Perturbation Of Gut Microbiome Research Articles

Temporal Changes in Fecal Unabsorbed Carbohydrates Relative to Perturbations in Gut Microbiome of Neonatal Calves: Emerging of Diarrhea Induced by Extended-Spectrum β-lactamase-Producing Enteroaggregative Escherichia coli.

Early gut microbiota development and colonization are crucial for the long-term health and performance of ruminants. However, cognition among these microbiota is still vague, particularly among the neonatal dairy calves. Here, extended-spectrum β-lactamase-producing enteroaggregative E. coli (ESBL-EAEC)-induced temporal changes in diversity, stability, and composition of gut microbiota were investigated among the neonatal female calves, with the view of discerning potential biomarkers of this arising diarrhea cases in local pastures. Nearly, 116 newborn calves were enrolled in this time period study during their first 2 weeks of life, and a total of 40 selected fecal samples from corresponding calves were used in this study. The results revealed that differentiated gut microbiome and metabolome discerned from neonatal calves were accompanied by bacterial infections over time. Commensal organisms like Butyricicoccus, Faecalibacterium, Ruminococcus, Collinsella, and Coriobacterium, as key microbial markers, mainly distinguish “healthy” and “diarrheic” gut microbiome. Random forest machine learning algorithm indicated that enriched fecal carbohydrates, including rhamnose and N-acetyl-D-glucosamine, and abundant short-chain fatty acids (SCFAs) existed in healthy ones. In addition, Spearman correlation results suggested that the presence of Butyricicoccus, Faecalibacterium, Collinsella, and Coriobacterium, key commensal bacteria of healthy calves, is positively related to high production of unabsorbed carbohydrates, SCFAs, and other prebiotics, and negatively correlated to increased concentrations of lactic acid, hippuric acid, and α-linolenic acid. Our data suggested that ESBL-EAEC-induced diarrhea in female calves could be forecasted by alterations in the gut microbiome and markedly changed unabsorbed carbohydrates in feces during early lives, which might be conducive to conduct early interventions to ameliorate clinical symptoms of diarrhea induced by the rising prevalence of ESBL-EAEC.

Multiomics analyses uncover nanoceria triggered oxidative injury and nutrient imbalance in earthworm Eisenia fetida

The toxic stress caused by nanoceria remains vague owing to the limited efforts scrutinizing its molecular mechanisms. Herein, we investigated the impacts of nanoceria on earthworm Eisenia fetida, at the molecular level using the multiomics-based profiling approaches (transcriptomics, metabolomics, and 16 S rRNA sequencing). Nanoceria (50 and 500 mg/kg) significantly increased the contents of malondialdehyde (MDA), Fe, and K in worms, suggesting oxidative injury and nutrient imbalance. This was corroborated by the transcriptomic and metabolomic analyses. Nanoceria decreased the levels of certain genes and metabolites associated with glycerolipid and glycerophospholipid metabolisms, suggesting the production of reactive oxygen species and subsequent oxidative stress. Additionally, the ABCD3 gene belonging to ABC transporter family was upregulated, facilitating Fe uptake by worms. Moreover, the higher contents of MDA, Fe, and K after exposure were tightly associated with the imbalanced intestinal flora. Specifically, a higher relative abundance of Actinobacteriota and a lower relative abundance of Proteobacteria and Patescibacteria were induced. This study, for the first time, revealed that nanoceria at nonlethal levels caused oxidative stress and nutrient imbalance of earthworms from the perspective of genes, metabolites, and gut microbiome perturbations, and also established links between the gut microbiome and the overall physiological responses of the host.

Crosstalk between gut microbiota and lung inflammation in murine toxicity models of respiratory exposure or co-exposure to carbon nanotube particles and cigarette smoke extract

Carbon nanotubes (CNTs) are emerging environmental and occupational toxicants known to induce lung immunotoxicity. While the underlying mechanisms are evolving, it is yet unknown whether inhaled CNTs would cause abnormalities in gut microbiota (dysbiosis), and if such microbiota alteration plays a role in the modulation of CNT-induced lung immunotoxicity. It is also unknown whether co-exposure to tobacco smoke will modulate CNT effects. We compared the effects of lung exposure to multi-wall CNT, cigarette smoke extract (CSE), and their combination (CNT + CSE) in a 4-week chronic toxicity mouse model. The exposures induced differential perturbations in gut microbiome as evidenced by altered microbial α- and β- diversity, indicating a lung-to-gut communication. The gut dysbiosis due to CNTs, unlike CSE, was characterized by an increase in Firmicutes/Bacteroidetes ratio typically associated with proinflammatory condition. Notably, while all three exposures reduced Proteobacteria, the CNT exposure and co-exposure induced appearance of Tenericutes and Cyanobacteria, respectively, implicating them as potential biomarkers of exposure. CNTs differentially induced certain lung proinflammatory mediators (TNF-α, IL-1β, CCL2, CXCL5) whereas CNTs and CSE commonly induced other mediators (CXCL1 and TGF-β). The co-exposure showed either a component-dominant effect or a summative effect for both dysbiosis and lung inflammation. Depletion of gut microbiota attenuated both the differentially-induced and commonly-induced (TGF-β) lung inflammatory mediators as well as granulomas indicating gut-to-lung communication and a modulatory role of gut dysbiosis. Taken together, the results demonstrated gut dysbiosis as a systemic effect of inhaled CNTs and provided the first evidence of a bidirectional gut-lung crosstalk modulating CNT lung immunotoxicity.

Intestinal inflammation alters the antigen-specific immune response to a skin commensal.

SUMMARYResident microbes in skin and gut predominantly impact local immune cell function during homeostasis. However, colitis-associated neutrophilic skin disorders suggest possible breakdown of this compartmentalization with disease. Using a model wherein neonatal skin colonization by Staphylococcus epidermidis facilitates generation of commensal-specific tolerance and CD4+ regulatory T cells (Tregs), we ask whether this response is perturbed by gut inflammation. Chemically induced colitis is accompanied by intestinal expansion of S. epidermidis and reduces gut-draining lymph node (dLN) commensal-specific Tregs. It also results in reduced commensal-specific Tregs in skin and skin-dLNs and increased skin neutrophils. Increased CD4+ circulation between gut and skin dLN suggests that the altered cutaneous response is initiated in the colon, and resistance to colitis-induced effects in Cd4creIl1r1fl/fl mice implicate interleukin (IL)-1 in mediating the altered commensal-specific response. These findings provide mechanistic insight into observed connections between inflammatory skin and intestinal diseases.

Susceptibility to epilepsy after traumatic brain injury is associated with preexistent gut microbiome profile.

We examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome. Adult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7months after LFPI, during 4-week continuous video-electroencephalographic monitoring. 16S ribosomal RNA gene sequencing was performed in fecal samples collected before LFPI/sham-LFPI and 1week, 1 month, and 7months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short-chain fatty acids (SCFAs) were measured in fecal samples collected before LFPI by liquid chromatography with tandem mass spectrometry. Alpha diversity changed over time in both LFPI and sham-LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post-LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI-dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis-à-vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE, with area under the curve (AUC) of .73. Global SCFA content was associated with the increased risk of PTE, with AUC of .722, and with 2-methylbutyric (depleted), valeric (depleted), isobutyric (enriched), and isovaleric (enriched) acids being the most important factors (AUC = .717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to .78. Whereas LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content.

Gut bacterial-derived 12,13-diHOME promotes inflammatory macrophage polarization and epigenetic modifications

Early-life gut microbiome perturbation and metabolic dysfunction precede atopy and asthma development in childhood. However, mechanisms by which gut-microbial metabolites drive long-lasting immune dysfunction remain elusive. We previously showed that elevated concentrations of the gut bacteria-derived lipid, 12,13-diHOME, is a risk factor for development of atopy and asthma in childhood, and that it suppresses regulatory T cells by altering dendritic cell function.

Food-derived cyanidin-3-O-glucoside reverses microplastic toxicity via promoting discharge and modulating the gut microbiota in mice.

Microplastics (MPs) ingested and accumulated by organisms would ultimately pose a threat to humans via the food chain. A balanced gut microbiota contributes to many health benefits, which is readily influenced by environmental chemicals such as MPs. Cyanidin-3-O-glucoside (C3G), a bioactive compound of the anthocyanin family, possesses a variety of functional effects including anti-oxidant and anti-inflammatory, as well as gut microbiota modulation. C3G has been demonstrated to prevent polystyrene (PS) induced toxicities in Caco-2 cells and Caenorhabditis elegans (C. elegans) via activating autophagy and promoting discharge. In the present study, we aimed to explore the alleviation effect of C3G on PS induced toxicities in C57BL/6 mice. Our results showed that the supplementation of C3G effectively reduced the tissue accumulation and promoted the fecal PS discharge, leading to alleviation of the PS-caused oxidative stress and inflammatory response. Meanwhile, C3G modulated PS-associated gut microbiome perturbations and regulated functional bacteria in inflammation such as Desulfovibrio, Helicobacter, Oscillospiraceae and Lachnoclostridium. Also, C3G administration initiated alterations in functional pathways in response to xenobiotic PS, and reduced bacterial functional genes related to inflammation and human diseases. These findings may offer evidence for the protective role of C3G in the intervention of PS-induced toxicity and gut dysbiosis.

Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

Sub-chronic low-dose arsenic in rice exposure induces gut microbiome perturbations in mice

Long-term consumption of arsenic-contaminated rice has become a public health issue that urgently needs to be addressed. In this study, mice were exposed to arsenic in rice (low dose, 0.91 mg/kg; medium dose, 9.1 mg/kg) for 30 days and 60 days, respectively, and the effects on pathological structures of spleen and skin, as well as the structure of the fecal microbiome were examined. The findings revealed dose/time cumulative effects on pathological changes, with even a low dose exposure for 30 days causing destruction of splenic follicular structure and thickening of dermal keratinized and epidermal layers. The Firmicutes/Bacteroidetes ratio in the community and the positive/negative ratio in network links were higher in arsenic groups, suggesting that arsenic resulted in a less healthy and unstable microbiome for the host. Thus lifetime consumption of arsenic in rice may have potential health effects on humans and must be carefully assessed to safeguard human health. Furthermore, in arsenic groups, arsenic-resistant bacteria or arsenic hazards remediation bacteria changed to be the dominant bacteria and acted as the core bacteria in the network modules. Some microbial arsenic transforming genes (arsC, arsR, arsA, ACR3, and aoxB) differed, indicating that the gut microbiome changed to withstand arsenic stress. Furthermore, Faecalibaculum, Lachnospiraceae_NK4A136_group, Angelakisella, Ruminiclostridium, and Desulfovibrionaceae are positively associated with arsenic dosage and may be useful in the early detection of arsenicals.

Leveraging diet to engineer the gut microbiome.

Autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, have distinct clinical presentations but share underlying patterns of gut microbiome perturbation and intestinal barrier dysfunction. Their potentially common microbial drivers advocate for treatment strategies aimed at restoring appropriate microbiome function, but individual variation in host factors makes a uniform approach unlikely. In this Perspective, we consolidate knowledge on diet-microbiome interactions in local inflammation, gut microbiota imbalance and host immune dysregulation. By understanding and incorporating the effects of individual dietary components on microbial metabolic output and host physiology, we examine the potential for diet-based therapies for autoimmune disease prevention and treatment. We also discuss tools targeting the gut microbiome, such as faecal microbiota transplantation, probiotics and orthogonal niche engineering, which could be optimized using custom dietary interventions. These approaches highlight paths towards leveraging diet for precise engineering of the gut microbiome at a time of increasing autoimmune disease.

Targeting the Gut Microbiota in Coronavirus Disease 2019: Hype or Hope?

Targeting the Gut Microbiota in Coronavirus Disease 2019: Hype or Hope?

Effects of gut microbiota remodeling on the dysbiosis induced by high fat diet in a mouse model of Gulf war illness

Gulf war illness (GWI) is a chronic disorder of unknown etiology characterized by multiple symptoms such as pain, fatigue, gastrointestinal disturbances and neurocognitive problems. Increasing evidence suggests that gut microbiome perturbations play a key role in the pathology of this disorder. GWI courses with gut microbiota alterations and their metabolites (e.g. short chain fatty acids -SCFA-), which can be aggravated by lifestyle risk factors such as a high fat diet (HF). To investigate the causative role of the gut microbiome, non-absorbable antibiotics (Abx) were administered to mice treated with GWI agents and concomitantly fed with a HF. In light of the wide use of Abx as pseudo-germ-free models, we evaluated the effects of Abx exposure on GWI and HF on body weight, food intake, gut microbiota changes and levels of the SCFA acetate. Results show that HF decreased food intake while increasing body weight in both controls and GWI. Exposure to Abx prevented these HF effects by offsetting the body weight gain in GWI. GWI and HF led to decreases in α-diversity, disruptions in the composition and structure of the gut bacterial community and decreases in acetate levels. This Abx-induced remodeling of the gut microbiome was characterized by an expansion of Proteobacteria, decreases in Bacteroidetes and Firmicutes, and overall increases in acetate levels, as well as by the proliferation of potential pathobionts. Therefore, the use of Abx may not represent a dependable approach to deplete the gut microbiome and its advantages as a pseudo germ-free model warrant further investigation.

Microbiome-metabolomics signature in anorexia nervosa (AN) before and after weight regain

IntroductionThe intestinal microbiota has been indicated to have a role in the pathophysiology of AN.ObjectivesAim of this study was to analyze fecal microbiome profiles of AN women before and after weight restoration and to combine them with fecal metabolomic profiles according to a multi-omics approach.MethodsThe gut microbiome and fecal metabolites were characterized in 21 underweight AN women and after weight restoration and compared with those of 20 healthy women. Microbiome data were correlated with the relevant fecal metabolites.ResultsAN subjects showed a decreased intra-individual bacterial richness, an increased Bacteroidetes-to-Firmicutes abundance ratio and significant changes in the relative abundances of several bacteria at different order levels in both the underweight and weight-restored condition compared to healthy women. The untargeted metabolomic procedure allowed the characterization of 224 metabolites involved in energy, lipid and amino acid metabolism. A genetic algorithm identified 49 relevant metabolites. The relationships among these fecal metabolites and bacteria genera showed structures of different complexity in the 3 groups. In particular, a quarter of those relationships showed a divergent direction in the acute phase of AN than in the weight-restored phase or normal controls. Finally, in acute AN 70% of those correlations showed a negative sign suggesting a prevalent metabolites consummation by gut microbiome.ConclusionsOur results provide a picture of the connections between gut bacteria and fecal metabolites in both the acute phase of AN and after short-term weight restoration. Further studies should aim to investigate the significance of gut microbiome perturbations in development and treatment of AN.

Neonatal antibiotic exposure impairs child growth during the first six years of life by perturbing intestinal microbial colonization

Exposure to antibiotics in the first days of life is thought to affect various physiological aspects of neonatal development. Here, we investigate the long-term impact of antibiotic treatment in the neonatal period and early childhood on child growth in an unselected birth cohort of 12,422 children born at full term. We find significant attenuation of weight and height gain during the first 6 years of life after neonatal antibiotic exposure in boys, but not in girls, after adjusting for potential confounders. In contrast, antibiotic use after the neonatal period but during the first 6 years of life is associated with significantly higher body mass index throughout the study period in both boys and girls. Neonatal antibiotic exposure is associated with significant differences in the gut microbiome, particularly in decreased abundance and diversity of fecal Bifidobacteria until 2 years of age. Finally, we demonstrate that fecal microbiota transplant from antibiotic-exposed children to germ-free male, but not female, mice results in significant growth impairment. Thus, we conclude that neonatal antibiotic exposure is associated with a long-term gut microbiome perturbation and may result in reduced growth in boys during the first six years of life while antibiotic use later in childhood is associated with increased body mass index.

Gut microbiome and Clostridioides difficile infection: a closer look at the microscopic interface.

The pathogenesis of Clostridioides difficile infection (CDI) was recognized with its link to the use of antimicrobials. Antimicrobials significantly alter gut microbiota structure and composition, which led to the discovery of the association of this gut perturbation with the development of CDI. A number of factors implicated in its pathogenesis, such as advancing age, proton-pump inhibitors, and gastrointestinal diseases, are linked to gut microbiota perturbations. In an effort to better understand CDI, a multitude of studies have tried to ascertain protective and predictive microbial footprints linked with CDI. It has further been realized that CDI in itself can alter the gut microbiome. Its spore-forming capability poses as an impediment in the management of the infection and contributes to its recurrence. Antibiotic therapies used for its management have also been linked to gut microbiota changes, making its treatment a little more challenging. In an effort to exploit and utilize this association, gut microbial restoration therapies, particularly in the form of fecal microbial transplant, are increasingly being put to use and are proving to be beneficial. In this review, we summarize the association of the gut microbiome and microbial perturbation with initial and recurrent CDI.

Gut microbiome perturbations influence brain amyloidosis only in the presence of microglia in APPPS1‐21 mice

AbstractBackgroundIn prior efforts, we demonstrated reduced amyloidosis and altered microgliosis in long‐term antibiotics (abx)‐treated APPPS1‐21 male mice. Restoration of the gut microbiome into abx‐treated male mice by fecal microbiota transfer (FMT) established a causality between the gut microbiome and amyloidosis. We have used FMT studies using our current short‐term abx APPPS1‐21 mice to evaluate the microbiome‐microglia‐amyloidosis axis.MethodShort‐term, postnatal abx (4mg/ml Kanamycin, 0.35mg/ml Gentamicin, 8500U/ml Colistin, 2.15mg/ml Metronidazole, 0.45mg/ml Vancomycin: post‐natal day 14 to day 21) was performed. To establish causality, we performed FMT (200µl of 5mg/ml fecal slurry daily gavage) into abx‐treated APPPS1‐21 male mice. Pathogenicity of the gut microbiome in WT or Tg mice were confirmed using age‐matched FMT from WT and Tg controls into abx‐treated male mice. We performed total RNAseq transcriptome analysis to evaluate potential mechanism(s). The role of microglial cells were evaluated in PLX6522 (CSF‐1 receptor inhibitor)‐treated FMT‐transplanted abx‐treated APPPS1‐21 male mice. Nine weeks old GF APPPS1‐21 were used to characterize the amyloidosis and glial cells in both genders.ResultAn early life abx treatment resulted in gut microbiota changes in a sex‐dependent manner. Only male mice showed reduced amyloidosis and altered microglial phenotypes. Age matched Tg FMT or WT FMT resulted in higher amyloidosis in abx‐treated male mice. RNAseq analysis of total cortical RNA showed significantly different mRNA levels that occurred in a sex‐specific manner and changes in abx‐treated male mice were restored with FMT. GO term analysis showed gliogenesis and microglia development as significantly altered pathways in abx‐treated male group only. To confirm the exact role of the microglia in this model, we employed PLX6522 in FMT‐treated ABX‐male mice. Microglia depletion did not result in an FMT‐dependent increase in amyloidosis in abx‐treated male mice. Finally, germ‐free APPPS1‐21 mice showed reduced amyloidosis that occurs in a sex‐specific manner.ConclusionFrom GF APPPS1‐21 and FMT‐treated abx‐male APPPS1‐21 studies, we conclude that gut microbiome plays a critical role in modulating amyloidosis in APPPS1‐21 mice. Furthermore, microglia mediates the effects of early life gut microbiota perturbations, which results in altered amyloidosis in APPPS1‐21 male mice.

Gut Microbial Regulation of Autism Spectrum Disorder Symptoms

Relationships between gut microbiome perturbation and autism spectrum disorder (ASD) have been observed in several human studies, but the functional implications and molecular mechanisms by which microbes may influence disease symptomology remain enigmatic. A recently published study by Sharon et al. offers evidence that the gut microbiome has a causative role in ASD and highlights the importance of early-life gut microbial metabolites in shaping mammalian behavior.

Infants exposed to antibiotics after birth have altered recognition memory responses at one month of age.

Background:Neonatal exposure to antibiotics, in the absence of infection, results in abnormal learning and memory in animals and is linked to changes in gut microbes. The relevance of early-life antibiotic exposure to brain function in humans is not known.Methods:Recognition memory was assessed at 1 month of age in 15 term-born infants exposed to antibiotics (with negative cultures) and 57 unexposed infants using event-related potentials (ERPs). Linear regression analysis, adjusting for covariates, was employed to compare groups with respect to ERP features representing early stimulus processing (P2 amplitude) and discrimination between mother and stranger voices.Results:Infants exposed to antibiotics exhibited smaller P2 amplitudes for both voice conditions (p = 0.001), with greatest reductions observed for mother’s voice in frontal and central scalp regions (p < 0.04). Infants exposed to antibiotics showed larger P2 amplitudes to stranger’s as compared to mother’s voice, a reversal of the typical response exhibited by unexposed infants. Abnormal ERP responses did not consistently correlate with increased inflammatory cytokines within the antibiotic-exposed group.Conclusion:Otherwise healthy infants exposed to antibiotics soon after birth demonstrated altered auditory processing and recognition memory responses, supporting the possibility of a microbiota-gut-brain axis in humans during early life.

Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis

There is increasing evidence that gut microbiome perturbations, also known as dysbiosis, can influence colorectal cancer development. To understand the mechanisms by which the gut microbiome modulates cancer susceptibility, we examine two wild-type mouse colonies with distinct gut microbial communities that develop significantly different tumor numbers using a mouse model of inflammation-associated tumorigenesis. We demonstrate that adaptive immune cells contribute to the different tumor susceptibilities associated with the two microbial communities. Mice that develop more tumors have increased colon lamina propria CD8+ IFNγ+ Tcells before tumorigenesis but reduced CD8+ IFNγ+ Tcells in tumors and adjacent tissues compared with mice that develop fewer tumors. Notably, intratumoral Tcells in mice that develop more tumors exhibit increased exhaustion. Thus, these studies suggest that microbial dysbiosis can contribute to colon tumor susceptibility by hyperstimulating CD8 Tcells to promote chronic inflammation and early Tcell exhaustion, which can reduce anti-tumor immunity.

MP46-01 DEFICIENCY OF HOST MICROBIOME BY ANTIBIOTIC EXPOSURE COMPROMISES INNATE IMMUNE RESPONSES OF THE URINARY BLADDER AGAINST UROPATHOGENIC E. COLI

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Kidney & Bladder I (MP46)1 Apr 2020MP46-01 DEFICIENCY OF HOST MICROBIOME BY ANTIBIOTIC EXPOSURE COMPROMISES INNATE IMMUNE RESPONSES OF THE URINARY BLADDER AGAINST UROPATHOGENIC E. COLI Yan Liu, Abbey Lepor, Hongying Huang, Herbert Lepor, Xue-Ru Wu, and Ellen Shapiro* Yan LiuYan Liu More articles by this author , Abbey LeporAbbey Lepor More articles by this author , Hongying HuangHongying Huang More articles by this author , Herbert LeporHerbert Lepor More articles by this author , Xue-Ru WuXue-Ru Wu More articles by this author , and Ellen Shapiro*Ellen Shapiro* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000901.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Host microbiome is critical for maintaining immune homeostasis and priming systemic and local immune responses. Little is known about whether microbiome perturbation affects innate responses of the bladder against infections caused by uropathogenic E. coli (UPEC). A recent population-based study showed a link between antibiotic use, gut microbiome perturbation and recurrent urinary tract infection (UTI). This study was to explore the effects of antibiotic-induced host microbiome perturbation on experimental UTI. METHODS: Antibiotic (Abx) treatment (1 g/L each of ampicillin, neomycin, metronidazole, 0.5 g/L of vancomycin in drinking water) started for conventionally raised female mouse breeders (129/SvEv strain), continued during pregnancy until after weaning of the offspring which were treated for 2 more weeks. Treatment ceased 10 days before UPEC infection. Control mice received no Abx. Due to technical difficulties to quantify urine microbiome in mice, fecal microbiome was used as a surrogate by Q-PCR and 16S-rDNA MiSeq. Female mice (n=15) were transurethrally infected with UPEC strain UTI89 (107 cfu in 50 ul). Bladders were homogenized/plated to enumerate UPEC or immunostained with anti-E.coli, uroplakin Ia, p65 of NF-kB and Ly6G. Neutrophil infiltration was assessed by myeloperoxidase (MPO) assay. RESULTS: Abx treatment resulted in a 90% reduction of fecal microbiome and its diversity by 34% but it did not affect urinary tract anatomy, urothelial morphology or apical distribution of uroplakin Ia – the urothelial receptor for type 1-piliated UPEC. UPEC induced rapid activation of NF-kB in the umbrella cells in both the Abx-treated and control mice at 2 hours post-infection (hpi). However, bacterial colonization at 24 hpi was 5-fold higher in the Abx-treated mouse bladders than the controls. The number of intracellular bacterial communities at 12 and 24 hpi was 2.5-fold and 5-folder higher, respectively, in the Abx mice than in controls. In contrast, neutrophil infiltration and neutrophil MPO activity were significantly lower in the Abx mice. CONCLUSIONS: Our study provides the first experimental evidence demonstrating that the host microbiome plays a critical role in innate immune defenses against UTI and that its deficiency caused by early-age antibiotic exposure leads to compromised neutrophil infiltration and increased bacterial burden in the bladder. Further studies are needed to ascertain whether these effects are caused by gut and/or urinary microbiome. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e673-e673 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yan Liu More articles by this author Abbey Lepor More articles by this author Hongying Huang More articles by this author Herbert Lepor More articles by this author Xue-Ru Wu More articles by this author Ellen Shapiro* More articles by this author Expand All Advertisement PDF downloadLoading ...