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  • Journal article
    Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, Forslund SK, Assmann K, Valles-Colomer M, Nguyen TTD, Proost S, Prifti E, Tremaroli V, Pons N, Le Chatelier E, Andreelli F, Bastard J-P, Coelho LP, Galleron N, Hansen TH, Hulot J-S, Lewinter C, Pedersen HK, Quinquis B, Rouault C, Roume H, Salem J-E, Søndertoft NB, Touch S, MetaCardis Consortium, Dumas M-E, Ehrlich SD, Galan P, Gøtze JP, Hansen T, Holst JJ, Køber L, Letunic I, Nielsen J, Oppert J-M, Stumvoll M, Vestergaard H, Zucker J-D, Bork P, Pedersen O, Bäckhed F, Clément K, Raes Jet al., 2020,

    Statin therapy is associated with lower prevalence of gut microbiota dysbiosis.

    , Nature, Vol: 581, Pages: 310-315

    Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effec

  • Journal article
    Pean N, Le Lay A, Brial F, Wasserscheid J, Rouch C, Vincent M, Myridakis A, Hedjazi L, Dumas M-E, Grundberg E, Lathrop M, Magnan C, Dewar K, Gauguier Det 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: 0012-186X

    Aims/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.

  • Journal article
    Brial F, Alzaid F, Sonomura K, Kamatani Y, Meneyrol K, Le Lay A, Pean N, Hedjazi L, Sato T-A, Venteclef N, Magnan C, Lathrop M, Dumas M-E, Matsuda F, Zalloua P, Gauguier Det al., 2020,

    The natural metabolite 4-cresol improves glucose homeostasis and enhances beta-cell function

    , Cell Reports, Vol: 30, Pages: 2306-2320, ISSN: 2211-1247

    Exposure 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.

  • Journal article
    Groves HT, Higham SL, Moffatt MF, Cox MJ, Tregoning JSet al., 2020,

    Respiratory viral infection alters the gut microbiota by inducing inappetence

    , mBio, Vol: 11, ISSN: 2150-7511

    Respiratory 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.

  • Journal article
    Harrison XA, Sewell T, Fisher M, Antwis REet al., 2020,

    Designing probiotic therapies with broad-spectrum activity against a wildlife pathogen

    , Frontiers in Microbiology, Vol: 10, Pages: 1-11, ISSN: 1664-302X

    Host-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.

  • Journal article
    Singanayagam A, Glanville N, Cuthbertson L, Bartlett NW, Finney LJ, Turek E, Bakhsoliani E, Calderazzo MA, Trujillo-Torralbo M-B, Footitt J, James PL, Fenwick P, Kemp SV, Clarke TB, Wedzicha JA, Edwards MR, Moffatt M, Cookson WO, Mallia P, Johnston SLet al., 2019,

    Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease

    , Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234

    Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

  • Journal article
    Bates KA, Shelton JMG, Mercier VL, Hopkins KP, Harrison XA, Petrovan SO, Fisher MCet al., 2019,

    Captivity and infection by the fungal pathogen batrachochytrium salamandrivorans perturb the amphibian skin microbiome

    , Frontiers in Microbiology, Vol: 10, ISSN: 1664-302X

    The emerging fungal pathogen, Batrachochytrium salamandrivorans (Bsal) is responsible for the catastrophic decline of European salamanders and poses a threat to amphibians globally. The amphibian skin microbiome can influence disease outcome for several host-pathogen systems, yet little is known of its role in Bsal infection. In addition, many experimental in-vivo amphibian disease studies to date have relied on specimens that have been kept in captivity for long periods without considering the influence of environment on the microbiome and how this may impact the host response to pathogen exposure. We characterized the impact of captivity and exposure to Bsal on the skin bacterial and fungal communities of two co-occurring European newt species, the smooth newt, Lissotriton vulgaris and the great-crested newt, Triturus cristatus. We show that captivity led to significant losses in bacterial and fungal diversity of amphibian skin, which may be indicative of a decline in microbe-mediated protection. We further demonstrate that in both L. vulgaris and T. cristatus, Bsal infection was associated with changes in the composition of skin bacterial communities with possible negative consequences to host health. Our findings advance current understanding of the role of host-associated microbiota in Bsal infection and highlight important considerations for ex-situ amphibian conservation programmes.

  • Journal article
    Abdul Rahim MBH, Chilloux J, Martinez-Gili L, Neves AL, Myridakis A, Gooderham N, Dumas M-Eet al., 2019,

    Diet-induced metabolic changes of the human gut microbiome: importance of short-chain fatty acids, methylamines and indoles

    , Acta Diabetologica, Vol: 56, Pages: 493-500, ISSN: 0940-5429

    The human gut is a home for more than 100 trillion bacteria, far more than all other microbial populations resident on the body's surface. The human gut microbiome is considered as a microbial organ symbiotically operating within the host. It is a collection of different cell lineages that are capable of communicating with each other and the host and has an ability to undergo self-replication for its repair and maintenance. As the gut microbiota is involved in many host processes including growth and development, an imbalance in its ecological composition may lead to disease and dysfunction in the human. Gut microbial degradation of nutrients produces bioactive metabolites that bind target receptors, activating signalling cascades, and modulating host metabolism. This review covers current findings on the nutritional and pharmacological roles of selective gut microbial metabolites, short-chain fatty acids, methylamines and indoles, as well as discussing nutritional interventions to modulate the microbiome.

  • Journal article
    Ahmed B, Cox M, Cuthbertson L, James P, Cookson W, Davies J, Moffatt M, Bush Aet al., 2019,

    Longitudinal development of the airway microbiota in infants with cystic fibrosis

    , Scientific Reports, Vol: 9, ISSN: 2045-2322

    The pathogenesis of airway infection in cystic fibrosis (CF) is poorly understood. We performed a longitudinal study coupling clinical information with frequent sampling of the microbiota to identify changes in the airway microbiota in infancy that could underpin deterioration and potentially be targeted therapeutically. Thirty infants with CF diagnosed on newborn screening (NBS) were followed for up to two years. Two hundred and forty one throat swabs were collected as a surrogate for lower airway microbiota (median 35 days between study visits) in the largest longitudinal study of the CF oropharyngeal microbiota. Quantitative PCR and Illumina sequencing of the 16S rRNA bacterial gene were performed. Data analyses were conducted in QIIME and Phyloseq in R. Streptococcus spp. and Haemophilus spp. were the most common genera (55% and 12.5% of reads respectively) and were inversely related. Only beta (between sample) diversity changed with age (Bray Curtis r2 = 0.15, P = 0.03). Staphylococcus and Pseudomonas were rarely detected. These results suggest that Streptococcus spp. and Haemophilus spp., may play an important role in early CF. Whether they are protective against infection with more typical CF micro-organisms, or pathogenic and thus meriting treatment needs to be determined.

  • Journal article
    Wootton DG, Cox MJ, Gloor GB, Litt D, Hoschler K, German E, Court J, Eneje O, Keogan L, Macfarlane L, Wilks S, Diggles PJ, Woodhead M, Moffatt MF, Cookson WOC, Gordon SBet al., 2019,

    A haemophilus sp. dominates the microbiota of sputum from UK adults with non-severe community acquired pneumonia and chronic lung disease

    , Scientific Reports, Vol: 9, ISSN: 2045-2322

    The demographics and comorbidities of patients with community acquired pneumonia (CAP) vary enormously but stratified treatment is difficult because aetiological studies have failed to comprehensively identify the pathogens. Our aim was to describe the bacterial microbiota of CAP and relate these to clinical characteristics in order to inform future trials of treatment stratified by co-morbidity. CAP patients were prospectively recruited at two UK hospitals. We used 16S rRNA gene sequencing to identify the dominant bacteria in sputum and compositional data analysis to determine associations with patient characteristics. We analysed sputum samples from 77 patients and found a Streptococcus sp. and a Haemophilus sp. were the most relatively abundant pathogens. The Haemophilus sp. was more likely to be dominant in patients with pre-existing lung disease, and its relative abundance was associated with qPCR levels of Haemophilus influenzae. The most abundant Streptococcus sp. was associated with qPCR levels of Streptococcus pneumoniae but dominance could not be predicted from clinical characteristics. These data suggest chronic lung disease influences the microbiota of sputum in patients with CAP. This finding could inform a trial of stratifying empirical CAP antibiotics to target Haemophilus spp. in addition to Streptococcus spp. in those with chronic lung disease.

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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