Publications by authors named "Lutz Krause"

82 Publications

Evaluation of the Microba Community Profiler for Taxonomic Profiling of Metagenomic Datasets From the Human Gut Microbiome.

Front Microbiol 2021 20;12:643682. Epub 2021 Apr 20.

Microba Life Sciences Limited, Brisbane, QLD, Australia.

A fundamental goal of microbial ecology is to accurately determine the species composition in a given microbial ecosystem. In the context of the human microbiome, this is important for establishing links between microbial species and disease states. Here we benchmark the Microba Community Profiler (MCP) against other metagenomic classifiers using 140 moderate to complex microbial communities and a standardized reference genome database. MCP generated accurate relative abundance estimates and made substantially fewer false positive predictions than other classifiers while retaining a high recall rate. We further demonstrated that the accuracy of species classification was substantially increased using the Microba Genome Database, which is more comprehensive than reference datasets used by other classifiers and illustrates the importance of including genomes of uncultured taxa in reference databases. Consequently, MCP classifies appreciably more reads than other classifiers when using their recommended reference databases. These results establish MCP as best-in-class with the ability to produce comprehensive and accurate species profiles of human gastrointestinal samples.
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http://dx.doi.org/10.3389/fmicb.2021.643682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093879PMC
April 2021

Gastrointestinal Helminth Infection Improves Insulin Sensitivity, Decreases Systemic Inflammation, and Alters the Composition of Gut Microbiota in Distinct Mouse Models of Type 2 Diabetes.

Front Endocrinol (Lausanne) 2020 5;11:606530. Epub 2021 Feb 5.

Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.

Type 2 diabetes (T2D) is a major health problem and is considered one of the top 10 diseases leading to death globally. T2D has been widely associated with systemic and local inflammatory responses and with alterations in the gut microbiota. Microorganisms, including parasitic worms and gut microbes have exquisitely co-evolved with their hosts to establish an immunological interaction that is essential for the formation and maintenance of a balanced immune system, including suppression of excessive inflammation. Herein we show that both prophylactic and therapeutic infection of mice with the parasitic hookworm-like nematode, , significantly reduced fasting blood glucose, oral glucose tolerance and body weight gain in two different diet-induced mouse models of T2D. Helminth infection was associated with elevated type 2 immune responses including increased eosinophil numbers in the mesenteric lymph nodes, liver and adipose tissues, as well as increased expression of and alternatively activated macrophage marker genes in adipose tissue, liver and gut. infection was also associated with significant compositional changes in the gut microbiota at both the phylum and order levels. Our findings show that infection drives changes in local and systemic immune cell populations, and that these changes are associated with a reduction in systemic and local inflammation and compositional changes in the gut microbiota which cumulatively might be responsible for the improved insulin sensitivity observed in infected mice. Our findings indicate that carefully controlled therapeutic hookworm infection in humans could be a novel approach for treating metabolic syndrome and thereby preventing T2D.
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http://dx.doi.org/10.3389/fendo.2020.606530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892786PMC
February 2021

Author Correction: Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

Sci Rep 2020 Jul 24;10(1):12742. Epub 2020 Jul 24.

Neuroscience & Infectious Disease Group, The University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-69649-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378188PMC
July 2020

Fully Convolutional Neural Network for Detection and Counting of Diatoms on Coatings after Short-Term Field Exposure.

Environ Sci Technol 2020 08 28;54(16):10022-10030. Epub 2020 Jul 28.

Analytical Chemistry-Biointerfaces, Ruhr University Bochum, 44801 Bochum, Germany.

While the use of deep learning is a valuable technology for automatic detection systems for medical data and images, the biofouling community is still lacking an analytical tool for the detection and counting of diatoms on samples after short-term field exposure. In this work, a fully convolutional neural network was implemented as a fast and simple approach to detect diatoms on two-channel (fluorescence and phase-contrast) microscopy images by predicting bounding boxes. The developed approach performs well with only a small number of trainable parameters and a F1 score of 0.82. Counting diatoms was evaluated on a data set of 600 microscopy images of three different surface chemistries (hydrophilic and hydrophobic) and is very similar to counting by humans while demanding only a fraction of the analysis time.
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http://dx.doi.org/10.1021/acs.est.0c01982DOI Listing
August 2020

Chronic High-Fat Diet Induces Early Barrett's Esophagus in Mice through Lipidome Remodeling.

Biomolecules 2020 05 16;10(5). Epub 2020 May 16.

QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, QLD, Australia.

Esophageal adenocarcinoma (EAC) incidence has been rapidly increasing, potentially associated with the prevalence of the risk factors gastroesophageal reflux disease (GERD), obesity, high-fat diet (HFD), and the precursor condition Barrett's esophagus (BE). EAC development occurs over several years, with stepwise changes of the squamous esophageal epithelium, through cardiac metaplasia, to BE, and then EAC. To establish the roles of GERD and HFD in initiating BE, we developed a dietary intervention model in C57/BL6 mice using experimental HFD and GERD (0.2% deoxycholic acid, DCA, in drinking water), and then analyzed the gastroesophageal junction tissue lipidome and microbiome to reveal potential mechanisms. Chronic (9 months) HFD alone induced esophageal inflammation and metaplasia, the first steps in BE/EAC pathogenesis. While 0.2% deoxycholic acid (DCA) alone had no effect on esophageal morphology, it synergized with HFD to increase inflammation severity and metaplasia length, potentially via increased microbiome diversity. Furthermore, we identify a tissue lipid signature for inflammation and metaplasia, which is characterized by elevated very-long-chain ceramides and reduced lysophospholipids. In summary, we report a non-transgenic mouse model, and a tissue lipid signature for early BE. Validation of the lipid signature in human patient cohorts could pave the way for specific dietary strategies to reduce the risk of BE in high-risk individuals.
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http://dx.doi.org/10.3390/biom10050776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277507PMC
May 2020

Infection with the sheep gastrointestinal nematode Teladorsagia circumcincta increases luminal pathobionts.

Microbiome 2020 04 30;8(1):60. Epub 2020 Apr 30.

Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, UK.

Background: The multifaceted interactions between gastrointestinal (GI) helminth parasites, host gut microbiota and immune system are emerging as a key area of research within the field of host-parasite relationships. In spite of the plethora of data available on the impact that GI helminths exert on the composition of the gut microflora, whether alterations of microbial profiles are caused by direct parasite-bacteria interactions or, indirectly, by alterations of the GI environment (e.g. mucosal immunity) remains to be determined. Furthermore, no data is thus far available on the downstream roles that qualitative and quantitative changes in gut microbial composition play in the overall pathophysiology of parasite infection and disease.

Results: In this study, we investigated the fluctuations in microbiota composition and local immune microenvironment of sheep vaccinated against, and experimentally infected with, the 'brown stomach worm' Teladorsagia circumcincta, a parasite of worldwide socio-economic significance. We compared the faecal microbial profiles of vaccinated and subsequently infected sheep with those obtained from groups of unvaccinated/infected and unvaccinated/uninfected animals. We show that alterations of gut microbial composition are associated mainly with parasite infection, and that this involves the expansion of populations of bacteria with known pro-inflammatory properties that may contribute to the immunopathology of helminth disease. Using novel quantitative approaches for the analysis of confocal microscopy-derived images, we also show that gastric tissue infiltration of T cells is driven by parasitic infection rather than anti-helminth vaccination.

Conclusions: Teladorsagia circumcincta infection leads to an expansion of potentially pro-inflammatory gut microbial species and abomasal T cells. This data paves the way for future experiments aimed to determine the contribution of the gut flora to the pathophysiology of parasitic disease, with the ultimate aim to design and develop novel treatment/control strategies focused on preventing and/or restricting bacterial-mediated inflammation upon infection by GI helminths. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00818-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193420PMC
April 2020

Helminths, polyparasitism, and the gut microbiome in the Philippines.

Int J Parasitol 2020 03 3;50(3):217-225. Epub 2020 Mar 3.

School of Biological Sciences, Queen's University Belfast, Belfast, United Kingdom. Electronic address:

Polyparasitism, involving soil-transmitted helminths. and Schistosoma blood flukes, is common in low to middle income countries. These helminths impact on the gut environment and can cause changes to the gut microbiome composition. Here we examined the gut microbiome in individuals with polyparasitism from two human cohorts in the Philippines utilising DNA sequencing-based profiling. Multiple helminth species infections were high with 70.3% of study participants harbouring at least two parasite species, and 16% harbouring at least five species. Increased numbers of helminth co-infections, in particular with the gut-resident soil-transmitted helminths, were significantly associated with increased bacterial diversity; however no significant parasite-gut microbiome associations were evident for individuals infected only with Schistosoma japonicum. In general, a healthy gut is associated with high bacterial diversity, which in these human cohorts may be the result of helminth-mediated immune modulation, or due to changes in the gut environment caused by these parasitic helminths.
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http://dx.doi.org/10.1016/j.ijpara.2019.12.008DOI Listing
March 2020

Chromosome arm aneuploidies shape tumour evolution and drug response.

Nat Commun 2020 01 23;11(1):449. Epub 2020 Jan 23.

University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD, 4102, Australia.

Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform  mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology.
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http://dx.doi.org/10.1038/s41467-020-14286-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978319PMC
January 2020

Potential clinical utility of multiple target quantitative polymerase chain reaction (qPCR) array to detect microbial pathogens in patients with chronic obstructive pulmonary disease (COPD).

J Thorac Dis 2019 Oct;11(Suppl 17):S2254-S2265

The University of Queensland Thoracic Research Centre, The Prince Charles Hospital, Brisbane, QLD, Australia.

Background: Culture-independent methods such as quantitative polymerase chain reaction (qPCR) are more sensitive for detecting pathogens than conventional culture. This study aimed to test the clinical potential of a multiple target qPCR array in identifying sputum pathogens, compared to traditional culture.

Methods: Forty chronic obstructive pulmonary disease (COPD) patients provided spontaneous sputum and blood samples during an exacerbation event (n=25 patients) and in stable state (n=15 patients). Sputum was processed and analysed by microscopy, culture and sensitivity testing (MCS) to identify living microbial isolates, and multiple target qPCR (44 targets for bacterial and fungal pathogens and antibiotic resistance genes), and 16S rRNA gene sequencing.

Results: Six microbial isolates (5 bacterial, 1 fungal) were cultured from 20 exacerbation and 10 stable patient sputum samples. Four of these microbial isolates had their presence in patient sputum confirmed by qPCR. All bacterial targets detected by qPCR were further confirmed by 16S rRNA gene sequencing at a genus level. qPCR identified significantly more bacterial pathogens than culture (P<0.001). The most prevalent bacterial species identified by qPCR were (72% of patients), (40%), (32%) and (17%). Microbial species diversity and richness were not significantly different between samples obtained from exacerbating and clinically stable cases. 16S rRNA gene sequencing identified (P=0.022, FDR =0.043 AUC =0.72) as a significantly different bacterial OTU (operational taxonomic units) in exacerbation sputum samples compared to stable state samples.

Conclusions: Multiple target qPCR was more sensitive for detection of sputum pathogens in COPD patients than conventional culture. 16S rRNA gene sequencing confirmed the identity at a genus level of all bacterial targets detected by qPCR, as well as identifying bacterial OTUs that could potentially be used to distinguish between exacerbation and stable COPD disease states. Multiple target qPCR pathogen detection in the sputum of COPD patients warrants further investigation to determine how it may influence COPD clinical management.
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http://dx.doi.org/10.21037/jtd.2019.10.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831922PMC
October 2019

Immune Signature Against Antigens Predicts Clinical Immunity in Distinct Malaria Endemic Communities.

Mol Cell Proteomics 2020 01 28;19(1):101-113. Epub 2019 Oct 28.

Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Electronic address:

A large body of evidence supports the role of antibodies directed against the parasite in the development of naturally acquired immunity to malaria, however an antigen signature capable of predicting protective immunity against remains to be identified. Key challenges for the identification of a predictive immune signature include the high dimensionality of data produced by high-throughput technologies and the limitation of standard statistical tests in accounting for synergetic interactions between immune responses to multiple targets. In this study, using samples collected from young children in Ghana at multiple time points during a longitudinal study, we adapted a predictive modeling framework which combines feature selection and machine learning techniques to identify an antigen signature of clinical immunity to malaria. Our results show that an individual's immune status can be accurately predicted by measuring antibody responses to a small defined set of 15 target antigens. We further demonstrate that the identified immune signature is highly versatile and capable of providing precise and accurate estimates of clinical protection from malaria in an independent geographic community. Our findings pave the way for the development of a robust point-of-care test to identify individuals at high risk of disease and which could be applied to monitor the impact of vaccinations and other interventions. This approach could be also translated to biomarker discovery for other infectious diseases.
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http://dx.doi.org/10.1074/mcp.RA118.001256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944240PMC
January 2020

The Association between the Comprehensive Epstein-Barr Virus Serologic Profile and Endemic Burkitt Lymphoma.

Cancer Epidemiol Biomarkers Prev 2020 01 16;29(1):57-62. Epub 2019 Oct 16.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.

Background: The discovery of Epstein-Barr virus (EBV) in Burkitt lymphoma tumors represented the first link between a virus and cancer in humans, but the underlying role of this virus in endemic Burkitt lymphoma remains unclear. Nearly all children in Burkitt lymphoma-endemic areas are seropositive for EBV, but only a small percentage develop disease. Variation in EBV-directed immunity could be an explanatory cofactor.

Methods: We examined serum from 150 Burkitt lymphoma cases and 150 controls using a protein microarray that measured IgG and IgA antibodies against 202 sequences across the entire EBV proteome. Variation in the EBV-directed antibody repertoire between Burkitt lymphoma cases and controls was assessed using unpaired tests. ORs quantifying the association between anti-EBV IgG response tertiles and Burkitt lymphoma status were adjusted for age, sex, and study year.

Results: Thirty-three anti-EBV IgG responses were elevated in Burkitt lymphoma cases compared with controls ( ≤ 0.0003). Burkitt lymphoma-associated IgG elevations were strongest for EBV proteins involved in viral replication and antiapoptotic signaling. Specifically, we observed ORs ≥4 for BMRF1 (early antigen), BBLF1 (tegument protein), BHRF1 (Bcl-2 homolog), BZLF1 (Zebra), BILF2 (glycoprotein), BLRF2 [viral capsid antigen (VCA)p23], BDLF4, and BFRF3 (VCAp18). Adjustment for malaria exposure and inheritance of the sickle cell variant did not alter associations.

Conclusions: Our data suggest that the anti-EBV serologic profile in patients with Burkitt lymphoma is altered, with strong elevations in 33 of the measured anti-EBV IgG antibodies relative to disease-free children.

Impact: The Burkitt lymphoma-specific signature included EBV-based markers relevant for viral replication and antiapoptotic activity, providing clues for future Burkitt lymphoma pathogenesis research.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954331PMC
January 2020

Microbiota and Body Composition During the Period of Complementary Feeding.

J Pediatr Gastroenterol Nutr 2019 12;69(6):726-732

Children's Nutrition Research Centre, Child Health Research Centre.

Objectives: This study aimed to explore the associations between food group intake, faecal microbiota profile, and body composition during the period of complementary feeding.

Methods: Diet was assessed using a quantitative food frequency questionnaire, faecal microbiota profile was assessed using 16S rRNA gene sequencing, and body composition was assessed using bioelectrical impedance analysis and dual energy x-ray absorptiometry, in a cohort of 50 infants aged 6 to 24 months of age.

Results: During this critical period of microbiota development, age was the strongest predictor of microbiota composition with network analysis revealing a cluster of genera positively associated with age. A separate cluster comprised genera associated with fat mass index with Bifidobacterium showing the strongest correlation with fat mass index (rho = 0.55, P = 0.001, false discovery rate [FDR] = 0.018). Dairy intake was both negatively correlated with Bacteroides (rho = -0.49, P < 0.001, FDR = 0.024) and positively correlated with lean mass index (rho = 0.44, P = 0.007, FDR = 0.024). Antibiotics use in the first month of life had the most striking influence on body composition and was associated with an increase in mean body mass index z score of 1.17 (P = 0.001) and body fat of 3.5% (P = 0.001).

Conclusions: Our results suggested that antibiotics use in the first month of life had the most striking influence on body composition in this cohort of infants aged 6 to 24 months, whereas dairy intake interacted with both microbiota and body composition in early life.
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http://dx.doi.org/10.1097/MPG.0000000000002490DOI Listing
December 2019

Author Correction: A comprehensive analysis of the faecal microbiome and metabolome of Strongyloides stercoralis infected volunteers from a non-endemic area.

Sci Rep 2019 06 7;9(1):8571. Epub 2019 Jun 7.

Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-43508-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554465PMC
June 2019

Whole-genome sequencing of human malignant mesothelioma tumours and cell lines.

Carcinogenesis 2019 07;40(6):724-734

Thoracic Research Centre, Faculty of Medicine, The University of Queensland, Queensland, Australia.

Pleural mesothelioma is a cancer of serosal surfaces caused by environmental exposure to asbestos. Clinical outcome remains poor and while trials of new treatments are ongoing it remains an understudied cancer. Mesothelioma cell lines can readily be grown from primary tumour and from tumour cells shed into pleural effusion with the latter representing a particularly valuable source of DNA in clinical settings, procurable without the need for additional invasive procedures. However, it is not well understood how accurately patient-derived cultured tumour cells represent the molecular characteristics of their primary tumour. We used whole-genome sequencing of primary tumour and matched cultured cells to comprehensively characterize mutations and structural alterations. Most cases had complex rearranged genomes with evidence of chromoanagenesis and rearrangements reminiscent of chromoplexy. Many of the identified driver mutations were structural, indicating that mesothelioma is often caused by structural alterations and catastrophic genomic events, rather than point mutations. Because the majority of genomic changes detected in tumours were also displayed by the genomes of cultured tumour cells, we conclude that low-passage cultured tumour cells are generally suitable for molecular characterization of mesothelioma and may be particularly useful where tissue samples with high tumour cell content are not available. However, the subclonal compositions of the cell lines did not fully recapitulate the subclonal diversity of the primary tumours. Furthermore, longitudinal acquisition of major alterations in subclonal cell populations was observed after long-term passaging. These two factors define limitations of tumour-derived cell lines as genomic substrate for clinical purposes.
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http://dx.doi.org/10.1093/carcin/bgz066DOI Listing
July 2019

Analysis of the Effects of Dietary Pattern on the Oral Microbiome of Elite Endurance Athletes.

Nutrients 2019 Mar 13;11(3). Epub 2019 Mar 13.

Faculty of Medicine, Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia.

Although the oral microbiota is known to play a crucial role in human health, there are few studies of diet x oral microbiota interactions, and none in elite athletes who may manipulate their intakes of macronutrients to achieve different metabolic adaptations in pursuit of optimal endurance performance. The aim of this study was to investigate the shifts in the oral microbiome of elite male endurance race walkers from Europe, Asia, the Americas and Australia, in response to one of three dietary patterns often used by athletes during a period of intensified training: a High Carbohydrate (HCHO; = 9; with 60% energy intake from carbohydrates; ~8.5 g kg day carbohydrate, ~2.1 g kg day protein, 1.2 g kg day fat) diet, a Periodised Carbohydrate (PCHO; = 10; same macronutrient composition as HCHO, but the intake of carbohydrates is different across the day and throughout the week to support training sessions with high or low carbohydrate availability) diet or a ketogenic Low Carbohydrate High Fat (LCHF; = 10; 0.5 g kg day carbohydrate; 78% energy as fat; 2.1 g kg day protein) diet. Saliva samples were collected both before (Baseline; BL) and after the three-week period (Post treatment; PT) and the oral microbiota profiles for each athlete were produced by 16S rRNA gene amplicon sequencing. Principal coordinates analysis of the oral microbiota profiles based on the weighted UniFrac distance measure did not reveal any specific clustering with respect to diet or athlete ethnic origin, either at baseline (BL) or following the diet-training period. However, discriminant analyses of the oral microbiota profiles by Linear Discriminant Analysis (LDA) Effect Size (LEfSe) and sparse Partial Least Squares Discriminant Analysis (sPLS-DA) did reveal changes in the relative abundance of specific bacterial taxa, and, particularly, when comparing the microbiota profiles following consumption of the carbohydrate-based diets with the LCHF diet. These analyses showed that following consumption of the LCHF diet the relative abundances of and spp. were decreased, and the relative abundance of spp. was increased. Such findings suggest that diet, and, in particular, the LCHF diet can induce changes in the oral microbiota of elite endurance walkers.
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http://dx.doi.org/10.3390/nu11030614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471070PMC
March 2019

Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

Sci Rep 2019 02 22;9(1):2627. Epub 2019 Feb 22.

Neuroscience & Infectious Disease Group, The University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.

Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. Upper airway infections are common in patients and S. pneumoniae is associated with these infections. We demonstrate here that the upper airway microbiome in patients with A-T is different from that to healthy controls, with S. pneumoniae detected largely in patients only. Patient-specific airway epithelial cells and differentiated air-liquid interface cultures derived from these were hypersensitive to infection which was at least in part due to oxidative damage since it was partially reversed by catalase. We also observed increased levels of the pro-inflammatory cytokines IL-8 and TNF-α (inflammasome-independent) and a decreased level of the inflammasome-dependent cytokine IL-β in patient cells. Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells. These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients.
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http://dx.doi.org/10.1038/s41598-019-38901-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385340PMC
February 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
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http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019

The Effects of Dietary Pattern during Intensified Training on Stool Microbiota of Elite Race Walkers.

Nutrients 2019 Jan 24;11(2). Epub 2019 Jan 24.

Faculty of Medicine, Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia.

We investigated extreme changes in diet patterns on the gut microbiota of elite race walkers undertaking intensified training and its possible links with athlete performance. Numerous studies with sedentary subjects have shown that diet and/or exercise can exert strong selective pressures on the gut microbiota. Similar studies with elite athletes are relatively scant, despite the recognition that diet is an important contributor to sports performance. In this study, stool samples were collected from the cohort at the beginning (baseline; BL) and end (post-treatment; PT) of a three-week intensified training program during which athletes were assigned to a High Carbohydrate (HCHO), Periodised Carbohydrate (PCHO) or ketogenic Low Carbohydrate High Fat (LCHF) diet (post treatment). Microbial community profiles were determined by 16S rRNA gene amplicon sequencing. The microbiota profiles at BL could be separated into distinct "enterotypes," with either a or dominated enterotype. While enterotypes were relatively stable and remained evident post treatment, the LCHF diet resulted in a greater relative abundance of and and a reduction of Significant negative correlations were observed between and fat oxidation and between and economy test following LCHF intervention.
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http://dx.doi.org/10.3390/nu11020261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413084PMC
January 2019

Whole-genome sequence of the bovine blood fluke Schistosoma bovis supports interspecific hybridization with S. haematobium.

PLoS Pathog 2019 01 23;15(1):e1007513. Epub 2019 Jan 23.

The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.

Mesenteric infection by the parasitic blood fluke Schistosoma bovis is a common veterinary problem in Africa and the Middle East and occasionally in the Mediterranean Region. The species also has the ability to form interspecific hybrids with the human parasite S. haematobium with natural hybridisation observed in West Africa, presenting possible zoonotic transmission. Additionally, this exchange of alleles between species may dramatically influence disease dynamics and parasite evolution. We have generated a 374 Mb assembly of the S. bovis genome using Illumina and PacBio-based technologies. Despite infecting different hosts and organs, the genome sequences of S. bovis and S. haematobium appeared strikingly similar with 97% sequence identity. The two species share 98% of protein-coding genes, with an average sequence identity of 97.3% at the amino acid level. Genome comparison identified large continuous parts of the genome (up to several 100 kb) showing almost 100% sequence identity between S. bovis and S. haematobium. It is unlikely that this is a result of genome conservation and provides further evidence of natural interspecific hybridization between S. bovis and S. haematobium. Our results suggest that foreign DNA obtained by interspecific hybridization was maintained in the population through multiple meiosis cycles and that hybrids were sexually reproductive, producing viable offspring. The S. bovis genome assembly forms a highly valuable resource for studying schistosome evolution and exploring genetic regions that are associated with species-specific phenotypic traits.
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http://dx.doi.org/10.1371/journal.ppat.1007513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361461PMC
January 2019

Whole-genome sequence of the oriental lung fluke Paragonimus westermani.

Gigascience 2019 01 1;8(1). Epub 2019 Jan 1.

The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, 37 Kent St, Translational Research Institute (TRI), Wooloongabba, QLD 4102.

Background: Foodborne infections caused by lung flukes of the genus Paragonimus are a significant and widespread public health problem in tropical areas. Approximately 50 Paragonimus species have been reported to infect animals and humans, but Paragonimus westermani is responsible for the bulk of human disease. Despite their medical and economic importance, no genome sequence for any Paragonimus species is available.

Results: We sequenced and assembled the genome of P. westermani, which is among the largest of the known pathogen genomes with an estimated size of 1.1 Gb. A 922.8 Mb genome assembly was generated from Illumina and Pacific Biosciences (PacBio) sequence data, covering 84% of the estimated genome size. The genome has a high proportion (45%) of repeat-derived DNA, particularly of the long interspersed element and long terminal repeat subtypes, and the expansion of these elements may explain some of the large size. We predicted 12,852 protein coding genes, showing a high level of conservation with related trematode species. The majority of proteins (80%) had homologs in the human liver fluke Opisthorchis viverrini, with an average sequence identity of 64.1%. Assembly of the P. westermani mitochondrial genome from long PacBio reads resulted in a single high-quality circularized 20.6 kb contig. The contig harbored a 6.9 kb region of non-coding repetitive DNA comprised of three distinct repeat units. Our results suggest that the region is highly polymorphic in P. westermani, possibly even within single worm isolates.

Conclusions: The generated assembly represents the first Paragonimus genome sequence and will facilitate future molecular studies of this important, but neglected, parasite group.
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http://dx.doi.org/10.1093/gigascience/giy146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329441PMC
January 2019

A comprehensive analysis of the faecal microbiome and metabolome of Strongyloides stercoralis infected volunteers from a non-endemic area.

Sci Rep 2018 10 23;8(1):15651. Epub 2018 Oct 23.

Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

Data from recent studies support the hypothesis that infections by human gastrointestinal (GI) helminths impact, directly and/or indirectly, on the composition of the host gut microbial flora. However, to the best of our knowledge, these studies have been conducted in helminth-endemic areas with multi-helminth infections and/or in volunteers with underlying gut disorders. Therefore, in this study, we explore the impact of natural mono-infections by the human parasite Strongyloides stercoralis on the faecal microbiota and metabolic profiles of a cohort of human volunteers from a non-endemic area of northern Italy (S+), pre- and post-anthelmintic treatment, and compare the findings with data obtained from a cohort of uninfected controls from the same geographical area (S-). Analyses of bacterial 16S rRNA high-throughput sequencing data revealed increased microbial alpha diversity and decreased beta diversity in the faecal microbial profiles of S+ subjects compared to S-. Furthermore, significant differences in the abundance of several bacterial taxa were observed between samples from S+ and S- subjects, and between S+ samples collected pre- and post-anthelmintic treatment. Faecal metabolite analysis detected marked increases in the abundance of selected amino acids in S+ subjects, and of short chain fatty acids in S- subjects. Overall, our work adds valuable knowledge to current understanding of parasite-microbiota associations and will assist future mechanistic studies aimed to unravel the causality of these relationships.
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http://dx.doi.org/10.1038/s41598-018-33937-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199319PMC
October 2018

Vitamin D and the gut microbiome: a systematic review of in vivo studies.

Eur J Nutr 2019 Oct 15;58(7):2895-2910. Epub 2018 Oct 15.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Purpose: Variation in the human microbiome has been linked with a variety of physiological functions, including immune regulation and metabolism and biosynthesis of vitamins, hormones, and neurotransmitters. Evidence for extraskeletal effects of vitamin D has been accruing and it has been suggested that the effect of vitamin D on health is partially mediated through the microbiome. We aimed to critically evaluate the evidence linking vitamin D and the gastrointestinal microbiome.

Methods: We systematically searched the Embase, Web of Science, PubMed and CINAHL databases, including peer-reviewed publications that reported an association between a measure of vitamin D and the gastrointestinal microbiome in humans or experimental animals.

Results: We included 10 mouse and 14 human studies. Mouse studies compared mice fed diets containing different levels of vitamin D (usually high versus low), or vitamin D receptor knockout or Cyp27B1 knockout with wild-type mice. Five mouse studies reported an increase in Bacteroidetes (or taxa within that phylum) in the low vitamin D diet or gene knockout group. Human studies were predominantly observational; all but two of the included studies found some association between vitamin D and the gut microbiome, but the nature of differences observed varied across studies.

Conclusions: Despite substantial heterogeneity, we found evidence to support the hypothesis that vitamin D influences the composition of the gastrointestinal microbiome. However, the research is limited, having been conducted either in mice or in mostly small, selected human populations. Future research in larger population-based studies is needed to fully understand the extent to which vitamin D modulates the microbiome.
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http://dx.doi.org/10.1007/s00394-018-1842-7DOI Listing
October 2019

Mapping the virome in wild-caught Aedes aegypti from Cairns and Bangkok.

Sci Rep 2018 03 16;8(1):4690. Epub 2018 Mar 16.

Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, Qld, 4029, Australia.

Medically important arboviruses such as dengue, Zika, and chikungunya viruses are primarily transmitted by the globally distributed mosquito Aedes aegypti. Increasing evidence suggests that transmission can be influenced by mosquito viromes. Herein RNA-Seq was used to characterize RNA metaviromes of wild-caught Ae. aegypti from Bangkok (Thailand) and from Cairns (Australia). The two mosquito populations showed a high degree of similarity in their viromes. BLAST searches of assembled contigs suggest up to 27 insect-specific viruses may infect Ae. aegypti, with up to 23 of these currently uncharacterized and up to 16 infecting mosquitoes from both Cairns and Bangkok. Three characterized viruses dominated, Phasi Charoen-like virus, Humaita-Tubiacanga virus and Cell fusing agent virus, and comparisons with other available RNA-Seq datasets suggested infection levels with these viruses may vary in laboratory-reared mosquitoes. As expected, mosquitoes from Bangkok showed higher mitochondrial diversity and carried alleles associated with knock-down resistance to pyrethroids. Blood meal reads primarily mapped to human genes, with a small number also showing homology with rat/mouse and dog genes. These results highlight the wide spectrum of data that can be obtained from such RNA-Seq analyses, and suggests differing viromes may need to be considered in arbovirus vector competence studies.
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http://dx.doi.org/10.1038/s41598-018-22945-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856816PMC
March 2018

Patterns of Interindividual Variability in the Antibody Repertoire Targeting Proteins Across the Epstein-Barr Virus Proteome.

J Infect Dis 2018 05;217(12):1923-1931

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Background: Little is known about variation in antibody responses targeting the full spectrum of Epstein-Barr virus (EBV) proteins and how such patterns inform disease risk.

Methods: We used a microarray to measure immunoglobulin G (IgG) and immunoglobulin A (IgA) antibody responses against 199 EBV protein sequences from 5 EBV strains recovered from 289 healthy adults from Taiwan. We described positivity patterns, estimated the correlation between antibodies, and investigated the associations between environmental and genetic risk factors and variations in antibody responses.

Results: Healthy adults were more likely to mount IgG antibody responses to EBV proteins (median positivity frequency, 46.5% for IgG and 17.3% for IgA; P = 1.6 × 10-46, by the Wilcoxon rank sum test). Responses against glycoproteins were particularly prevalent. The correlations between antibody responses of the same class were higher than correlations across classes. The mucosal exposure to proteins involved in EBV reactivation (as determined by the IgA response) was associated with smoking (P = .002, by the sequence kernel association test-combined), and approximately one quarter of adults displayed antibody responses associated with EBV-related cancer risk.

Conclusions: These data comprehensively define the variability in human IgG and IgA antibody responses to the EBV proteome. Patterns observed can serve as the foundation for elucidating which individuals are at highest risk of EBV-associated clinical conditions and for identifying targets for effective immunodiagnostic tests.
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http://dx.doi.org/10.1093/infdis/jiy122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279144PMC
May 2018

Growth and protein-rich food intake in infancy is associated with fat-free mass index at 2-3 years of age.

J Paediatr Child Health 2018 07 1;54(7):770-775. Epub 2018 Mar 1.

Children's Nutrition Research Centre, Child Health Research Centre, Brisbane, Queensland, Australia.

Aim: The reduction of infant protein intake and associated growth velocity is a recommended public health strategy for reducing the risk of childhood obesity. This study tests the hypothesis that infants' growth and protein-rich food (dairy, meat, fish and egg) intake influences childhood body size and composition at 2-3 years of age.

Methods: Thirty-six children were studied from the Feeding Queensland Babies Study Cohort, which prospectively collected data on infant growth and diet. Body composition was estimated using the deuterium oxide dilution technique at 2-3 years of age.

Results: Fat-free mass index Z score at 2-3 years of age was positively associated with animal protein food (dairy, meat, fish and egg) intake at 12 months of age (r = 0.58, P = 0.002, false discovery rate corrected P value = 0.008) and negatively associated with weight-for-length growth velocity from 6 to 12 months of age (r = -0.75, P = 0.019, false discovery rate corrected P value = 0.038), which in turn was negatively associated with growth velocity from 0 to 6 months of age (r = -0.790, P = 0.007).

Conclusion: This study suggests that strategies to reduce protein intake and growth velocity in early life may limit fat-free mass growth, potentially predisposing to increased adiposity in later life.
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http://dx.doi.org/10.1111/jpc.13863DOI Listing
July 2018

Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan.

Clin Cancer Res 2018 03 4;24(6):1305-1314. Epub 2018 Jan 4.

Queensland Institute of Medical Research, Brisbane, Australia.

Epstein-Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls ( < 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status-BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%-98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%; 95% CI, 75%-90%, ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%; 95% CI, 82%-96%) compared with current biomarkers (78%; 95% CI, 66%-90%, ≤ 0.03). We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856605PMC
March 2018

Male-specific Association Between Fat-Free Mass Index and Fecal Microbiota in 2- to 3-Year-Old Australian Children.

J Pediatr Gastroenterol Nutr 2018 01;66(1):147-151

Children's Nutrition Research Centre, Child Health Research Centre.

Objectives: Maturation of the gut microbiota has been shown to influence childhood growth, whereas alterations in microbiota composition are proposed to be causally related to the development of overweight and obesity. The objective of this study is to explore the association between microbiota profile, body size, and body composition in young children.

Methods: Fecal microbiota was examined by 16S rRNA gene sequencing, whereas body composition was assessed using the deuterium oxide dilution technique in a cohort of 37 well-nourished 2- to 3-year-old Australian children.

Results: Microbiota composition (weighted UniFrac distance) was shown to be significantly associated with FFMI (fat-free mass index) z score (P = 0.027, adonis) in boys but not girls. In boys, FFMI z score was significantly correlated with the relative abundance of an OUT (Operational Taxonomic Unit) belonging to the Ruminococcaceae family (Rho = 0.822, P < 0.001, pFDR (false discovery rate adjusted P value) = 0.002, n = 18). At a FDR <0.2, FFMI z score in boys was positively associated with the relative abundance of OTU related to Dorea formicigenerans and Faecalibacterium prausnitzii and negatively correlated to an OTU related to Bacteroides cellulosilyticus.

Conclusions: These results suggest that previously reported associations between microbiota composition and body size may be driven by an association with fat-free mass, particularly in males.
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http://dx.doi.org/10.1097/MPG.0000000000001780DOI Listing
January 2018

Infections by human gastrointestinal helminths are associated with changes in faecal microbiota diversity and composition.

PLoS One 2017 11;12(9):e0184719. Epub 2017 Sep 11.

Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

Investigations of the impact that patent infections by soil-transmitted gastrointestinal nematode parasites exert on the composition of the host gut commensal flora are attracting growing interest by the scientific community. However, information collected to date varies across experiments, and further studies are needed to identify consistent relationships between parasites and commensal microbial species. Here, we explore the qualitative and quantitative differences between the microbial community profiles of cohorts of human volunteers from Sri Lanka with patent infection by one or more parasitic nematode species (H+), as well as that of uninfected subjects (H-) and of volunteers who had been subjected to regular prophylactic anthelmintic treatment (Ht). High-throughput sequencing of the bacterial 16S rRNA gene, followed by bioinformatics and biostatistical analyses of sequence data revealed no significant differences in alpha diversity (Shannon) and richness between groups (P = 0.65, P = 0.13 respectively); however, beta diversity was significantly increased in H+ and Ht when individually compared to H-volunteers (P = 0.04). Among others, bacteria of the families Verrucomicrobiaceae and Enterobacteriaceae showed a trend towards increased abundance in H+, whereas the Leuconostocaceae and Bacteroidaceae showed a relative increase in H- and Ht respectively. Our findings add valuable knowledge to the vast, and yet little explored, research field of parasite-microbiota interactions and will provide a basis for the elucidation of the role such interactions play in pathogenic and immune-modulatory properties of parasitic nematodes in both human and animal hosts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184719PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593201PMC
October 2017

Microbiota of little penguins and short-tailed shearwaters during development.

PLoS One 2017 14;12(8):e0183117. Epub 2017 Aug 14.

School of Exercise and Nutritional Sciences, Deakin University, Burwood, Australia.

The establishment and early colonisation of the gastrointestinal (GI) tract has been recognised as a crucial stage in chick development, with pioneering microbial species responsible for influencing the development of the GI tract and influencing host health, fitness and disease status throughout life. Development of the microbiota in long lived seabirds is poorly understood. This study characterised the microbial composition of little penguin and short-tailed shearwater chicks throughout development, using Quantitative Real Time PCR (qPCR) and 16S rRNA sequencing. The results indicated that microbial development differed between the two seabird species with the short-tailed shearwater microbiota being relatively stable throughout development whilst significant fluctuations in the microbial composition and an upward trend in the abundance of Firmicutes and Bacteroidetes were observed in the little penguin. When the microbial composition of adults and chicks was compared, both species showed low similarity in microbial composition, indicating that the adult microbiota may have a negligible influence over the chick's microbiota.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183117PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555571PMC
October 2017