PMID: 

Epidemiol Infect. 2019 Jan ;147:e119. PMID: 30869014

Abstract Title: 

Associations between antibiotic prescriptions and recurrent urinary tract infections in female college students.

Abstract: 

Urinary tract infections (UTIs) are common among college-aged women and often recur. Some antibiotics recommended to treat UTIs trigger dysbiosis of intestinal and vaginal microbiomes – where uropathogens originate, though few studies have investigated associations between these therapies with recurrent infections. We retrospectively analysed the electronic medical records of 6651 college-aged women diagnosed with a UTI at a US university student health centre between 2006 and 2014. Women were followed for 6 months for incidence of a recurrent infection. In a secondary analysis, associations in women whose experienced UTI recurrence within 2 weeks were also considered for potential infection relapse. Logistic regression was used to assess associations between infection recurrence or relapse and antibiotics prescribed, in addition to baseline patient characteristics including age, race/ethnicity, region of origin, year of encounter, presence of symptomology, pyelonephritis, vaginal coinfection and birth control consultation. There were 1051 instances of infection recurrence among the 6620 patients, indicating a prevalence of 16%. In the analysis of patient characteristics, Asian women were statistically more likely to experience infection recurrence whereas African American were less likely. No significant associations were identified between the antibiotic administered at the initial infection and the risk of infection recurrence after multivariable adjustment. Treatment with trimethoprim-sulphamethoxazole and being born outside of the USA were significantly associated with increased odds of infection relapse in the multivariate analysis. The results of the analyses suggest that treatment with trimethoprim-sulphamethoxazole may lead to an increased risk of UTI relapse, warranting further study.

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PMID: 

PLoS One. 2019 ;14(2):e0212856. Epub 2019 Feb 22. PMID: 30794676

Abstract Title: 

Antibiotic treatment-induced dysbiosis differently affects BDNF and TrkB expression in the brain and in the gut of juvenile mice.

Abstract: 

Antibiotic use during adolescence may result in dysbiosis-induced neuronal vulnerability both in the enteric nervous system (ENS) and central nervous system (CNS) contributing to the onset of chronic gastrointestinal disorders, such as irritable bowel syndrome (IBS), showing significant psychiatric comorbidity. Intestinal microbiota alterations during adolescence influence the expression of molecular factors involved in neuronal development in both the ENS and CNS. In this study, we have evaluated the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TrkB) in juvenile mice ENS and CNS, after a 2-week antibiotic (ABX) treatment. In both mucosa and mucosa-deprived whole-wall small intestine segments of ABX-treated animals, BDNF and TrKB mRNA and protein levels significantly increased. In longitudinal muscle-myenteric plexus preparations of ABX-treated mice the percentage of myenteric neurons staining for BDNF and TrkB was significantly higher than in controls. After ABX treatment, a consistent population of BDNF- and TrkB-immunoreactive neurons costained with SP and CGRP, suggesting up-regulation of BDNF signaling in both motor and sensory myenteric neurons. BDNF and TrkB protein levels were downregulated in the hippocampus and remained unchanged in the prefrontal cortex of ABX-treated animals. Immunostaining for BDNF and TrkB decreased in the hippocampus CA3 and dentate gyrus subregions, respectively, and remained unchanged in the prefrontal cortex. These data suggest that dysbiosis differentially influences the expression of BDNF-TrkB in the juvenile mice ENS and CNS. Such changes may potentially contribute later to the development of functional gut disorders, such as IBS, showing psychiatric comorbidity.

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PMID: 

Microbiome. 2019 Apr 25 ;7(1):66. Epub 2019 Apr 25. PMID: 31018870

Abstract Title: 

Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis.

Abstract: 

BACKGROUND: Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues.RESULTS: Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity.CONCLUSIONS: Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis.

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PMID: 

BMC Pediatr. 2019 Jul 5 ;19(1):225. Epub 2019 Jul 5. PMID: 31277618

Abstract Title: 

Early antibiotic exposure and development of asthma and allergic rhinitis in childhood.

Abstract: 

BACKGROUND: The prevalence of pediatric allergic diseases has increased rapidly in the United States over the past few decades. Recent studies suggest an association between the increase in allergic disease and early disturbances to the gut microbiome. The gut microbiome is a set of intestinal microorganisms that begins to form during birth and is highly susceptible to disturbance during the first year of life. Early antibiotic exposure may negatively impact the gut microbiota by altering the bacterial composition and causing dysbiosis, thus increasing the risk for developing childhood allergic disease.METHODS: We performed a retrospective chart review of data in Loyola University Medical Center's (LUMC) Epic system from 2007 to 2016. We defined antibiotic exposure as orders in both the outpatient and inpatient settings. Inclusion criteria were being born at LUMC with at least two follow up visits. Asthma and allergic rhinitis diagnoses were obtained using ICD 9 and ICD 10 codes. We controlled for multiple confounding factors. Using Stata, bivariate logistic regression was performed between antibiotics from 0 to 12 months of life and development of disease. This analysis was repeated for total lifetime antibiotics. We defined statistically significant as p 

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PMID: 

J Gastroenterol Hepatol. 2019 Jul 29. Epub 2019 Jul 29. PMID: 31359491

Abstract Title: 

Dietary emulsifier polysorbate-80 induces small-intestinal vulnerability to indomethacin-induced lesions via dysbiosis.

Abstract: 

OBJECTIVE: Dietary emulsifiers are widely used in processed foods and officially approved as safe for intake. However, recent studies have demonstrated that some emulsifiers alter the colonic microbiota, leading to colonic low-grade inflammation, in mice. The effect of dietary emulsifiers on small-intestinal microbiota, which is important for gut immunity, has not been studied. We aimed to investigate the effect of a representative dietary emulsifier, polysorbate-80 (P80), on the small-intestinal microbiota in normal mice.METHODS: Some mice were pretreated with P80 for 8 weeks with or without indomethacin administration on the last 2 days, and intestinal damage was evaluated histologically. The ileal and colonic microbiota composition was assessed using 16S rRNA polymerase chain reaction.RESULTS: P80 increased the Gammaproteobacteria abundance, decreased theα-diversity in the small intestine. No decrease in α-diversity was observed in the colon. P80 pretreatment exacerbated the indomethacin-induced small-intestinal lesions and significantly increased the interleukin-1β expression. Culture of ileal content on DHL agar showed that P80 significantly increased the colonies of the sulfide-producing bacteria Proteus spp. (genetically identified as Proteus mirabilis). Antibiotic pretreatment abolished the P80-induced aggravation of indomethacin-induced ileitis. Motility assay in semisolid agar showed that adding 0.02% P80 to the agar significantly increased the diameter of P. mirabilis colonies but not that of Escherichia coli colonies.CONCLUSIONS: P80 enhances the vulnerability of the small intestine to indomethacin-induced injury by inducing ileal dysbiosis. Direct enhancement of the motility of specific flagellated microbiota by P80 might be related to dysbiosis and intestinal injury.

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n/a

PMID: 

Environ Int. 2018 11 ;120:421-430. Epub 2018 Aug 18. PMID: 30125859

Abstract Title: 

Antidepressant fluoxetine induces multiple antibiotics resistance in Escherichia coli via ROS-mediated mutagenesis.

Abstract: 

BACKGROUND: Antibiotic resistance poses a great threat to global public health. Overuse of antibiotics is generally considered as the major factor contributing to it. However, little is known about whether non-antibiotic drugs could play potential roles in the emergence of antibiotic resistance.
OBJECTIVE: We aimed to investigate whether antidepressant fluoxetine induces multiple antibiotic resistances and reveal underlying mechanisms.
METHODOLOGY: Escherichia coli K12 was exposed to different concentrations of fluoxetine (0, 0.5, 5, 50 and 100 mg/L) and the resistant strains were isolated by plating on antibiotic containing plates. Resistant strains were randomly selected to determine the increase of minimum inhibition concentration (MIC) of multiple antibiotics. Genome-wide DNA sequencing was performed on cells cultured in lysogeny broth (LB) without any fluoxetine or antibiotics exposure. RNA sequencing and proteomic profiling of isolated mutants grown in LB with 100 mg/L fluoxetine were analyzed to reveal the underlying mechanisms.
RESULTS: Exposure of Escherichia coli to fluoxetine at 5-100 mg/L after repeated subculture in LB for 30 days promoted its mutation frequency resulting in increased resistance against the antibiotics chloramphenicol, amoxicillin and tetracycline. This increase was up to 5.0 × 10fold in a dose-time pattern. Isolated mutants with resistance to one of these antibiotics also exhibited multiple resistances against fluoroquinolone, aminoglycoside,β-lactams, tetracycline and chloramphenicol. According to global transcriptional and proteomic analyses, the AcrAB-TolC pump together with the YadG/YadH transporter, a Tsx channel and the MdtEF-TolC pump have been triggered to export the antibiotics to the exterior of the cell. Whole-genome DNA analysis of the mutants further revealed that ROS-mediated mutagenesis (e.g., deletion, insertion, and substitution) of DNA-binding transcriptional regulators (e.g., marR, rob, sdiA, cytR and crp) to up-regulate the expression of efflux pumps, may further enhance the antibiotic efflux.
CONCLUSIONS: Our findings for the first time demonstrated that the exposure to antidepressant fluoxetine induces multiple antibiotic resistance in E. coli via the ROS-mediated mutagenesis.

PMID: 

Environ Int. 2019 05 ;126:193-201. Epub 2019 Feb 22. PMID: 30802636

Abstract Title: 

Detecting fluoxetine and norfluoxetine in wild bird tissues and feathers.

Abstract: 

The contamination of the environment with human pharmaceuticals is widespread and demand for such products is mounting globally. Wild vertebrates may be at particular risk from any effects from pharmaceuticals, because of the evolutionary conservation of drug targets. However, exposure of wildlife to pharmaceuticals is poorly characterised, partly due to challenges associated with detecting rapidly metabolised compounds. As part of a wider study on the behavioural effects of fluoxetine (Prozac) on Eurasian starlings (Sturnus vulgaris), we investigated which avian samples are best suited for detecting exposure to fluoxetine in free-living birds. We analysed plasma, various tissues and tail feathers (grown both in the wild and in captivity during the dosing period) from fluoxetine-treated birds (dosed daily with 0.035 mg kgbodyweight for 28 weeks), and liver tissue and tail feathers from sham-dosed birds. We detected fluoxetine in only two of twelve plasma samples from dosed birds. In dosed birds, median concentrations of free fluoxetine/norfluoxetine in tissues (two hour post-final dose) were: 111.2/67.6 ng gin liver, 29.6/5.7 ng gin kidney, 14.2/4.0 ng gin lung, 15.1/1.6 ng gin brain. We estimated that fluoxetine would remain detectable in liver and kidney approximately 4.5 times longer (90 h) than in brain (20h). In dosed birds, fluoxetine was detected in feathers regrown during the dosing period (median concentration = 11.4 ng g) at concentrations significantly higher than in regrown feathers from control birds. Fluoxetine residues were detected in wild-grown feathers (grown before the birds were brought into captivity) at concentrations up to 27.0 ng g, providing some evidence of likely exposure in the wild. Our results show liver and kidney can be used for detecting fluoxetine in avian carcasses and provide a first indication that feathers may be useful for assessing exposure to fluoxetine, and possibly other pharmaceuticals.

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PMID: 

Am J Otolaryngol. 2015 Jan-Feb;36(1):39-46. Epub 2014 Oct 5. PMID: 25456509

Abstract Title: 

The effect of 2100 MHz radiofrequency radiation of a 3G mobile phone on the parotid gland of rats.

Abstract: 

PURPOSE: We aimed to evaluate the effect of 2100 MHz radiofrequency radiation on the parotid gland of rats in short and relatively long terms.MATERIAL AND METHODS: Thirty Wistar albino rats were divided into four groups. Groups A and B served as the control groups (for 10 days and 40 days, respectively), and each group included six rats. Groups C and D were composed of nine rats each, and they were the exposure groups. The rats were exposed to 2100 MHz radiofrequency radiation emitted by a generator, simulating a third generation mobile phone for 6 hours/day, 5 days/week, for 10 or 40 days. Following exposure, the rats were sacrificed and parotid glands were removed. Histopathological and biochemical examinations were performed.RESULTS: Although there were no histopathological changes in the control groups except for two animals in group A and three animals in group B, the exposure groups C (10 days) and D (40 days) showed numerous histopathological changes regarding salivary gland damage including acinar epithelial cells, interstitial space, ductal system, vascular system, nucleus, amount of cytoplasm and variations in cell size. The histopathological changes were more prominent in group D compared to group C. There was statistically significant different parameter regarding variation in cell size between the groups B and D (p=0.036).CONCLUSION: The parotid gland of rats showed numerous histopathological changes after exposure to 2100 MHz radiofrequency radiation, both in the short and relatively long terms. Increased exposure duration led to an increase in the histopathological changes.

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PMID: 

Korean J Physiol Pharmacol. 2017 Mar ;21(2):179-188. Epub 2017 Feb 21. PMID: 28280411

Abstract Title: 

Activation of autophagy at cerebral cortex and apoptosis at brainstem are differential responses to 835 MHz RF-EMF exposure.

Abstract: 

With the explosive increase in exposure to radiofrequency electromagnetic fields (RF-EMF) emitted by mobile phones, public concerns have grown over the last few decades with regard to the potential effects of EMF exposure on the nervous system in the brain. Many researchers have suggested that RF-EMFs can effect diverse neuronal alterations in the brain, thereby affecting neuronal functions as well as behavior. Previously, we showed that long-term exposure to 835 MHz RF-EMF induces autophagy in the mice brain. In this study, we explore whether short-term exposure to RF-EMF leads to the autophagy pathway in the cerebral cortex and brainstem at 835 MHz with a specific absorption rate (SAR) of 4.0 W/kg for 4 weeks. Increased levels of autophagy genes and proteins such as LC3B-II and Beclin1 were demonstrated and the accumulation of autophagosomes and autolysosomes was observed in cortical neurons whereas apoptosis pathways were up-regulated in the brainstem but not in the cortex following 4 weeks of RF exposure. Taken together, the present study indicates that monthly exposure to RF-EMF induces autophagy in the cerebral cortex and suggests that autophagic degradation in cortical neurons against a stress of 835 MHz RF during 4 weeks could correspond to adaptation to the RF stress environment. However, activation of apoptosis rather than autophagy in the brainstem is suggesting the differential responses to the RF-EMF stresses in the brain system.

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PMID: 

Mol Brain. 2019 04 1 ;12(1):29. Epub 2019 Apr 1. PMID: 30935412

Abstract Title: 

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice.

Abstract: 

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HTR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HTR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.

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