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Journal articlePean N, Le Lay A, Brial F, et al., 2020,
Dominant gut Prevotella copri in gastrectomised non-obese diabetic Goto-Kakizaki rats improves glucose homeostasis through enhanced FXR signalling
, Diabetologia, Vol: 63, Pages: 1223-1235, ISSN: 0012-186XAims/hypothesisDrug and surgical-based therapies in type 2 diabetes are associated with altered gut microbiota architecture. Here we investigated the role of the gut microbiome in improved glucose homeostasis following bariatric surgery.MethodsWe carried out gut microbiome analyses in gastrectomised (by vertical sleeve gastrectomy [VSG]) rats of the Goto–Kakizaki (GK) non-obese model of spontaneously occurring type 2 diabetes, followed by physiological studies in the GK rat.ResultsVSG in the GK rat led to permanent improvement of glucose tolerance associated with minor changes in the gut microbiome, mostly characterised by significant enrichment of caecal Prevotella copri. Gut microbiota enrichment with P. copri in GK rats through permissive antibiotic treatment, inoculation of gut microbiota isolated from gastrectomised GK rats, and direct inoculation of P. copri, resulted in significant improvement of glucose tolerance, independent of changes in body weight. Plasma bile acids were increased in GK rats following inoculation with P. copri and P. copri-enriched microbiota from VSG-treated rats; the inoculated GK rats then showed increased liver glycogen and upregulated expression of Fxr (also known as Nr1h4), Srebf1c, Chrebp (also known as Mlxipl) and Il10 and downregulated expression of Cyp7a1.ConclusionsOur data underline the impact of intestinal P. copri on improved glucose homeostasis through enhanced bile acid metabolism and farnesoid X receptor (FXR) signalling, which may represent a promising opportunity for novel type 2 diabetes therapeutics.
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Conference paperWoodhouse C, Edwards L, Mullish BH, et al., 2020,
LBP29 Results of the PROFIT trial, a PROspective randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation in advanced cirrhosis
, Digital International Liver Congress, Publisher: Elsevier, Pages: S77-S78, ISSN: 0168-8278 -
Journal articleMichael 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
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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 BH, 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 -
Journal articleGhani R, Mullish BH, 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 -
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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