Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation.

Neoadjuvant chemotherapy (NAC) is linked with clinical advantages in urothelial carcinoma for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive research into the influence of tumor mutation expression profiles and clinicopathological factors on chemotherapy response, the role of the gut microbiome (GM) in bladder cancer(BC) chemotherapy response remains poorly understood. This study examines the variance in the gut microbiome(GM) of BC patients compared to healthy adults, and investigates GM compositional differences between patients who respond to chemotherapy versus those who exhibit residual disease. Our study reveals distinct clustering, effectively separating the BC and healthy cohorts. However, no significant differences were observed between chemotherapy responders and non-responders within community subgroups. Machine Learning models based on responder status outperformed clinical variables in predicting complete response (AUC 0.88 vs AUC 0.50), although no single microbial species emerged as a fully reliable biomarker. The evaluation of short-chain fatty acid (SCFA) concentration in blood and stool revealed no correlation with responder status. Still, SCFA analysis showed a higher abundance of Akkermansia (rs = 0.51, p = 0.017) and Clostridia (rs = 0.52, p = 0.018), which correlated with increased levels of detectable fecal isobutyric acid. Higher levels of fecal Lactobacillus (rs = 0.49, p=0.02) and Enterobacteriaceae (rs = 0.52, p < 0.03) correlated with increased fecal propionic acid. In conclusion, our study constitutes the first large-scale, multi-center assessment of GM composition, suggesting the potential for a complex microbial signature to predict patients more likely to respond to NAC based on multiple taxa.

Dermatophytomas in Onychomycosis: A Scoping Review of Prevalence, Diagnosis, and Treatment.

BACKGROUND: Dermatophytoma, also described as a longitudinal streak/spike, is a form of onychomycosis that presents as yellow/white streaks or patches in the subungual space, with dense fungal masses encased in biofilm. This scoping review of the literature was conducted to address a general lack of information about the epidemiology, pathophysiology, and treatment of dermatophytomas in onychomycosis. METHODS: A search was performed in the PubMed and Embase databases for the terms "longitudinal spike" or "dermatophytoma." Outcomes of interest were definition, prevalence, methods used for diagnosis, treatments, and treatment efficacy. Inclusion and exclusion of search results required agreement between two independent reviewers. RESULTS: Of a total of 51 records, 37 were included. Two reports provided the first unique definitions/clinical features of dermatophytomas. Overall, many descriptions were found, but one conclusive definition was lacking. Prevalence data were limited and inconsistent. The most frequently mentioned diagnostic techniques were clinical assessment, potassium hydroxide/microscopy, and fungal culture/mycology. Oral terbinafine and topical efinaconazole 10% were the most frequently mentioned treatments, followed by topical luliconazole 5% and other oral treatments (itraconazole, fluconazole, fosravuconazole). In studies with five or more patients without nail excision, cure rates were highest with efinaconazole 10%, which ranged from 41% to 100% depending on the clinical and/or mycologic assessment evaluated. Other drugs with greater than or equal to 50% cure rates were topical luliconazole 5% (50%), oral fosravuconazole (57%), and oral terbinafine (67%). In studies that combined oral terbinafine treatment with nail excision using surgical or chemical (40% urea) methods, cure rates ranged from 50% to 100%. CONCLUSIONS: There is little published information regarding dermatophytomas in onychomycosis. More clinical research and physician education are needed. Although dermatophytomas have historically been considered difficult to treat, the efficacy data gathered in this scoping review have demonstrated that newer topical treatments are effective, as are oral antifungals in combination with chemical or surgical methods.

Candida tropicalis Affects Candida albicans Virulence by Limiting Its Capacity to Adhere to the Host Intestinal Surface, Leading to Decreased Susceptibility to Colitis in Mice.

Candida (C.) infections represent a serious health risk for people affected by inflammatory bowel disease. An important fungal virulence factor is the capacity of the fungus to form biofilms on the colonized surface of the host. This research study aimed to determine the effect of a C. tropicalis and C. albicans co-infection on dextran sodium sulfate (DSS)-induced colitis in mice. The colitis severity was evaluated using histology and a colonoscopy. The mice were mono-inoculated with C. albicans or C. tropicalis or co-challenged with both species. The mice were administered 3% DSS to induce acute colitis. The biofilm activity was assessed using (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] 2H-tetrazoliumhydroxide (XTT) and dry-weight assays. The abundance of C. albicans in the colon tissues was assessed by immunohistochemistry. The co-challenged mice showed a decreased colitis severity compared to the mono-inoculated mice. The dry-weight assay demonstrated a marked decrease in C. albicans biofilm production in a C. albicans culture incubated with C. tropicalis supernatant. Immunohistochemical staining showed that C. albicans was more abundant in the mucosa of C. albicans mono-inoculated mice compared to the co-inoculated group. These data indicate an antagonistic microbial interaction between the two Candida species, where C. tropicalis may produce molecules capable of limiting the ability of C. albicans to adhere to the host intestinal surface, leading to a reduction in biofilm formation.

Potential Sexual Transmission of Antifungal-Resistant Trichophyton indotineae.

We describe a case of tinea genitalis in an immunocompetent woman in Pennsylvania, USA. Infection was caused by Trichophyton indotineae potentially acquired through sexual contact. The fungus was resistant to terbinafine (first-line antifungal) but improved with itraconazole. Clinicians should be aware of T. indotineae as a potential cause of antifungal-resistant genital lesions.

Treatment of onychomycosis in an era of antifungal resistance: Role for antifungal stewardship and topical antifungal agents.

A growing body of literature has marked the emergence and spread of antifungal resistance among species of Trichophyton, the most prevalent cause of toenail and fingernail onychomycosis in the United States and Europe. We review published data on rates of oral antifungal resistance among Trichophyton species; causes of antifungal resistance and methods to counteract it; and in vitro data on the role of topical antifungals in the treatment of onychomycosis. Antifungal resistance among species of Trichophyton against terbinafine and itraconazole-the two most common oral treatments for onychomycosis and other superficial fungal infections caused by dermatophytes-has been detected around the globe. Fungal adaptations, patient characteristics (e.g., immunocompromised status; drug-drug interactions), and empirical diagnostic and treatment patterns may contribute to reduced antifungal efficacy and the development of antifungal resistance. Antifungal stewardship efforts aim to ensure proper antifungal use to limit antifungal resistance and improve clinical outcomes. In the treatment of onychomycosis, critical aspects of antifungal stewardship include proper identification of the fungal infection prior to initiation of treatment and improvements in physician and patient education. Topical ciclopirox, efinaconazole and tavaborole, delivered either alone or in combination with oral antifungals, have demonstrated efficacy in vitro against susceptible and/or resistant isolates of Trichophyton species, with low potential for development of antifungal resistance. Additional real-world long-term data are needed to monitor global rates of antifungal resistance and assess the efficacy of oral and topical antifungals, alone or in combination, in counteracting antifungal resistance in the treatment of onychomycosis.

The Response of the Urinary Microbiome to Botox.

INTRODUCTION AND HYPOTHESIS: Our objective was to evaluate if botox alters the urinary microbiome of patients with overactive bladder and whether this alteration is predictive of treatment response. METHODS: This multicenter prospective cohort study included 18-89-year-old patients undergoing treatment for overactive bladder with 100 units of botox. Urine samples were collected by straight catheterization on the day of the procedure (S1) and again 4 weeks later (S2). Participants completed the Patient Global Impression of Improvement form at their second visit for dichotomization into responders and nonresponders. The microbiome was sequenced using 16s rRNA sequencing. Wilcoxon signed rank and Wilcoxon rank sum were used to compare the microbiome, whereas chi-square, Wilcoxon rank sum, and the independent t-test were utilized for clinical data. RESULTS: Sixty-eight participants were included in the analysis. The mean relative abundance and prevalence of Beauveria bassiana, Xerocomus chrysenteron, Crinipellis zonata, and Micrococcus luteus were all found to increase between S1 and S2 in responders; whereas in nonresponders the mean relative abundance and prevalence of Pseudomonas fragi were found to decrease. The MRA and prevalence of Weissella cibaria, Acinetobacter johnsonii, and Acinetobacter schindleri were found to be greater in responders than nonresponders at the time of S1. Significant UM differences in the S1 of patients who did (n = 5) and did not go on to develop a post-treatment UTI were noted. CONCLUSIONS: Longitudinal urobiome differences may exist between patients who do and do not respond to botox.

Impact of Erythromycin as a Prokinetic on the Gut Microbiome in Children with Feeding Intolerance-A Pilot Study.

BACKGROUND: Studies have demonstrated that the gut microbiome changes upon exposure to systemic antibiotics. There is a paucity of literature regarding impact on the gut microbiome by long-term usage of erythromycin ethyl succinate (EES) when utilized as a prokinetic. METHODS: Stool samples from pediatric patients with feeding intolerance who received EES (N = 8) as a prokinetic were analyzed for both bacteriome and mycobiome. Age-matched children with similar clinical characteristics but without EES therapy were included as controls (N = 20). RESULTS: In both groups, Proteobacteria, Firmicutes, and Bacteroidetes were the most abundant bacterial phyla. Ascomycota was the most abundant fungal phyla, followed by Basidiomycota. There were no significant differences in richness between the groups for both bacterial and fungal microbiome. Alpha diversity (at genus and species levels) and beta diversity (at the genus level) were not significantly different between the groups for both bacterial and fungal microbiome. At the species level, there was a significant difference between the groups for fungal microbiota, with a p-value of 0.029. We also noted that many fungal microorganisms had significantly higher p-values in the EES group than controls at both genera and species levels. CONCLUSIONS: In this observational case-control study, the prokinetic use of EES was associated with changes in beta diversity between the groups for mycobiome at the species level. Many fungal microorganisms were significantly higher in the EES group when compared to the controls. Confirmation of these results in larger trials will provide further evidence regarding the impact of EES on gut microbiota when utilized as a prokinetic agent.

Skin and gut microbial associations with squamous cell carcinoma in solid organ transplant recipients.

Solid organ transplant recipients (SOTRs) are burdened with a significantly higher risk of squamous cell carcinoma (SCC) compared to the general population. Accumulating evidence suggests the potential influence of microbial dysbiosis on transplant outcomes. Based on these observations, we sought to identify differences in the cutaneous and gut microbiomes of SOTRs with and without a history of SCC. This case-control study collected and analyzed non-lesional skin and fecal samples of 20 SOTRs > 18 years old with either ≥ 4 diagnoses of SCC since most recent transplant (n = 10) or 0 diagnoses of SCC (n = 10). The skin and gut microbiomes were investigated with Next-Generation Sequencing, and analysis of variance (ANOVA) followed by Tukey pairwise comparison procedure was used to test for differences in taxonomic relative abundances and microbial diversity indices between the two cohorts. Analyses of the skin microbiome showed increased bacterial and reduced fungal diversity in SOTRs with a history of SCC compared to SOTRs without a history of SCC (bacterial median Shannon diversity index (SDI) = 3.636 and 3.154, p < 0.05; fungal SDI = 4.474 and 6.174, p < 0.05, respectively). Analyses of the gut microbiome showed reduced bacterial and fungal diversity in the SCC history cohort compared to the SCC history-negative cohort (bacterial SDI = 2.620 and 3.300, p < 0.05; fungal SDI = 3.490 and 3.812, p < 0.05, respectively). The results of this pilot study thus show a trend toward the bacterial and fungal communities of the gut and skin being distinct in SOTRs with a history of SCC compared to SOTRs without a history of SCC. It furthermore demonstrates the potential for microbial markers to be used in the prognostication of squamous cell carcinoma risk in solid organ transplant recipients.

Changes in the gut microbiota of NOD mice in response to an oral Salmonella-based vaccine against type 1 diabetes.

We developed an oral Salmonella-based vaccine that prevents and reverses diabetes in non-obese diabetic (NOD) mice. Related to this, the gastrointestinal tract harbors a complex dynamic population of microorganisms, the gut microbiome, that influences host homeostasis and metabolism. Changes in the gut microbiome are associated with insulin dysfunction and type 1 diabetes (T1D). Oral administration of diabetic autoantigens as a vaccine can restore immune balance. However, it was not known if a Salmonella-based vaccine would impact the gut microbiome. We administered a Salmonella-based vaccine to prediabetic NOD mice. Changes in the gut microbiota and associated metabolome were assessed using next-generation sequencing and gas chromatography-mass spectrometry (GC-MS). The Salmonella-based vaccine did not cause significant changes in the gut microbiota composition immediately after vaccination although at 30 days post-vaccination changes were seen. Additionally, no changes were noted in the fecal mycobiome between vaccine- and control/vehicle-treated mice. Significant changes in metabolic pathways related to inflammation and proliferation were found after vaccine administration. The results from this study suggest that an oral Salmonella-based vaccine alters the gut microbiome and metabolome towards a more tolerant composition. These results support the use of orally administered Salmonella-based vaccines that induced tolerance after administration.

Antifungal Activity of Efinaconazole Compared to Fluconazole, Itraconazole, and Terbinafine against Terbinafine- and Itraconazole-Resistant and -Susceptible Clinical Isolates of Dermatophytes, Candida, and Mold.

BACKGROUND: Recently, an increasing number of resistant-to-terbinafine dermatophytosis cases have been reported. Thus, identifying an alternative antifungal agent that possesses a broad-spectrum activity, including against resistant strains, is needed. METHODS: In this study, we compared the antifungal activity of efinaconazole to fluconazole, itraconazole, and terbinafine against clinical isolates of dermatophyte, Candida, and molds using in vitro assays. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of each antifungal was quantified and compared. Both susceptible and resistant clinical isolates of Trichophyton mentagrophytes (n=16), T. rubrum (n=43), T. tonsurans (n=18), T. violaceum (n=4), Candida albicans (n=55), C. auris (n=30), Fusarium sp., Scedosporium sp., and Scopulariopsis sp. (n=15 for each) were tested. RESULTS: Our data shows that efinaconazole was the most active antifungal, compared to the other agents tested, against dermatophytes with MIC50 and MIC90 (Concentration that inhibited 50% and 90% of strains tested, respectively) values of 0.002 and 0.03 µg/ml, respectively. Fluconazole, itraconazole and terbinafine showed MIC50 and MIC90 values of 1 and 8 µg/ml, 0.03 and 0.25 µg/ml, and 0.031 and 16 µg/ml, respectively. Against Candida isolates, efinaconazole MIC50 and MIC90 values were 0.016 and 0.25 µg/ml, respectively, whereas fluconazole, itraconazole and terbinafine had MIC50 and the MIC90 values of 1 and 16 µg/ml, 0.25 and 0.5 µg/ml, and 2 and 8 µg/ml, respectively. Against various mold species, efinaconazole MIC values ranged from 0.016 and 2 µg/ml, compared to 0.5 to greater than 64 µg/ml for the comparators. CONCLUSIONS: efinaconazole showed superior potent activity against a broad panel of susceptible and resistant dermatophyte, Candida, and mold isolates.

Global Meta-analysis of Urine Microbiome: Colonization of Polycyclic Aromatic Hydrocarbon-degrading Bacteria Among Bladder Cancer Patients.

BACKGROUND: The application of next-generation sequencing techniques has enabled characterization of urinary tract microbiome. Although many studies have demonstrated associations between the human microbiome and bladder cancer (BC), these have not always reported consistent results, thereby necessitating cross-study comparisons. Thus, the fundamental questions remain how we can utilize this knowledge. OBJECTIVE: The aim of our study was to examine the disease-associated changes in urine microbiome communities globally utilizing a machine learning algorithm. DESIGN, SETTING, AND PARTICIPANTS: Raw FASTQ files were downloaded for the three published studies in urinary microbiome in BC patients, in addition to our own prospectively collected cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demultiplexing and classification were performed using the QIIME 2020.8 platform. De novo operational taxonomic units were clustered using the uCLUST algorithm and defined by 97% sequence similarity and classified at the phylum level against the Silva RNA sequence database. The metadata available from the three studies included were used to evaluate the differential abundance between BC patients and controls via a random-effect meta-analysis using the metagen R function. A machine learning analysis was performed using the SIAMCAT R package. RESULTS AND LIMITATIONS: Our study includes 129 BC urine and 60 healthy control samples across four different countries. We identified a total of 97/548 genera to be differentially abundant in the BC urine microbiome compared with that of healthy patients. Overall, while the differences in diversity metrics were clustered around the country of origin (Kruskal-Wallis, p < 0.001), collection methodology was a driver of microbiome composition. When assessing dataset from China, Hungary, and Croatia, data demonstrated no discrimination capacity to distinguish between BC patients and healthy adults (area under the curve [AUC] 0.577). However, inclusion of samples with catheterized urine improved the diagnostic accuracy of prediction for BC to AUC 0.995, with precision-recall AUC = 0.994. Through elimination of contaminants associated with the collection methodology among all cohorts, our study identified increased abundance of polycyclic aromatic hydrocarbon (PAH)-degrading bacteria Sphingomonas, Acinetobacter, Micrococcus, Pseudomonas, and Ralstonia to be consistently present in BC patients. CONCLUSIONS: The microbiota of the BC population may be a reflection of PAH exposure from smoking, environmental pollutants, and ingestion. Presence of PAHs in the urine of BC patients may allow for a unique metabolic niche and provide necessary metabolic resources where other bacteria are not able to flourish. Furthermore, we found that while compositional differences are associated with geography more than with disease, many are driven by the collection methodology. PATIENT SUMMARY: The goal of our study was to compare the urine microbiome of bladder cancer patients with that of healthy controls and evaluate any potential bacteria that may be more likely to be found in patients with bladder cancer. Our study is unique as it evaluates this across multiple countries, to find a common pattern. After we removed some of the contamination, we were able to localize several key bacteria that are more likely to be found in the urine of bladder cancer patients. These bacteria all share their ability to break down tobacco carcinogens.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation.

Treatment with neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) is associated with clinical benefit in urothelial carcinoma. While extensive research evaluating role of tumor mutational expression profiles and clinicopathologic factors into chemoresponse has been published, the role of gut microbiome (GM) in bladder cancer in chemoresponse has not been thoroughly evaluated. A working knowledge of the microbiome and its effect on all forms of cancer therapy in BC is critical. Here we examine gut microbiome of bladder cancer patients undergoing NAC. Overall, there was no significant difference in alpha and beta diversity by responder status. However, analysis of fecal microbiome samples showed that a higher abundance of Bacteroides within both institutional cohorts during NAC was associated with residual disease at the time of radical cystectomy regardless of chemotherapy regimen. Group community analysis revealed presence of favorable microbial subtypes in complete responders. Finally, fecal microbial composition outperformed clinical variables in prediction of complete response (AUC 0.88 vs AUC 0.50), however, no single microbial species could be regarded as a fully consistent biomarker. Microbiome-based community signature as compared to single microbial species is more likely to be associated as the link between bacterial composition and NAC response.

A Novel Probiotic Combination Ameliorates Crohn's Disease-Like Ileitis by Increasing Short-Chain Fatty Acid Production and Modulating Essential Adaptive Immune Pathways.

BACKGROUND: Crohn's disease (CD) represents a significant public health challenge. We identified a combination of beneficial probiotic strains (Saccharomyces boulardii, Lactobacillus rhamnosus, Lactobacillus acidophilus, and Bifidobacterium breve) and amylase that may antagonize elevated bacterial pathogens in the inflamed gut. Our aim was to characterize the effect(s) of this novel probiotic supplement in SAMP1/YitFc (SAMP) mice with CD-like ileitis. METHODS: Three groups of 7-week-old SAMP mice were used in this study. The first experimental group was administered 1 dose of the probiotic supplement (probiotic strains + amylase) diluted in sterile phosphate-buffered saline (PBS) (0.25 mg in 100 µL of PBS) every day for 56 days through the gavage technique, the second group had a probiotic supplement (probiotic strains without amylase), and the third group was a control group in which animals were administered sterile PBS. At the end of the treatment, mice were sacrificed and ilea were collected for histological scoring of ileitis and NanoString analysis. Stool samples were evaluated by 16S ribosomal RNA and gas chromatography-mass spectrometry analyses. RESULTS: Histology scores showed that mice treated with probiotics + amylase had a significant decrease of ileitis severity compared with the other 2 groups. 16S ribosomal RNA and gas chromatography-mass spectrometry analysis showed that abundance of species belonging to genus Lachnoclostridium and Mucispirillum schaedleri were significantly increased compared with the other 2 groups, and this increase was associated with augmented production of short-chain fatty acids. NanoString data showed that 21 genes involved in B memory cell development and T cell infiltration were significantly upregulated in probiotic-treated mice and that 3 genes were significantly downregulated. CONCLUSIONS: Our data provide experimental proof for a beneficial effect of the designed probiotic formulation on the severity of CD-like ileitis in the SAMP mouse model, involving both alteration of intestinal genetic pathways and microbial rearrangements. Thus, we propose that this novel probiotic mixture should be further tested as an adjuvant therapy in the treatment of biofilm-associated disorders such as CD, in which it has been proven that polymicrobial imbalance plays a critical role in dysbiosis and gut inflammation.

In this study, we report that consumption of a novel probiotic and amylase mixture reduced intestinal inflammation in SAMP1/YitFc mice. These findings provide the rationale for clinical testing of the designed probiotic as an adjuvant therapy for Crohn's disease treatment.

Modulating the Microbiome for Crohn's Disease Treatment.

The central role of the gut microbiota in the regulation of health and disease has been convincingly demonstrated. Polymicrobial interkingdom interactions between bacterial (the bacteriome) and fungal (the mycobiome) communities of the gut have become a prominent focus for development of potential therapeutic approaches. In addition to polymicrobial interactions, the complex gut ecosystem also mediates interactions between the host and the microbiota. These interactions are complex and bidirectional; microbiota composition can be influenced by host immune response, disease-specific therapeutics, antimicrobial drugs, and overall ecosystems. However, the gut microbiota also influences host immune response to a drug or therapy by potentially transforming the drug's structure and altering bioavailability, activity, or toxicity. This is especially true in cases where the gut microbiota has produced a biofilm. The negative ramifications of biofilm formation include alteration of gut permeability, enhanced antimicrobial resistance, and alteration of host immune response effectiveness. Natural modulation of the gut microbiota, using probiotic and prebiotic approaches, may also be used to affect the host microbiome, a type of "natural" modulation of the host microbiota composition. In this review, we discuss potential bidirectional interactions between microbes and host, and we describe the changes in gut microbiota induced by probiotic and prebiotic approaches as well as their potential clinical consequences, including biofilm formation. We outline a systematic approach to designing probiotics capable of altering the host microbiota in disease states, using Crohn's disease as a model chronic disease. Understanding how the effective changes in the microbiome may enhance treatment efficacy may unlock the possibility of modulating the gut microbiome to improve treatment using a natural approach.

Characterization of Changes in Penile Microbiome Following Pediatric Circumcision.

BACKGROUND: While microbiome and host regulation contribute independently to many disease states, it is unclear how circumcision in pediatric population influences subsequent changes in penile microbiome. OBJECTIVE: Our study aims to analyze jointly paired taxonomic profiles and assess pathways implicated in inflammation, barrier protection, and energy metabolism. DESIGN, SETTING, AND PARTICIPANTS: We analyzed 11 paired samples, periurethral collection, before and after circumcision, to generate microbiome and mycobiome profiling. Sample preparation of 16S ribosomal RNA and internal transcribed spacer sequencing was adapted from the methods developed by the National Institutes of Health Human Microbiome Project. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We obtained the predictive functional attributes of the microbial communities between samples using Silva-Tax4Fun and the Greengenes-Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) approach. The predictive functioning of the microbial communities was determined by linearly combining the normalized taxonomic abundances into the precomputed association matrix of Kyoto Encyclopedia of Genes and Genomes orthology reference profiles. RESULTS AND LIMITATIONS: Several notable microbiome and mycobiome compositional differences were observed between pre- and postcircumcision patients. Pairwise comparisons across taxa revealed a significant decrease (p < 0.05, false discovery rate corrected) of microbiome organisms (Clostridiales, Bacteroidales, and Campylobacterales) and mycobiome (Saccharomycetales and Pleosporales) following circumcision. A total of 14 pathways were found to differ in abundance between the pre- and postcircumcision groups (p < 0.005, false discovery rate <0.1 and linear discriminant analysis score >3; five enriched and nine depleted). The pathways reduced after circumcision were mostly involved with amino acid and glucose metabolism, while pathways prior to circumcision were enriched in genetic information processing and transcription processes. As expected, enrichment in methyl-accepting chemotaxis protein, an integral membrane protein involved in directed motility of microbes to chemical cues and environment, occurred prior to circumcision, while the filamentous hemagglutinin pathway (a strong immunogenic protein) was depleted after circumcision CONCLUSIONS: Our results offer greater insight into the host-microbiota relationship of penile circumcision and may serve to lay the groundwork for future studies focused on drivers of inflammation, infection, and oncogenesis. PATIENT SUMMARY: Our study showed a significant reduction in bacteria and fungi after circumcision, particularly anaerobic bacteria, which are known to be potential inducers of inflammation and cancer. This is the first study of its kind showing the changes in microbiome after circumcision, and some of the changes that occur in healthy infants after circumcision that may explain the differences in cancer and inflammatory disorders in adulthood.

Mycobiome and Inflammatory Bowel Disease: Role in Disease Pathogenesis, Current Approaches and Novel Nutritional-based Therapies.

Inflammatory bowel disease (IBD), a disorder characterized by chronic inflammation of the gastrointestinal (GI) tract and a range of adverse health effects including diarrhea, abdominal pain, vomiting, and bloody stools, affects nearly 3.1 million genetically susceptible adults in the United States today. Although the etiology of IBD remains unclear, genetics, stress, diet, and gut microbiota dysbiosis- especially in immunocompromised individuals- have been identified as possible causes of disease. Although previous research has largely focused on the role of bacteria in IBD pathogenesis, recently observed alterations of fungal load and biodiversity in the GI tract of afflicted individuals suggest interkingdom interactions amongst different gut microbial communities, particularly between bacteria and fungi. These discoveries point to the potential utilization of treatment approaches such as antibiotics, antifungals, probiotics, and postbiotics that target both bacteria and fungi in managing IBD. In this review, we discuss the impact of specific fungi on disease pathogenesis, with a focus on the highly virulent genus Candida and how the presence of certain co-enzymes impacts its virulence. In addition, we evaluate current gut microbiome-based therapeutic approaches with the intention of better understanding the mechanisms behind novel therapies.

Recently observed alterations of fungal load in the gastrointestinal tract of IBD patients suggest interkingdom interactions amongst different gut microbial communities. These discoveries point to the potential utilization of antifungals and probiotics that target bacteria and fungi in managing IBD.

Efficacy of chlorhexidine in advanced performance technology formulation in decolonizing the skin using Candida auris skin colonization mouse model.

The incidence of Candida auris, an emerging multidrug resistant fungal species, is increasing. The ability of this yeast to colonize the human skin could lead to infections. Identifying agents to reduce the skin fungal burden is critical. Chlorhexidine formulated in a new Advanced Performance Technology formulation (APT-CH) was significantly more effective than untreated controls. Additional studies are warranted.

Fecal Microbiome Associated with Both Colon Adenomas and Lifetime Colorectal Cancer Risk.

BACKGROUND: Increasing data indicates the gut flora including bacteria and fungi combined with environmental factors are important in the pathogenesis of colorectal cancer (CRC). Understanding differences in the microbiome in patients with colon neoplasia will foster the development of biomarkers for early detection. AIMS: Determine the association of microbiome with presence of adenomas and predicted CRC risk. METHODS: In subjects referred for colonoscopy, the NCI CRC risk assessment tool was completed and stool for microbiome analysis as well as fecal immunochemical test (FIT) were collected. We calculated the microbiome alpha diversity using the Shannon index as well as individual bacterial and fungal species. RESULTS: Among 34 patients, we identified 10 with one or more adenomas. Only 2 patients were FIT positive. The median predicted lifetime CRC risk was 2.75% and the prevalence of adenoma was higher in the fourth quartile (P < 0.001). The measured alpha diversity was somewhat higher in patients with adenomas (P = 0.07). We identified 4 bacterial species with an increased relative abundance among patients with adenomas [P < 0.5]. Lifetime CRC risk was associated with 2 specific bacterial species, P. distasonis & E. hermannii [P = 0.05 & 0.09, respectively]. No associations were seen with fungal species and adenoma prevalence or lifetime CRC risk. CONCLUSIONS: In addition to a strong correlation of predicted CRC risk and adenoma prevalence, we also found important differences in specific bacterial species and both adenoma prevalence and CRC risk. Larger trials are needed to potentially implement further data in the clinical setting.

Dermatophyte Infections Worldwide: Increase in Incidence and Associated Antifungal Resistance.

The increase in incidence of superficial fungal infections combined with the emergence of antifungal resistance represents both a global health challenge and a considerable economic burden. Recently, dermatophytes, the main culprit causing superficial fungal infections, have started to exhibit antifungal resistance. This can be observed in some of the most common species such as Trichophyton rubrum and Trichophyton mentagrophytes. Importantly, the new subspecies, known as Trichophyton indotineae, has been reported to show high resistance to terbinafine, a first-line treatment for dermatophyte infections. Compounding these issues is the realization that diagnosing the causative infectious agents requires using molecular analysis that goes beyond the conventional macroscopic and microscopic methods. These findings emphasize the importance of conducting antifungal susceptibility testing to select the appropriate antifungal necessary for successful treatment. Implementing these changes may improve clinical practices that combat resistant dermatophyte infections.

Time to Think Antifungal Resistance Increased Antifungal Resistance Exacerbates the Burden of Fungal Infections Including Resistant Dermatomycoses.

Increased antifungal resistance is exacerbating the burden of invasive fungal infections, as well as potentially contributing to the increase in resistant dermatomycoses. In this commentary, we focus on antifungal drug resistance, in contrast to antibacterial resistance. We provide a brief historical perspective on the emergence of antifungal resistance and propose measures for combating this growing health concern. The increase in the incidence of invasive and cutaneous fungal infections parallels advancements in medical interventions, such as immunosuppressive drugs, to manage cancer and reduce organ rejection following transplant. A disturbing relatively new trend in antifungal resistance is the observation of several fungal species that now exhibit multidrug resistance (eg, Candida auris, Trichophyton indotineae). Increasing awareness of these multidrug-resistant species is paramount. Therefore, increased education regarding potential fungus-associated infections is needed to address awareness in the general healthcare setting, which may result in a more realistic picture of the prevalence of antifungal-resistant infections. In addition to education, increased use of diagnostic tests (eg, micro and macro conventional assays or molecular testing) should be routine for healthcare providers facing an unknown fungal infection. Two critical barriers that affect the low rates for Antifungal Susceptibility Testing (AST) are low (or a lack of) sufficient insurance reimbursement rates and the low number of qualified laboratories with the capacity to perform AST. The ultimate aim is to improve the quality of patient care through fungal identification, diagnosis, and, where appropriate, susceptibility testing. Here we propose an all-encompassing call to action to address this emerging challenge.