Gut microbiota analyses of cutaneous T-cell lymphoma patients undergoing narrowband ultraviolet B therapy reveal alterations associated with disease treatment.

Recent studies have shown a close relationship between cutaneous T-cell lymphoma (CTCL) and its microbiome. CTCL disease progression is associated with gut dysbiosis and alterations in bacterial taxa parallel those observed in immunologically similar atopic dermatitis. Moreover, the microbial profile of lesional skin may predict response to narrowband ultraviolet B (nbUVB), a common skin-directed therapy. However, the relationship between the gut microbiome, an immunologically vital niche, and nbUVB remains unexplored in CTCL. Herein, we performed 16S rRNA sequencing and PICRUSt2 predictive metagenomics on DNA extracted from stool swabs of 13 CTCL patients treated with nbUVB, 8 non-treated patients, and 13 healthy controls. Disease response was assessed with modified Severity Weighted Assessment Tool (mSWAT); of nbUVB-treated patients, 6 improved (decreased mSWAT), 2 remained stable, and 5 worsened (increased mSWAT). Protective commensal bacteria including Lactobacillaceae and Erysipelatoclostridiaceae were significantly less abundant in CTCL patients compared to controls. With treatment, the CTCL gut microbiome exhibited decreased phylogenetic diversity and lower relative abundance of pro-inflammatory Sutterellaceae. Sutterellaceae was also significantly more abundant in patients who worsened, and Eggerthellaceae and Erysipelotrichaceae trended higher in patients who improved. Finally, PICRUSt2 functional predictions based on shifts in abundance of bacterial sequences repeatedly identified alterations in inositol degradation, which plays a key role in host immunomodulation, including inositol phospholipid signaling relevant to T-cell survival and proliferation. Our results bolster the paradigm of gut dysbiosis in CTCL and its functional implications in disease pathogenesis, and further delineate bacterial taxa associated with nbUVB response and with nbUVB treatment itself.

Narrowband ultraviolet B response in cutaneous T-cell lymphoma is characterized by increased bacterial diversity and reduced Staphylococcus aureus and Staphylococcus lugdunensis.

Skin microbiota have been linked to disease activity in cutaneous T-cell lymphoma (CTCL). As the skin microbiome has been shown to change after exposure to narrowband ultraviolet B (nbUVB) phototherapy, a common treatment modality used for CTCL, we performed a longitudinal analysis of the skin microbiome in CTCL patients treated with nbUVB. 16S V4 rRNA gene amplicon sequencing for genus-level taxonomic resolution, tuf2 amplicon next generation sequencing for staphylococcal speciation, and bioinformatics were performed on DNA extracted from skin swabs taken from lesional and non-lesional skin of 25 CTCL patients receiving nbUVB and 15 CTCL patients not receiving nbUVB from the same geographical region. Disease responsiveness to nbUVB was determined using the modified Severity Weighted Assessment Tool: 14 (56%) patients responded to nbUVB while 11 (44%) patients had progressive disease. Microbial α-diversity increased in nbUVB-responders after phototherapy. The relative abundance of Staphylococcus, Corynebacterium, Acinetobacter, Streptococcus, and Anaerococcus differentiated nbUVB responders and non-responders after treatment (q<0.05). Microbial signatures of nbUVB-treated patients demonstrated significant post-exposure depletion of S. aureus (q=0.024) and S. lugdunensis (q=0.004) relative abundances. Before nbUVB, responder lesional skin harboured higher levels of S. capitis (q=0.028) and S. warneri (q=0.026) than non-responder lesional skin. S. capitis relative abundance increased in the lesional skin of responders (q=0.05) after phototherapy; a similar upward trend was observed in non-responders (q=0.09). Post-treatment skin of responders exhibited significantly reduced S. aureus (q=0.008) and significantly increased S. hominis (q=0.006), S. pettenkoferi (q=0.021), and S. warneri (q=0.029) relative abundances compared to that of no-nbUVB patients. Staphylococcus species abundance was more similar between non-responders and no-nbUVB patients than between responders and no-nbUVB patients. In sum, the skin microbiome of CTCL patients who respond to nbUVB is different from that of non-responders and untreated patients, and is characterized by shifts in S. aureus and S. lugdunensis. Non-responsiveness to phototherapy may reflect more aggressive disease at baseline.

Update on Associated Risk Factors, Diagnosis, and Management of Recurrent Urinary Tract Infections in Children.

Recurrent urinary tract infection (rUTI) continues to challenge pediatric care providers. The diagnosis of an rUTI can be difficult, especially in young febrile children. Antibiotic resistance rates continue to rise, which limits oral treatment options. Prophylactic antibiotics are used commonly to manage rUTI, but their use increases the risk of rUTI with antibiotic-resistant strains without significantly reducing renal scarring. Alternative therapies for rUTI include probiotics and anthocyanidins (eg, cranberry extract) to reduce gut colonization by uropathogens and prevent bacterial adhesion to uroepithelia, but efficacy data for these treatments are sparse. The future of rUTI care rests in addressing the following contemporary issues: best diagnostic practices, risk factors associated with rUTI, and the prevention of recurrent infection. In this review, we summarize the state of the art for each of these issues and highlight future studies that will aim to take an alternative approach to managing rUTI.

Predominant bacteria and patterns of antibiotic susceptibility in urinary tract infection in children with spina bifida.

BACKGROUND: Urinary tract infection is more common in children with spina bifida (SB) than neurologically intact children, and Escherichia coli is the most common urinary pathogen in the general pediatric population. Less is known of the pathogens responsible for urinary tract infections (UTI) in the pediatric SB population or their evolving antimicrobial resistance patterns. The goal of this study is to determine the epidemiology and antimicrobial resistance patterns of SB-associated urinary pathogens. METHODS: Between January 1996 and August 2013, 231 patients aged 1 month to 18 years were identified with a diagnosis of SB-NB and at least one symptomatic urinary tract infection (UTI) event (Table). Two-hundred and thirty-one normally voiding children with a single symptomatic UTI were age-matched based on age at diagnosis of UTI at a 1:1 ratio. Chi-square tests and Generalized Estimating Equation analysis, controlling for clinicopathological factors, were performed to compare rates of pathogen-associations with UTI between groups and likelihood of UTI with multi-drug resistant (MDR) organisms. RESULTS: Children in the SB-NB group had a higher rate of non-E. coli UTI compared with controls (64% vs. 41%, p < 0.01), particularly associated with Klebsiella species the SB-NB group had an overall higher infection rate with MDR organisms (21% vs. 10%, p < 0.01) and E. coli isolates, with a trend towards increased rates of antibiotic resistance to aminoglycosides, fluoroquinolones, cephalosporins, extended spectrum ß-lactams, and TMP-SMZ. Additionally, patients in the SB-NB group had a 10-fold increase of urosepsis with 57% of events caused by MDR organisms. CONCLUSIONS: Children with SB-NB are more likely to have non-E. coli UTI, UTIs with MDR organisms, and urosepsis than the general pediatric population.

Enteral High Fat-Polyunsaturated Fatty Acid Blend Alters the Pathogen Composition of the Intestinal Microbiome in Premature Infants with an Enterostomy.

OBJECTIVE: To determine the effect of enteral fish oil and safflower oil supplementation on the intestinal microbiome in infants with an enterostomy born premature. STUDY DESIGN: Infants with an enterostomy born premature were randomized to receive early enteral supplementation with a high-fat polyunsaturated fatty acid (HF-PUFA) blend of fish oil and safflower oil vs standard nutritional therapy. We used 16S rRNA gene sequencing for longitudinal profiling of the microbiome from the time of study entry until bowel reanastomosis. We used weighted gene coexpression network analysis to identify microbial community modules that differed between study groups over time. We performed imputed metagenomic analysis to determine metabolic pathways associated with the microbial genes. RESULTS: Sixteen infants were randomized to receive enteral HF-PUFA supplementation, and 16 infants received standard care. The intestinal microbiota of infants in the treatment group differed from those in the control group, with greater bacterial diversity and lower abundance of Streptococcus, Clostridium, and many pathogenic genera within the Enterobacteriaceae family. We identified 4 microbial community modules with significant differences between groups over time. Imputed metagenomic analysis of the microbial genes revealed metabolic pathways that differed between groups, including metabolism of amino acids, carbohydrates, fatty acids, and secondary bile acid synthesis. CONCLUSION: Enteral HF-PUFA supplementation was associated with decreased abundance of pathogenic bacteria, greater bacterial diversity, and shifts in the potential metabolic functions of intestinal microbiota. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01306838.

Lifting the mask: identification of new small molecule inhibitors of uropathogenic Escherichia coli group 2 capsule biogenesis.

Uropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs), with over 100 million UTIs occurring annually throughout the world. Increasing antimicrobial resistance among UPEC limits ambulatory care options, delays effective treatment, and may increase overall morbidity and mortality from complications such as urosepsis. The polysaccharide capsules of UPEC are an attractive target a therapeutic, based on their importance in defense against the host immune responses; however, the large number of antigenic types has limited their incorporation into vaccine development. The objective of this study was to identify small-molecule inhibitors of UPEC capsule biogenesis. A large-scale screening effort entailing 338,740 compounds was conducted in a cell-based, phenotypic screen for inhibition of capsule biogenesis in UPEC. The primary and concentration-response assays yielded 29 putative inhibitors of capsule biogenesis, of which 6 were selected for further studies. Secondary confirmatory assays identified two highly active agents, named DU003 and DU011, with 50% inhibitory concentrations of 1.0 µM and 0.69 µM, respectively. Confirmatory assays for capsular antigen and biochemical measurement of capsular sugars verified the inhibitory action of both compounds and demonstrated minimal toxicity and off-target effects. Serum sensitivity assays demonstrated that both compounds produced significant bacterial death upon exposure to active human serum. DU011 administration in mice provided near complete protection against a lethal systemic infection with the prototypic UPEC K1 isolate UTI89. This work has provided a conceptually new class of molecules to combat UPEC infection, and future studies will establish the molecular basis for their action along with efficacy in UTI and other UPEC infections.