The fungal microbiota of de-novo paediatric inflammatory bowel disease

Date of Acceptance:01/12/2014 Acknowledgements We are grateful for the expertise of our sequencing provider NewGene. We appreciate the generosity of the families who freely gave their time and samples to make this study possible and the theatre staff of all centres who allowed time for sample collection during busy endoscopy lists. This work was funded by a Clinical Academic Training Fellowship from the Chief Scientist Office in Scotland (CAF/08/01) which also funded the salary of RH, the Broad Medical Research programme and a project grant from NHS Grampian Endowments. The Yorkhill IBD team is generously supported by the Catherine McEwan Foundation and the Yorkhill IBD fund. RKR is supported by an NHS research Scotland fellowship. RKR has received support from a Medical Research Council (MRC) patient research cohorts initiative grant (G0800675) for PICTS.Peer reviewedPublisher PD

A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease

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Australia IBD Microbiome (AIM) Study: protocol for a multicentre longitudinal prospective cohort study.

INTRODUCTION: Crohn's disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia's first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota. METHODS: The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants; 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3 monthly intervals over a 24-month period. At each assessment oral and faecal samples are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be sampled whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated self-report questionnaires. Samples will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12619000911190

The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors (TLR) are key innate immunity receptors participating in an immune response. Growing evidence suggests that mutations of TLR2/TLR9 gene are associated with the progress of cancers. The present study aimed to investigate the temporal relationship of single nucleotide polymorphisms (SNP) of TLR2/TLR9 and the risk of hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>In this single center-based case-control study, SNaPshot method was used to genotype sequence variants of TLR2 and TLR9 in 211 patients with HCC and 232 subjects as controls.</p> <p>Results</p> <p>Two synonymous SNPs in the exon of TLR2 were closely associated with risk of HCC. Compared with those carrying wild-type homozygous genotypes (T/T), risk of HCC decreased significantly in individuals carrying the heterozygous genotypes (C/T) of the rs3804099 (adjusted odds ratio (OR), 0.493, 95% CI 0.331 - 0.736, <it>P </it>< 0.01) and rs3804100 (adjusted OR, 0.509, 95% CI 0.342 - 0.759, <it>P </it>< 0.01). There was no significant association found in two TLR9 SNPs concerning the risk of HCC. The haplotype TT for TLR2 was associated significantly with the decreased risk of HCC (OR 0.524, 95% CI 0.394 - 0.697, <it>P </it>= 0.000). Inversely, the risk of HCC increased significantly in patients with the haplotype CC (OR 2.743, 95% CI 1.915 - 3.930, <it>P </it>= 0.000).</p> <p>Conclusions</p> <p>These results suggested that TLR2 rs3804099 C/T and rs3804100 C/T polymorphisms were closely associated with HCC. In addition, the haplotypes composed of these two TLR2 synonymous SNPs have stronger effects on the susceptibility of HCC.</p

The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study

&lt;p&gt;Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.&lt;/p&gt; &lt;p&gt;Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.&lt;/p&gt; &lt;p&gt;Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).&lt;/p&gt; &lt;p&gt;Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.&lt;/p&gt

Genotype-Dependent Tumor Regression in Marek’s Disease Mediated at the Level of Tumor Immunity

Marek’s disease (MD) of chickens is a unique natural model of Hodgkin’s and Non Hodgkin’s lymphomas in which the neoplastically-transformed cells over-express CD30 (CD30hi) antigen. All chicken genotypes can be infected with MD virus and develop microscopic lymphomas. From 21 days post infection (dpi) microscopic lymphomas regress in resistant chickens but, in contrast, they progress to gross lymphomas in susceptible chickens. Here we test our hypothesis that in resistant chickens at 21 dpi the tissue microenvironment is pro T-helper (Th)-1 and compatible with cytotoxic T lymphocyte (CTL) immunity but in susceptible lines it is pro Th-2 or pro T-regulatory (T-reg) and antagonistic to CTL immunity. We used the B2, non-MHC-associated, MD resistance/susceptibility system (line [L]61/line [L]72) and quantified the levels of key mRNAs that can be used to define Th-1 (IL-2, IL-12, IL-18, IFNγ), Th-2 (IL-4, IL-10) and T-reg (TGFβ, GPR-83, CTLA-4, SMAD-7) lymphocyte phenotypes. We measured gene expression in both whole tissues (represents tissue microenvironment and tumor microenvironment) and in the lymphoma lesions (tumor microenvironment) themselves. Gene ontology-based modeling of our results shows that the dominant phenotype in whole tissue as well as in microscopic lymphoma lesions, is pro T-reg in both L61 and L72 but a minor pro Th-1 and anti Th-2 tissue microenvironment exists in L61 whereas there is an anti Th-1 and pro Th-2 tissue microenvironment in L72. The tumor microenvironment per se is pro T-reg, anti Th-1 and pro Th-2 in both L61 and L72. Together our data suggests that the neoplastic transformation is essentially the same in both L61 and L72 and that resistance/susceptibility is mediated at the level of tumor immunity in the tissues

Genetic Variation in Selenoprotein Genes, Lifestyle, and Risk of Colon and Rectal Cancer

BACKGROUND: Associations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process. METHODS: We used data from two population-based case-control studies of colon (n = 1555 cases, 1956 controls) and rectal (n = 754 cases, 959 controls) cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH), SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk. RESULTS: After adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208). Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300). Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR) and rectal cancer (SepX1 increased HRR). CONCLUSIONS: Findings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is modified by lifestyle

The Smell of Age: Perception and Discrimination of Body Odors of Different Ages

Our natural body odor goes through several stages of age-dependent changes in chemical composition as we grow older. Similar changes have been reported for several animal species and are thought to facilitate age discrimination of an individual based on body odors, alone. We sought to determine whether humans are able to discriminate between body odor of humans of different ages. Body odors were sampled from three distinct age groups: Young (20–30 years old), Middle-age (45–55), and Old-age (75–95) individuals. Perceptual ratings and age discrimination performance were assessed in 41 young participants. There were significant differences in ratings of both intensity and pleasantness, where body odors from the Old-age group were rated as less intense and less unpleasant than body odors originating from Young and Middle-age donors. Participants were able to discriminate between age categories, with body odor from Old-age donors mediating the effect also after removing variance explained by intensity differences. Similarly, participants were able to correctly assign age labels to body odors originating from Old-age donors but not to body odors originating from other age groups. This experiment suggests that, akin to other animals, humans are able to discriminate age based on body odor alone and that this effect is mediated mainly by body odors emitted by individuals of old age

Expression of neutrophil gelatinase-associated lipocalin in colorectal neoplastic progression:A marker of malignant potential?

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