OBJECTIVE.The aim of this study was to examine the contribution of a broad range of external influences to the gut microbiotic composition in early infancy. METHODS.Fecal samples from 1032 infants at 1 month of age, who were recruited from the KOALA Birth Cohort Study in the Netherlands, were subjected to quantitative real-time polymerase chain reaction assays for the enumeration of bifidobacteria, Escherichia coli, Clostridium difficile, Bacteroides fragilis group, lactobacilli, and total bacterial counts. Information on potential determinants of the gut microbiotic composition was collected with repeated questionnaires. The associations between these factors and the selected gut bacteria were analyzed with univariate and multivariate analyses. RESULTS.Infants born through cesarean section had lower numbers of bifidobacteria and Bacteroides, whereas they were more often colonized with C difficile, compared with vaginally born infants. Exclusively formula-fed infants were more often colonized with E coli, C difficile, Bacteroides, and lactobacilli, compared with breastfed infants. Hospitalization and prematurity were associated with higher prevalence and counts of C difficile. Antibiotic use by the infant was associated with decreased numbers of bifidobacteria and Bacteroides. Infants with older siblings had slightly higher numbers of bifidobacteria, compared with infants without siblings. CONCLUSIONS.The most important determinants of the gut microbiotic composition in infants were the mode of delivery, type of infant feeding, gestational age, infant hospitalization, and antibiotic use by the infant. Term infants who were born vaginally at home and were breastfed exclusively seemed to have the most “beneficial” gut microbiota (highest numbers of bifidobacteria and lowest numbers of C difficile and E coli).

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Factors influencing the composition of the intestinal microbiota in early infancy

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403-16. ©2018 AACR.See related commentary by Riquelme et al., p. 386This article is highlighted in the In This Issue feature, p. 371.

/pdf/the-pancreatic-cancer-microbiome-promotes-oncogenesis-by-3szkpofosl.pdf

The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression

The composition of the human intestinal microbiota is linked to health status. The aim was to analyze the microbiota of normal and colon cancer patients in order to establish cancer-related dysbiosis. Patients and Methods: Stool bacterial DNA was extracted prior to colonoscopy from 179 patients: 60 with colorectal cancer, and 119 with normal colonoscopy. Bacterial genes obtained by pyrosequencing of 12 stool samples (6 Normal and 6 Cancer) were subjected to a validated Principal Component Analysis (PCA) test. The dominant and subdominant bacterial population (C. leptum, C. coccoides, Bacteroides/Prevotella, Lactobacillus/Leuconostoc/Pediococcus groups, Bifidobacterium genus, and E. coli, and Faecalibacterium prausnitzii species) were quantified in all individuals using qPCR and specific IL17 producer cells in the intestinal mucosa were characterized using immunohistochemistry. Findings: Pyrosequencing (Minimal sequence 200 nucleotide reads) revealed 80% of all sequences could be assigned to a total of 819 taxa based on default parameter of Classifier software. The phylogenetic core in Cancer individuals was different from that in Normal individuals according to the PCA analysis, with trends towards differences in the dominant and subdominant families of bacteria. Consequently, All-bacteria [log(10) (bacteria/g of stool)] in Normal, and Cancer individuals were similar [11.88 +/- 0.35, and 11.80 +/- 0.56, respectively, (P = 0.16)], according to qPCR values whereas among all dominant and subdominant species only those of Bacteroides/Prevotella were higher (All bacteria-specific bacterium; P = 0.009) in Cancer (-1.04 +/- 0.55) than in Normal (-1.40 +/- 0.83) individuals. IL17 immunoreactive cells were significantly expressed more in the normal mucosa of cancer patients than in those with normal colonoscopy. Conclusion: This is the first large series to demonstrate a composition change in the microbiota of colon cancer patients with possible impact on mucosal immune response. These data open new filed for mass screening and pathophysiology investigations.

/pdf/microbial-dysbiosis-in-colorectal-cancer-crc-patients-1vv5ubtbi1.pdf

Microbial dysbiosis in colorectal cancer (CRC) patients.

Objective. Altered bacterial diversity of the intestinal mucosa-associated microbiota may reflect the net influence of lifestyle factors associated with the development of chronic inflammatory bowel diseases (IBD). While a reduced bacterial diversity has been reported in IBD, little is known about the fungal microbiota. The aim of this study was to carry out a systematic analysis of intestinal fungal microbiota in IBD. Material and methods. The mucosa-associated fungal microbiota of 104 colonic biopsy tissues from 47 controls and 57 IBD patients was investigated using metagenomic 18S rDNA-based denaturing gradient gel electrophoresis (DGGE), clone libraries, sequencing, and in situ hybridization techniques. Results. Fungi-specific 18S rDNA signatures could be detected in all 104 patients, accounting for only a small proportion of the intestinal microbiota (0.02% of the mucosal and 0.03% of the fecal microbiota). An overall fungal biodiversity of 43 different operational taxonomic units (OTUs) was found in...

Fungi and inflammatory bowel diseases: Alterations of composition and diversity

The human superorganism is a conglomerate of mammalian and microbial cells, with the latter estimated to outnumber the former by ten to one and the microbial genetic repertoire (microbiome) to be approximately 100-times greater than that of the human host. Given the ability of the immune response to rapidly counter infectious agents, it is striking that such a large density of microbes can exist in a state of synergy within the human host. This is particularly true of the distal gastrointestinal (GI) tract, which houses up to 1000 distinct bacterial species and an estimated excess of 1 × 1014 microorganisms. An ever-increasing body of evidence implicates the GI microbiota in defining states of health and disease. Here, we review the literature in adult and pediatric GI microbiome studies, the emerging links between microbial community structure, function, infection and disease, and the approaches to manipulate this crucial ecosystem to improve host health.

/pdf/role-of-the-gut-microbiota-in-defining-human-health-290qzf5uc0.pdf

Role of the gut microbiota in defining human health

The composition of the human intestinal flora is important for the health status of the host. The global composition and the presence of specific pathogens are relevant to the effects of the flora. Therefore, accurate quantification of all major bacterial populations of the enteric flora is needed. A TaqMan real-time PCR-based method for the quantification of 20 dominant bacterial species and groups of the intestinal flora has been established on the basis of 16S ribosomal DNA taxonomy. A PCR with conserved primers was used for all reactions. In each real-time PCR, a universal probe for quantification of total bacteria and a specific probe for the species in question were included. PCR with conserved primers and the universal probe for total bacteria allowed relative and absolute quantification. Minor groove binder probes increased the sensitivity of the assays 10- to 100-fold. The method was evaluated by cross-reaction experiments and quantification of bacteria in complex clinical samples from healthy patients. A sensitivity of 101 to 103 bacterial cells per sample was achieved. No significant cross-reaction was observed. The real-time PCR assays presented may facilitate understanding of the intestinal bacterial flora through a normalized global estimation of the major contributing species.

/pdf/quantification-of-intestinal-bacterial-populations-by-real-2d7mb8xrls.pdf

Quantification of Intestinal Bacterial Populations by Real-Time PCR with a Universal Primer Set and Minor Groove Binder Probes: a Global Approach to the Enteric Flora

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Quantification of Intestinal Bacterial Populations by Real-Time PCR with a Universal Primer Set and Minor Groove Binder Probes: a Global Approach to the Enteric Flora