64.1, 19 58.7, 22 <0.001</jats:p> <jats:p>Male 137 (48.8)328 (28) <0.001</jats:p> <jats:p>Associations Gram negative bacteraemia 35 (12.4) 37 (3.1) 0.001</jats:p> <jats:p>Colonisation with CPE 21 (7.5) 31 (2.7) <0.001</jats:p> <jats:p>Speciality Renal 84 (30.0) 196 (16.8)<0.001</jats:p> <jats:p>Urology 47 (16.7) 104 (8.9) <0.001</jats
Ghani R, Mullish B, Mcdonald J, et al., 2020, Cohort study of Faecal Microbiota Transplantation for patient’s colonised with MDROs - successful prevention of invasive disease despite low decolonisation rates, Access Microbiology, Vol: 2
<jats:p>Faecal Microbiota Transplantation (FMT) is widely utilised for recurrent <jats:italic>Clostridioides difficile</jats:italic> infection. Use of FMT for the intestinal eradication of multidrug-resistant organisms (MDROs) has been described in the literature with decolonisation rates from 37.5% to 87.5%. We perform FMT via naso-gastric tube using donor stool prepared anaerobically, using prevention of invasive disease as an endpoint.</jats:p> <jats:p>FMT was considered for either; 1) Patients who were colonised with >1 MDRO (carbapenem-resistant Enterobacteriaceae, vancomycin resistant Enterococci or extended-spectrum beta lactamase (ESBL) and at risk of invasive MDRO disease or 2) patients who had recurrent MDRO-mediated invasive disease.</jats:p> <jats:p>Sixteen MDRO colonised/infected patients underwent FMT. Nine patients had a haematological disorder. Eight of these patients had had prolonged admissions (range 6-20 weeks) complicated by septic episodes (5/9 had a MDR bacteraemia) pre-FMT. Post FMT all patients had shorter admissions including five who received higher intensity immunosuppression. Only 1/9 developed MDRO-mediated invasive disease.</jats:p> <jats:p>Seven FMT patients had recurrent ESBL urinary tract infections (UTIs). 4/7 were renal transplant patients. Following FMT the 3 non-transplant patients had no further UTIs up to six month period. Four transplant patients had reduced number of infections, admissions and use of antibiotics.</jats:p> <jats:p>5/13 (39%) patients were not MDRO colonised on rectal screens post-FMT (follow up range 12 weeks – 24 months).</jats:p> <jats:p>Although decolonisation rates were low, patient outcomes post-FMT were apparently improved. Mechanisms of FMT have not fully been established, improvement of colonisation resistance by restoration of microbiota comp
Fessas P, Possamai LA, Clark J, et al., 2020, Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms., Immunology, Vol: 159, Pages: 167-177
Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.
Ghani R, Mullish BH, McDonald J, et al., 2020, Disease prevention not decolonisation: a cohort study for faecal microbiota transplantation for patients colonised with multidrug-resistant organisms, ECCMID 2020
Segal J, Mullish B, Clark S, et al., 2020, P844 Higher proportions of genera and species in the Firmicutes phylum are associated with a healthy pouch compared with patients with chronic pouchitis, Journal of Crohn's and Colitis, Vol: 14, Pages: S652-S652, ISSN: 1873-9946
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Studies highlighting changes in bacterial composition in the ileoanal pouch are limited by heterogeneity in analysis techniques and sampling strategies Therefore, caution must be used when interpreting microbiota data. Similar to findings in IBD, a decrease in bacterial diversity and ‘dysbiosis’ are associated with acute and chronic inflammation in the pouch. Changes in Clostridium spp. and E. coli are associated with inflamed pouches and treatment response. This study aimed to compare the bacterial microbiota composition in patients with chronic pouchitis who responded to antibiotics vs. those who did not.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Patients with confirmed chronic pouchitis defined by a pouch disease activity score ≥ 7 were treated with antibiotics. If patients were already on antibiotics, they were offered the opportunity to stop. Follow up was at 4 weeks to check clinical status. Patients who came off antibiotics who flared were given the opportunity to restart the antibiotics to prevent deterioration. Patients were analysed as either on antibiotics if they received antibiotics 2 weeks prior to the clinic or off antibiotics if they had stopped all antibiotics 2 weeks prior to follow-up. Stool was collected from patients on follow-up and DNA was extracted from this stool. Sequencing was performed on an Illumina platform. Statistical analysis was performed using STAMP 2.1.3 software with Welch’s two-sided t-test for comparing two groups with false discovery rate correction.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <j
Allegretti JR, Mullish BH, 2020, Faecal microbiota transplantations and urinary tract infections – Authors' reply, The Lancet, Vol: 395, Pages: 271-271, ISSN: 0140-6736
Segal JP, Mullish BH, Quraishi MN, et al., 2020, Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease, Therapeutic Advances in Gastroenterology, Vol: 13, Pages: 175628482094690-175628482094690, ISSN: 1756-2848
<jats:p>Faecal microbiota transplantation (FMT) is currently a recommended therapy for recurrent/refractory Clostridioides difficile infection (CDI). The success of FMT for CDI has led to interest in its therapeutic potential in many other disorders. The mechanisms that underpin the efficacy of FMT are not fully understood. Importantly, FMT remains a crucial treatment in managing CDI and understanding the mechanisms that underpin its success will be critical to improve its clinical efficacy, safety and usability. Furthermore, a deeper understanding of this may allow us to expose FMT’s full potential as a therapeutic tool for other disease states. This review will explore the current understanding of the mechanisms underlying the efficacy of FMT across a variety of diseases.</jats:p>
Segal JP, Mak JWY, Mullish BH, et al., 2020, The gut microbiome: an under-recognised contributor to the COVID-19 pandemic?, Therapeutic Advances in Gastroenterology, Vol: 13, Pages: 175628482097491-175628482097491, ISSN: 1756-2848
<jats:p> The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus has spread rapidly across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ influencing propensity to, and potentially severity of, COVID-19 infection. Furthermore, the gut microbiome has been linked to a variety of risk factors for COVID-19 infection, and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While data profiling the gut microbiome in COVID-19 infection to date are limited, they support the possibility of several routes of interaction between COVID-19, the gut microbiome, angiotensin converting enzyme 2 (ACE-2) expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of COVID-19, and speculate about the gut microbiome’s capability as a therapeutic avenue against COVID-19. </jats:p><jats:sec><jats:title>Lay summary</jats:title><jats:p> It has been noted that certain baseline gut profiles of COVID-19 patients are associated with a more severe disease course, and the gut microbiome impacts the disease course of several contributory risk factors to the severity of COVID-19. A protein called ACE-2, which is found in the small intestine among other sites, is a key receptor for COVID-19 virus entry
McSweeney B, Allegretti JR, Fischer M, et al., 2020, In search of stool donors: a multicenter study of prior knowledge, perceptions, motivators, and deterrents among potential donors for fecal microbiota transplantation., Gut Microbes, Vol: 11, Pages: 51-62
Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection. Stool donors are essential, but difficult to recruit and retain. We aimed to identify factors influencing willingness to donate stool. This multi-center study with a 32-item questionnaire targeted young adults and health care workers via social media and university email lists in Edmonton and Kingston, Canada; London and Nottingham, England; and Indianapolis and Boston, USA. Items included baseline demographics and FMT knowledge and perception. Investigated motivators and deterrents included economic compensation, screening process, time commitment, and stool donation logistics. Logistic regression and linear regression models estimated associations of study variables with self-assessed willingness to donate stool. 802 respondents completed our questionnaire: 387 (48.3%) age 21-30 years, 573 (71.4%) female, 323 (40%) health care workers. Country of residence, age and occupation were not associated with willingness to donate stool. Factors increasing willingness to donate were: already a blood donor (OR 1.64), male, altruism, economic benefit, knowledge of how FMT can help patients (OR 1.32), and positive attitudes towards FMT (OR 1.39). Factors decreasing willingness to donate were: stool collection unpleasant (OR 0.92), screening process invasive (OR 0.92), higher stool donation frequency, negative social perception of stool, and logistics of collection/transporting feces. We conclude that 1) blood donors and males are more willing to consider stool donation; 2) altruism, economic compensation, and positive feedback are motivators; and 3) screening process, high donation frequency, logistics of collection/transporting feces, lack of public awareness, and negative social perception are deterrents. Considering these variables could maximize donor recruitment and retention.
Cammarota G, Ianiro G, Kelly CR, et al., 2019, International consensus conference on stool banking for faecal microbiota transplantation in clinical practice, Gut, Vol: 68, Pages: 2111-2121, ISSN: 0017-5749
<jats:p>Although faecal microbiota transplantation (FMT) has a well-established role in the treatment of recurrent <jats:italic>Clostridioides difficile</jats:italic> infection (CDI), its widespread dissemination is limited by several obstacles, including lack of dedicated centres, difficulties with donor recruitment and complexities related to regulation and safety monitoring. Given the considerable burden of CDI on global healthcare systems, FMT should be widely available to most centres.</jats:p><jats:p>Stool banks may guarantee reliable, timely and equitable access to FMT for patients and a traceable workflow that ensures safety and quality of procedures. In this consensus project, FMT experts from Europe, North America and Australia gathered and released statements on the following issues related to the stool banking: general principles, objectives and organisation of the stool bank; selection and screening of donors; collection, preparation and storage of faeces; services and clients; registries, monitoring of outcomes and ethical issues; and the evolving role of FMT in clinical practice,</jats:p><jats:p>Consensus on each statement was achieved through a Delphi process and then in a plenary face-to-face meeting. For each key issue, the best available evidence was assessed, with the aim of providing guidance for the development of stool banks in order to promote accessibility to FMT in clinical practice.</jats:p>
Nathwani R, Mullish BH, Kockerling D, et al., 2019, A review of liver fibrosis and emerging therapies, European Medical Journal Gastroenterology, Vol: 4, Pages: 105-116, ISSN: 2054-6203
With an increasing burden of liver cirrhosis, the most advanced stage of hepatic fibrosis, there is an emphasis to better understand the pathological processes and mechanisms to target specific treatments to reverse or cease fibrosis progression. Antiviral therapy for hepatitis B and C has effectively treated underlying causes of chronic liver disease and has induced fibrosis reversal in some however, this has not been targeted for the majority of aetiologies for cirrhosis including alcohol or non-alcoholic steatohepatitis. Fibrosis, characterized by the accumulation of extracellular matrix proteins, occurs due to chronic injury from toxic, infectious or metabolic causes. The primary event of fibrogenesis is increased matrix production and scar formation mediated by the hepatic stellate cell, the principal cell type involved. Experimental models using rodent and human cell lines of liver injury have assisted in better understanding fibrogenesis especially in recognising the role of procoagulant factors. This has led to interventional studies using anticoagulants in animal models with reversal of fibrosis as the primary endpoint. Though these trials have been encouraging, no antifibrotic therapies are currently licenced for human use. This literature review discusses current knowledge in the pathophysiology of hepatic fibrosis, including characteristics of the extracellular matrix, signalling pathways and hepatic stellate cells. We also review current types of experimental models used to induce fibrosis and up-to46 date anticoagulant therapies and agents targeting the hepatic stellate cell that have been trialled in animal and human studies with anti-fibrotic properties.
Pinato DJ, Gramenitskaya D, Altmann DM, et al., 2019, Antibiotic therapy and outcome from immune-checkpoint inhibitors, Journal for ImmunoTherapy of Cancer, Vol: 7
Mullish BH, Forlano R, Abeles RD, et al., 2019, Letter: role of mean platelet volume levels in the prediction of major acute cardiovascular events in patients with non‐alcoholic fatty liver disease—authors' reply, Alimentary Pharmacology & Therapeutics, Vol: 50, Pages: 1140-1141, ISSN: 0269-2813
<jats:p><jats:bold>LINKED CONTENT</jats:bold></jats:p><jats:p>This article is linked to Abeles et al and Liu et al papers. To view these articles, visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="https://doi.org/10.1111/apt.15192">https://doi.org/10.1111/apt.15192</jats:ext-link> and <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="https://doi.org/10.1111/apt.15527">https://doi.org/10.1111/apt.15527</jats:ext-link>.</jats:p>
Marchesi JR, McDonald JAK, Mullish BH, 2019, Clostridioides difficile
The invention relates to Clostridioides difficile, and in particular to compounds, polypeptides and mixtures for the treatment of C. difficile infections. The invention also relates to nucleic acids, vectors comprising these nucleic acids and microorganisms for the treatment of C. difficile infections, and to methods of identifying and matching faecal microbiota transplant (FMT) donors to FMT recipients.
Forlano R, Mullish B, Giannakeas N, et al., 2019, IMPACT OF BMI AND ETHNICITY ON HISTOLOGY AS ASSESSED BY AUTOMATED QUANTITATION IN LIVER BIOPSIES OF PATIENTS WITH NAFLD, Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 1359A-1359A, ISSN: 0270-9139
Mullish BH, McDonald JAK, Pechlivanis A, et al., 2019, Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent <i>Clostridioides difficile</i> infection, Gut, Vol: 68, Pages: 1791-1800, ISSN: 0017-5749
<jats:sec><jats:title>Objective</jats:title><jats:p>Faecal microbiota transplant (FMT) effectively treats recurrent <jats:italic>Clostridioides difficile</jats:italic> infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect <jats:italic>C. difficile</jats:italic> germination or vegetative growth. We hypothesised that loss of gut microbiota-derived bile salt hydrolases (BSHs) predisposes to CDI by perturbing gut bile metabolism, and that BSH restitution is a key mediator of FMT’s efficacy in treating the condition.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Using stool collected from patients and donors pre-FMT/post-FMT for rCDI, we performed 16S rRNA gene sequencing, ultra performance liquid chromatography mass spectrometry (UPLC-MS) bile acid profiling, BSH activity measurement, and qPCR of <jats:italic>bsh</jats:italic>/<jats:italic>bai</jats:italic>CD genes involved in bile metabolism. Human data were validated in <jats:italic>C. difficile</jats:italic> batch cultures and a C57BL/6 mouse model of rCDI.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>From metataxonomics, pre-FMT stool demonstrated a reduced proportion of BSH-producing bacterial species compared with donors/post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA, a potent <jats:italic>C. difficile</jats:italic> germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and <jats:italic>bsh</jats:italic>/<jats:italic>bai</jats:italic>CD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered <jats:italic>bsh</jats:italic>-expressing <jats:italic>E
Allegretti JR, Mullish B, Hurtado J, et al., 2019, 837 Short Chain Fatty Acid Profiles Are Altered by Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease and Recurrent Clostridioides difficile Infection, American Journal of Gastroenterology, Vol: 114, Pages: S484-S485, ISSN: 0002-9270
<jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Recurrent <jats:italic toggle="yes">C. difficile</jats:italic> infection (rCDI) is a major challenge among patients with inflammatory bowel disease (IBD). Perturbation of microbiota-mediated metabolism of short chain fatty acids (SCFA) has been reported in IBD patients. Fecal microbiota transplantation (FMT), an established therapy for rCDI, alters gut microbiota composition, but effects on SCFA are unclear. Accordingly, this study assessed SCFA profiles in IBD patients with rCDI pre- and post-FMT.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>This open-label, prospective, single-arm multi-center cohort study enrolled patients from 4 tertiary care centers. Patients with IBD and ≥2 episodes of CDI received a single colonoscopic FMT from a universal stool bank. The primary outcome was CDI recurrence up to week 8 defined as diarrhea and EIA-positive toxin testing for <jats:italic toggle="yes">C. difficile</jats:italic>. Stool for metabolomic profiling was collected pre-FMT and week 1, 8 and 12 weeks post-FMT. A targeted gas chromatography-mass spectrometry protocol was used for the identification and quantification of SCFA. SCFA concentrations were analyzed via univariate analysis, comparing groups (e.g. pre- <jats:italic toggle="yes">vs</jats:italic> post-FMT).</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>37 participants were enrolled, with mean age of 37.6 years (range 20-76) and primarily female (n = 21, 57%). 14 had Crohn’s disease (CD) (mean HBI = 6.4) and 23 had ulcerative colitis (UC) (mean Partial Mayo Score = 4.5). Mean baseline fecal calprotectin was 1804.8 +/- 2307.7 Overall, 3
Allegretti JR, Mullish B, Nativ L, et al., 2019, 185 Evaluating Dynamics of Bile Acid Metabolism to Predict Recurrence of Clostridioides difficile Infection, American Journal of Gastroenterology, Vol: 114, Pages: S113-S113, ISSN: 0002-9270
<jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Recurrent <jats:italic toggle="yes">Clostridioides difficile</jats:italic> infection (CDI) is a major public health problem. The ability of commensal gut microbiota to metabolize primary into secondary bile acids plays a role in protection against this infection. Current clinical prediction tools for CDI recurrence do not incorporate biomarkers predictive of protective microbiota functionalities. We investigated metabolomic predictors of <jats:italic toggle="yes">C. difficile</jats:italic> recurrence.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>We conducted a prospective longitudinal study of patients experiencing a first CDI episode. Patients testing positive with either enzyme immunoassay (EIA) toxin or polymerase chain reaction (PCR), and being treated for CDI, were eligible for inclusion. Serial stool samples were collected at diagnosis through week-8 post-completion of anti-CDI therapy if no recurrence, or until the point of recurrence (defined as diarrhea with positive <jats:italic toggle="yes">C</jats:italic>. <jats:italic toggle="yes">difficile</jats:italic> EIA toxin stool test). Liquid chromatography-mass spectrometry was performed to profile fecal bile acids. The week 1 post-antibiotic time point was chosen to assess for potential predictors. We derived a univariate logistic regression model predicting recurrence and computed the AUC (c-statistic) on discriminatory ability. The Youden index was calculated as the value that maximizes sensitivity and specificity.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>29 first episode CDI patients were enrolled. 10 patient
Mullish BH, 2019, The role of bile-metabolising enzymes in the pathogenesis of Clostridioides difficile infection, and the impact of faecal microbiota transplantation
Allegretti JR, Mullish BH, Kelly C, et al., 2019, The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications., Lancet, Vol: 394, Pages: 420-431
Developments in high-throughput microbial genomic sequencing and other systems biology techniques have given novel insight into the potential contribution of the gut microbiota to health and disease. As a result, an increasing number of diseases have been characterised by distinctive changes in the composition and functionality of the gut microbiota; however, whether such changes are cause, consequence, or incidental to the disease in question remains largely uncertain. Restoration of the gut microbiota to a premorbid state is a key novel therapeutic approach of interest, and faecal microbiota transplantation-the transfer of prescreened stool from healthy donors into the gastrointestinal tract of patients-is gaining increasing importance in both the clinical and research settings. At present, faecal microbiota transplantation is only recommended in the treatment of recurrent Clostridioides difficile infection, although a large number of trials are ongoing worldwide exploring other potential therapeutic indications.
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