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Journal articleOvadia 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>
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Journal articleBrial F, Alzaid F, Sonomura K, et al., 2020,
The natural metabolite 4-cresol improves glucose homeostasis and enhances beta-cell function
, Cell Reports, Vol: 30, Pages: 2306-2320, ISSN: 2211-1247Exposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration of non-toxic doses of 4-cresol in complementary preclinical models of CMD reduces adiposity, glucose intolerance, and liver triglycerides, enhances insulin secretion in vivo, stimulates islet density and size, and pancreatic β-cell proliferation, and increases vascularization, suggesting activated islet enlargement. In vivo insulin sensitivity is not affected by 4-cresol. The incubation of mouse isolated islets with 4-cresol results in enhanced insulin secretion, insulin content, and β-cell proliferation of a magnitude similar to that induced by GLP-1. In both CMD models and isolated islets, 4-cresol is associated with the downregulated expression of the kinase DYRK1A, which may mediate its biological effects. Our findings identify 4-cresol as an effective regulator of β-cell function, which opens up perspectives for therapeutic applications in syndromes of insulin deficiency.
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Journal articleGroves HT, Higham SL, Moffatt MF, et al., 2020,
Respiratory viral infection alters the gut microbiota by inducing inappetence
, mBio, Vol: 11, ISSN: 2150-7511Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined.
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Journal articleGhani 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
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Journal articleGhani 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
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Conference paperGhani 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 -
Journal articleHarrison XA, Sewell T, Fisher M, et al., 2020,
Designing probiotic therapies with broad-spectrum activity against a wildlife pathogen
, Frontiers in Microbiology, Vol: 10, Pages: 1-11, ISSN: 1664-302XHost-associated microbes form an important component of immunity that protect against infection by pathogens. Treating wild individuals with these protective microbes, known as probiotics, can reduce rates of infection and disease in both wild and captive settings. However, the utility of probiotics for tackling wildlife disease requires that they offer consistent protection across the broad genomic variation of the pathogen that hosts can encounter in natural settings. Here we develop multi-isolate probiotic consortia with the aim of effecting broad-spectrum inhibition of growth of the lethal amphibian pathogen Batrachochytrium dendrobatidis (Bd) when tested against nine Bd isolates from two distinct lineages. Though we achieved strong growth inhibition between 70 and 100% for seven Bd isolates, two isolates appeared consistently resistant to inhibition, irrespective of probiotic strategy employed. We found no evidence that genomic relatedness of the chytrid predicted similarity of inhibition scores, nor that increasing the genetic diversity of the bacterial consortia could offer stronger inhibition of pathogen growth, even for the two resistant isolates. Our findings have important consequences for the application of probiotics to mitigate wildlife diseases in the face of extensive pathogen genomic variation.
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Journal articleSegal 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: 1873-9946BackgroundStudies 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.MethodsPatients 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.ResultsThere were 28 patients in the cohort; 23 patients with chronic pouchitis and 5 healthy controls who had never had pouchitis. Ten patients were female. The median age of the cohort was 47 years (range 26–74 years). A total of 12 samples on antibiotics and 11 off antibiotics. There were 10 responders and 13 non-responders. There were no differences between responders and non-responders and no differences in those taking antibiotics vs. those not taking antibiotics with chroni
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Journal articleAllegretti JR, Mullish BH, 2020,
Faecal microbiota transplantations and urinary tract infections – Authors' reply
, The Lancet, Vol: 395, Pages: 271-271, ISSN: 0140-6736 -
Journal articleMcSweeney 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: 51-62Fecal 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.
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