Faculty Bibliography

BACKGROUND: Previous studies have demonstrated an association between antibiotic use and the development of skin abscesses. We tested the hypothesis that alterations in the composition of the cutaneous microbiota may predispose individuals to skin abscesses. METHODS: We studied 25 patients with skin abscesses and 25 age-matched controls, who each completed a questionnaire. Skin swab samples were obtained for DNA analysis from 4 sites around the abscess site (hereafter, "peri-abscess specimens") and from similar sites on the patient's contralateral side and on healthy control subjects. DNA was extracted and analyzed by quantitative polymerase chain reaction (qPCR) and high-throughput sequencing. The purulent abscess drainage was sent for culture. RESULTS: Fifteen patients with abscess were infected with Staphylococcus aureus. Use of nuc qPCR to quantitate S. aureus revealed a significantly greater frequency of positive results for peri-abscess and contralateral skin samples, compared with control skin specimens. Analysis of community structure showed greater heterogeneity in the control samples than in the peri-abscess and contralateral samples. Metagenomic analysis detected significantly more predicted genes related to metabolic activity in the peri-abscess specimens than in the control samples. CONCLUSIONS: The peri-abscess microbiome was similar to the contralateral microbiome, but both microbiomes differed from that for control patients. Host characteristics affecting microbial populations might be important determinants of abscess risk.

Helicobacter pylori persistently colonizes the human stomach, with mixed roles in human health. The CagA protein, a key host-interaction factor, is translocated by a type IV secretion system into host epithelial cells, where its EPIYA tyrosine phosphorylation motifs (TPMs) are recognized by host cell kinases, leading to multiple host cell signaling cascades. The CagA TPMs have been described as type A, B, C or D, each with a specific conserved amino acid sequence surrounding EPIYA. Database searching revealed strong non-random distribution of the B-motifs (including EPIYA and EPIYT) in Western H. pylori isolates. In silico analysis of Western H. pylori CagA sequences provided evidence that the EPIYT B-TPMs are significantly less associated with gastric cancer than the EPIYA B-TPMs. By generating and using a phosphorylated CagA B-TPM-specific antibody, we demonstrated the phosphorylated state of the CagA B-TPM EPIYT during H. pylori co-culture with host cells. We also showed that within host cells, CagA interaction with phosphoinositol 3-kinase (PI3-kinase) was B-TPM tyrosine-phosphorylation-dependent, and the recombinant CagA with EPIYT B-TPM had higher affinity to PI3-kinase and enhanced induction of AKT than the isogenic CagA with EPIYA B-TPM. Structural modeling of the CagA B-TPM motif bound to PI3-kinase indicated that the threonine residue at the pY+1 position forms a side-chain hydrogen bond to N-417 of PI3-kinase, which cannot be formed by alanine. During co-culture with AGS cells, an H. pylori strain with a CagA EPIYT B-TPM had significantly attenuated induction of interleukin-8 and hummingbird phenotype, compared to the isogenic strain with B-TPM EPIYA. These results suggest that the A/T polymorphisms could regulate CagA activity through interfering with host signaling pathways related to carcinogenesis, thus influencing cancer risk.

BACKGROUND: More than half of the world's adults carry Helicobacter pylori. The eradication of H. pylori may affect the regulation of human metabolic hormones. The aim of this study was to evaluate the effect of H. pylori eradication on meal-associated changes in appetite-controlled insulinotropic and digestive hormones, and to assess post-eradication changes in body mass index as part of a currently on-going multicentre ESSAY (Eradication Study in Stable Adults/Youths) study. METHODS: We enrolled 29 H. pylori-positive young adult (18-30 year-old) volunteer subjects to evaluate the effect of H. pylori eradication on meal-associated changes on eight gastrointestinal hormones, using a multiplex bead assay. Changes in body mass index and anthropometric measurements were recorded, pre- and post-eradication therapy. RESULTS: Pre-prandial active amylin, total peptide YY (PYY) and pancreatic polypeptide (PP) levels were significantly elevated 12 months post-eradication compared with baseline (n = 18; Wilcoxon's signed rank test, p<0.05). Four of the post-prandial gut metabolic hormones levels (GLP-1, total PYY, active amylin, PP) were significantly higher 12 months post-eradication compared to baseline (n = 18; p<0.05). Following H. pylori eradication, the BMI and anthropometric values did not significantly change. CONCLUSIONS: Our study indicates that H. pylori eradication was associated with long-term disturbance in three hormones (active amylin, PP and total PYY) both pre- and post-prandially and one hormone (GLP-1) post-prandially. Longer post-eradication monitoring is needed to investigate the long-term impact of the observed hormonal changes on metabolic homeostasis.

The isolation of Helicobacter pylori from the human stomach produced significant changes in how gastroenterologists, immunologists, epidemiologists, pathologists and microbiologists have approached gastro-duodenal diseases in the last half of the XX century. However, research of this organism has progressed greatly in the first decade of this century, evidence suggest that H. pylori is associated with disease only in humans older than 40 years, while, the lack of H. pylori colonization is associated with the emergence of new diseases, particularly in younger individuals. These differing effects of H. pylori colonization have created two contrasting concepts: the 'bad' and the 'good' Helicobacter. Following from renewed interest in the normal human microbiome, we need to reconsider our definitions and perhaps recognize that H. pylori might be a normal member of the human gastric microbiome in ancient humans that gradually, as results of the improvement in our environment, is disappearing.

INTRODUCTION: Helicobacter pylori (H. pylori) colonization rates in childhood have declined in Western populations, but it is unknown whether this trend is similar in children of non-Western ethnic backgrounds, who are born in a Western country. Insight into colonization and transmission of H. pylori could improve approaches to assessing H. pylori-related diseases. AIMS & METHODS: We aimed to identify H. pylori status in mothers and their children, and to determine both mother-to-child transmission and factors associated with loss of H. pylori in one generation. Antibodies against H. pylori and cytotoxin-associated gene A (CagA) were measured in mothers and children participating in a population-based prospective cohort study in Rotterdam, the Netherlands. Information on demographics, maternal and child's characteristics was collected using questionnaires. Logistic regression analysis was used to assess factors associated with loss of H. pylori, including the following: gender, ethnicity, mother's educational level, delivery mode, breastfeeding, number of older siblings, day-care attendance, and cumulative antibiotic exposures. RESULTS: H. pylori and CagA status were determined in 3,185 mothers and their children. In mothers (mean age of 30.5 +/-5.0 years), the overall H. pylori colonization rate was 42%, compared to 10% (p<0.001) in their children (mean age of 6.2 +/-0.5 years). An H. pylori-positive mother was associated with an H. pylori-positive child (OR 3.22; 95% CI 2.52-4.12). Overall, the H. pylori prevalence decreased 76% comparing mothers and their children. A significant and consistent decline in both H. pylori⁺CagA^- and H. pylori⁺CagA⁺- strains was observed across all nine ethnic groups studied. Multivariate analysis of the loss of H. pylori in children with an H. pylori-positive mother (n = 1,328) revealed male gender (OR 1.64; 95% CI 1.21-2.23), higher maternal education level (OR 1.78; 95% CI 1.15-2.76), and no older siblings (OR 1.37; 95% CI 1.01- 1.88) independently associated with an H. pylori-negative child. CONCLUSION: We identified a large decline in H. pylori colonization rate in children living in a European city. The observed drop was uniform across all ethnic groups, implying the importance of environmental factors in H. pylori transmission in modern cities, independent of ethnicity

INTRODUCTION: The declined Helicobacter pylori (H. pylori) prevalence in Western countries is suggested to be associated with the simultaneous increases in childhood asthma and allergic diseases. Bacterial exposure during childhood may be protective for asthma and atopy. AIMS & METHODS: We aimed to examine the association between children's H. pylori colonization and asthma or related diseases. This study was embedded in The Generation R Study, a population-based prospective multi-ethnic cohort study among children, followed from early pregnancy onwards. We measured anti-H. pylori and anti-CagA-IgG antibodies in serum of children obtained at age of 6 years. Also at age 6 years, asthma-related outcomes including ever wheezing, physician-diagnosed asthma, and eczema were obtained by questionnaires. Data analyses were performed in the total cohort as well as in different ethnic groups (Western vs. non-Western). Multivariate logistic regression analyses were adjusted for maternal educational level, history of asthma and atopy, smoking during pregnancy, and parity, and for child's gender, ethnicity, gestational age at birth, birth weight, breastfeeding habits, day-care attendance, pet keeping, and lower respiratory tract infections. RESULTS: In total 3,838 children (mean age 6.1 +/- SD 0.5) were available for these analyses. Of those, 328 (9%) were H. pylori-positive, of whom 100 (30%) were CagA-positive. Univariate analyses revealed the following results of comparison between H. pylori-positive versus negative children: ever wheezing [63.3% vs. 56.0% (p=0.07)], physician-diagnosed asthma [11.2% vs. 6.6% (p=0.01)], and eczema [27.0% vs. 22.2% (p=0.07)]. In multivariate analyses H. pylori-positivity was associated with physician-diagnosed asthma (odds ratio (OR) 1.63; 95% CI 1.02-2.61), but not with ever wheezing (OR 1.02; 95% CI 0.85-1.23) or eczema (OR 1.06; 95% CI 0.79-1.41). A significant interaction between H. pylori and ethnicity was found for wheezing (p<0.001) and eczema (p=0.006). Analyses stratified according to ethnicity showed that H. pylori-positivity was inversely associated with ever wheezing (OR 0.66; 95% CI 0.48-0.91), and eczema (OR 0.64; 95% CI 0.41-1.00) in children of non-Western ethnicity (n= 1,155), but not in children of Western ethnicity (n= 2,683). This negative association was mainly explained by the CagA-positive strains. CONCLUSION: H. pylori colonization is negatively associated with both wheezing and eczema in children of non-Western ethnicity, with the strongest inverse effect found for CagA-positive strains. In contrast, in all children H. pyloricolonization was positively associated with physician-diagnosed asthma to the age of 6 years. Trends in the Western and non-Western children appear opposite

BACKGROUND: Skin is our first line of defense against pathogenic microorganisms and the intimate contact between the epidermis and microbes has been well known. PURPOSES: Microbes that cause infection are associated with inflammatory dermatoses and exacerbate wound healing. It is therefore of vital importance to understand the intricacies of skin-microbiota interactions. However, until recently our knowledge and understanding was limited by being unable to deal with uncultivatable microorganisms, which constitute a large majority. BASIC PROCEDURES: Recent advances in DNA sequencing methodologies, analysis tools and affordability led to major breakthroughs in defining the cutaneous microbiome. MAIN FINDINGS: We now know that four phyla, Actinobacteria, Firmicytes, Proteobacteria and Bacteroidetes, constitute preponderance of skin bacteria, while Malassezia dominates the fungal microbiome. We know that there are some 300 different bacteria inhabiting our skin. We also know that there is remarkable interpersonal variation, that the microbiota change over time, that different body sites harbor specific microbial arrays and that microbiota characteristically change in skin diseases. PRINCIPAL CONCLUSIONS: The recent advances led to appreciation that microbes are, for the most part, our allies, useful and protective, and that with increased understanding we will be able to harness our cutaneous friends to maintain and promote our health.

BACKGROUND: Gastric Helicobacter pylori (H. pylori) infection and colorectal polyps are more prevalent in African Americans than in the general population. We aimed to investigate whether gastric H. pylori infection is associated with colorectal polyps in African Americans. METHODS: Medical records of African Americans, 40 years and older (n = 1256) who underwent bidirectional gastrointestinal endoscopy on the same day were reviewed. H. pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of colorectal biopsies. A subset of serum samples from healthy and polyp-bearing patients (n = 163) were analyzed by ELISA for anti-H. pylori and anti-CagA antibodies. The crude and adjusted effect of H. pylori on the risk of colorectal adenoma and polyp were computed by logistic regression models. RESULTS: The prevalence of colorectal polyps and adenomas were 456 (36%) and 300 (24%) respectively. Colorectal polyps were more prevalent in gastric H. pylori infected than non-infected subjects [43% vs. 34%; Odds Ratio (OR) (95% CI): 1.5 (1.2-1.9), P = 0.001]. Patients with H. pylori-associated chronic active gastritis were at high risk to have adenomas [Unadjusted OR (95% CI): 1.3 (1.0-1.8); P = 0.04]. There was no difference in histopathology, size, or location of polyps with respect to H. pylori status. Gastric H. pylori infection, age, male gender and high risk clinical presentations were independent risk factors for colorectal polyps. Serological testing also revealed a higher prevalence of H. pylori and its toxin Cag-A in polyp patients vs. non polyp patients' sera, although in a non-statistically significant manner. CONCLUSIONS: This study showed that current gastric H. pylori infection is associated with an increased risk of colorectal polyps in African Americans. Patients with H. pylori induced gastritis may benefit from early screening colonoscopy as a preventative measure for colorectal cancer.

Helicobacter pylori (H. pylori) affects nearly half of the world's population and, thus, is one of the most frequent and persistent bacterial infections worldwide. H. pylori is associated with peptic ulcer disease, gastric ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Various diagnostic methods exist to detect infection, and the choice of one method or another depends on several factors, such as accessibility, advantages and disadvantages of each method, cost, and the age of patients. Once H. pylori infection is diagnosed, the clinician decides whether treatment is necessity, according to the patient's clinical condition. Typically, eradication of H. pylori is recommended for treatment and prevention of the infection. Cure rates with the standard triple therapy are acceptable, and effective quadruple therapies, sequential therapies, and concomitant therapies have been introduced as key alternatives to treat H. pylori infection. In this work, we review the main diagnostic methods used to identify H. pylori infection and to confirm eradication of infection. In addition, key factors related to treatment are reviewed.