Biology subjects

Young, V. B.

Publications and source records attributed to Young, V. B..

29 records · Page 2Linked to original sources

bioRxiv2019

Dietary xanthan gum alters antibiotic efficacy against the murine gut microbiota and attenuates Clostridioides difficile colonization

Dietary fiber provides a variety of microbiota-mediated benefits ranging from anti-inflammatory metabolites to pathogen colonization resistance. A healthy gut microbiota protects against Clostridioides difficile colonization. Manipulation of these microbes through diet may increase colonization resistance to improve clinical outcomes. The primary objective of this study was to identify how the dietary fiber xanthan gum affects the microbiota and C. difficile colonization.\n\nWe added 5% xanthan gum to the diet of C57Bl/6 mice and examined its effect on the microbiota through 16S rRNA-gene amplicon sequencing and short-chain fatty acid analysis. Following either cefoperazone or an antibiotic cocktail administration, we challenged mice with C. difficile and measured colonization by monitoring colony-forming units.\n\nXanthan gum administration associates with increases in fiber degrading taxa and short-chain fatty acid concentrations. However, by maintaining both the diversity and absolute abundance of the microbiota during antibiotic treatment, the protective effects of xanthan gum administration on the microbiota were more prominent than the enrichment of these fiber degrading taxa. As a result, mice that were on the xanthan gum diet experienced limited to no C. difficile colonization.\n\nXanthan gum administration alters mouse susceptibility to C. difficile colonization by maintaining the microbiota during antibiotic treatment. While antibiotic-xanthan gum interactions are not well understood, xanthan gum has previously been used to bind drugs and alter their pharmacokinetics. Thus, xanthan gum may alter the activity of the oral antibiotics used to make the microbiota susceptible. Future research should further characterize how this and other common dietary fibers interact with drugs.\n\nIMPORTANCEA healthy gut bacterial community benefits the host by breaking down dietary nutrients and protecting against pathogens. Clostridioides difficile capitalizes on the absence of this community to cause diarrhea and inflammation. Thus, a major clinical goal is to find ways to increase resistance to C. difficile colonization by either supplementing with bacteria that promote resistance or a diet to enrich for those already present in the gut. In this study, we describe an interaction between xanthan gum, a human dietary additive, and the microbiota resulting in an altered gut environment that is protective against C. difficile colonization.

microbiology↗

bioRxiv2019

Evidence that vertical transmission of the vaginal microbiota can persist into adolescence

BackgroundFactors that influence vaginal microbiota composition, including its source, are not well understood. To determine if vaginal microbiota transmission from mother to daughter at birth influences the human vaginal microbiota composition in adolescence, we investigated the relationship between the vaginal microbiota of 13 mother/daughter pairs and the daughters birth mode. ResultsBased on analysis of bacterial 16S rRNA gene sequences, the vaginal microbiotas of mother/daughter pairs were more similar to each other if the daughter was born by vaginal delivery rather than by C-section. Additionally, genome sequences from an important member of the vaginal microbiota, Lactobacillus crispatus, isolated from one mother/daughter pair in which the daughter was born by vaginal delivery, were highly similar. ConclusionsBoth community-level analysis and isolate genome sequence analysis are consistent with birth-mode dependent transmission and persistence of at least some members of the vaginal microbiota. ImportanceThe composition of the human vaginal microbiota is related to many aspects of health from infection susceptibility to preterm birth. Our study provides evidence that transmission of vaginal bacteria from mother to daughter at birth may be an important factor influencing vaginal microbiota composition into adolescence.

microbiology↗

bioRxiv2019

Effects of the copper IUD on composition of the vaginal microbiota in the olive baboon

ObjectivesAssess the impact of transcervical insertion, use, and removal of copper intrauterine devices (Cu-IUD) on baboon physiology (e.g. weight, menstruation) and vaginal microbiota.\n\nStudy designVaginal swabs were taken before insertion (pre-IUD), during IUD use (IUD), and after removal (post-IUD) and microbiota assessed by 16S rRNA-encoding gene sequence analysis.\n\nResultsNo animals showed physical changes or discomfort during pre-IUD, IUD, or post-IUD phases. There were no changes to the microbiome associated with insertion or use of Cu-IUD over 16 weeks, although removal resulted in perturbation to community structure.\n\nConclusionsBaboons tolerate Cu-IUD insertion with minimal device-associated changes to their vaginal microbiome throughout use and have no significant changes to their physiology or menstrual cycle during any phase.\n\nImplicationsA baboon model of Cu-IUD may allow investigations into the intersection of Cu-IUDs, reproductive tract disorders and pathogens that would not be possible in human studies.

microbiology↗

bioRxiv2019

Temporal Gut Microbial Changes Predict Recurrent Clostridium difficile in Patients with and without Ulcerative Colitis

BackgroundUlcerative colitis (UC) carries an increased risk of primary and recurrent Clostridium difficile infection (rCDI) and CDI is associated with UC flares. We hypothesized that specific fecal microbial changes associate with UC flare and rCDI.\n\nMethodsWe conducted a prospective observational cohort study of 57 patients with UC and CDI, CDI only, and UC flare only. Stool samples were collected at baseline, at the end of antibiotic therapy, and after reconstitution for 16S rRNA sequencing. The primary outcomes were recurrent UC flare and rCDI. Logistic regression and Lasso models were constructed for analysis.\n\nResultsThere were 21 (45.7%) patients with rCDI, while 11 (34.4%) developed UC flare. Patients with rCDI demonstrated significant inter-individual (P=.008) and intra-individual differences (P=.004 relative to baseline samples) in community structure by Jensen-Shannon distance (JSD) compared with non-rCDI. Two cross-validated models identified by Lasso regression predicted risk of rCDI: a baseline model with female gender, hospitalization for UC in the past year, increased Ruminococcaceae and Verrucomicrobia, and decreased Eubacteriaceae, Enterobacteriaceae, Lachnospiraceae, and Veillonellaceae (AuROC=0.94); and a model 14 days after completion of antibiotics with female gender, increased Shannon diversity, Ruminococcaceae and Enterobacteriaceae, and decreased community richness and Faecalibacterium (AuROC=0.9). Adding JSD between baseline and post-treatment samples to the latter model improved fit (AuROC=0.94). A baseline model including UC hospitalization in the past year and increased Bacteroidetes showed good fit characteristics for predicting increased risk of UC flare (AuROC=0.88).\n\nConclusionFecal microbial features at baseline and following therapy predict rCDI risk in patients with and without UC. These results may help risk stratify patients to guide management.

microbiology↗

bioRxiv2019

Evaluation of Bacteria Detected in Both Urine and Open Wounds in Nursing Facility Residents

Nursing home residents are at a greater risk of developing pressure injuries that develop into an open wound. Open wounds can be colonized with bacteria from multiple sources. Emerging evidence suggests the specific composition of the open wound microbial community can result in delayed wound healing and increased infection risk. Understanding the factors that influence microbial colonization of open wounds, can lead to the prevention of infections. The relationship between bacteria found in urine and that of open wounds, is currently unknown. Recent studies have shown that nursing home residents can harbor a urinary microbiota independent of symptoms and frequently experience urinary incontinence. To determine if the colonization of open wounds mirrors urinary colonization, we conducted a pilot study with nursing home residents, comparing bacteria present in open pressure injuries below the umbilicus and urine. To identify microbial species that were present in both urine and open wound at one timepoint, standard bacteriologic culture techniques followed by MALDI-TOF was used as well as16S rRNA-encoding gene amplicon sequencing. In this study we found that some bacteria detected in urine were also detected in open wounds in one individual at one timepoint, using both culture dependent and independent techniques. Bacterial species that were more often detected at both sites included Enterococcus faecalis, Proteus mirabilis, Escherichia coli, and Providencia stuartii. This pilot study provides evidence that urinary colonization can mirror open wound colonization. Further studies are needed to investigate if parallel colonization of these anatomical sites affect infection outcomes.

microbiology↗

bioRxiv2019

Outbreak of murine infection with Clostridium difficile associated with the administration of a pre- and peri-natal methyl-donor diet

Between October 2016 and June 2017, a C57BL/6J mouse colony that was undergoing a pre- and peri-natal methyl-donor supplementation diet intervention to study the impact of parental nutrition on offspring susceptibility to disease was found to suffer from an epizootic of unexpected deaths. Necropsy revealed the presence of severe colitis, and further investigation linked these outbreak deaths to a Clostridium difficile strain of ribotype 027 we term 16N203. C. difficile infection (CDI) is associated with antibiotic use in humans. Current murine models of CDI rely on antibiotic pretreatment to establish clinical phenotypes. In this report, the C. difficile outbreak occurs in F1 mice linked to alterations in the parental diet. The diagnosis of CDI in the affected mice was confirmed by cecal/colonic histopathology, presence of C. difficile bacteria in fecal/colonic culture, and detection of C. difficile toxins. F1 mice from parents fed the methyl-supplementation diet also had significantly reduced survival (p<0.0001) than F1 mice from parents fed the control diet. When we tested the 16N203 outbreak strain in an established mouse model of antibiotic-induced CDI, we confirmed that this strain is pathogenic. Our serendipitous observations from this spontaneous outbreak of C. difficile in association with a pre- and perinatal methyl-donor diet suggest the important role diet may play in host defense and CDI risk factors.\n\nImportanceClostridium difficile infection (CDI) has become the leading cause of infectious diarrhea in hospitals worldwide, owing its preeminence to the emergence of hyperendemic strains, such as ribotype 027 (RT027). A major CDI risk factor is antibiotic exposure which alters gut microbiota, resulting in the loss of colonization resistance. Current murine models of CDI also depend on pretreatment of antibiotics of animals to establish disease. The outbreak we report here is unique in that the CDI occurred in mice with no antibiotic exposure and is associated to a pre- and peri-natal methyl-supplementation donor diet intervention study. Our investigation subsequently reveals that the outbreak strain we term 16N203 is an RT027 strain, and this isolated strain is also pathogenic in an established murine model of CDI (with antibiotics). Our report of this spontaneous outbreak offers additional insight into the importance of environmental factors, such as diet, and CDI susceptibility.

epidemiology↗

bioRxiv2019

The gut microbiota is associated with clearance of Clostridium difficile infection independent of adaptive immunity

Clostridium (Clostridioides) difficile, a Gram-positive, anaerobic bacterium is the leading single cause of nosocomial infections in the United States. A major risk factor for C. difficile infection (CDI) is prior exposure to antibiotics as they increase susceptibility to CDI by altering the membership of the microbial community enabling colonization. The importance of the gut microbiota in providing protection from CDI is underscored by the reported 80-90% success rate of fecal microbial transplants in treating recurrent infection. Adaptive immunity, specifically humoral immunity, is also sufficient to protect from both acute and recurrent CDI. However, the role of the adaptive immune system in mediating clearance of C. difficile has yet to be resolved. Using murine models of CDI, we found that adaptive immunity is dispensable for clearance of C. difficile. However, Random Forest analysis using only 2 members of the resident bacterial community correctly identified animals that would go on to clear the infection with 66.7% accuracy. These findings indicate that the indigenous gut microbiota independent of adaptive immunity facilitates clearance of C. difficile from the murine gastrointestinal tract.\n\nImportanceC. difficile infection is a major cause of morbidity and mortality in hospitalized patients in the United States. Currently the role of the adaptive immune response in modulating levels of C. difficile colonization is unresolved. This work suggests that the indigenous gut microbiota is a main factor that promotes clearance of C. difficile from the GI tract. Our results show that clearance of C. difficile can occur without contributions from the adaptive immune response. This study also has implications for the design of preclinical studies testing the efficacy of vaccines on clearance of bacterial pathogens as inherent differences in the baseline community structure of animals may bias findings.

microbiology↗

bioRxiv2017

Clostridium difficile differentially alters the structure and metabolism of distinct cecal microbiomes to promote persistent colonization during infection

Susceptibility to Clostridium difficile infection is primarily associated with previous exposure to antibiotics, which compromise the structure and function of the gut bacterial community. Specific antibiotic classes correlate more strongly with recurrent or persistent C. difficile infection. As such, we utilized a mouse model of infection to explore the effect of distinct antibiotic classes on the impact that infection has on community-level transcription and metabolic signatures shortly following pathogen colonization and how those changes may associate with persistence of C. difficile. Untargeted metabolomic analysis revealed that C. difficile infection had significantly larger impacts on the metabolic environment across cefoperazone and streptomycin-pretreated mice, which become persistently colonized compared to clindamycin-pretreated mice where infection quickly became undetectable. Through metagenome-enabled metatranscriptomics we observed that transcripts for genes associated with carbon and energy acquisition were greatly reduced in infected animals, suggesting those niches were instead occupied by C. difficile. Furthermore, the largest changes in transcription were seen in the least abundant species indicating that C. difficile may \"attack the loser\" in gut environments where sustained infection occurs more readily. Overall, our results suggest that C. difficile is able to restructure the nutrient-niche landscape in the gut to promote persistent infection.

microbiology↗

bioRxiv2017

Bacterial Colonization Stimulates A Complex Physiological Response In The Immature Human Intestinal Epithelium

The human gastrointestinal tract is immature at birth, yet must adapt to dramatic changes such as oral nutrition and microbial colonization. The confluence of these factors can lead to severe inflammatory disease in premature infants; however, investigating complex environment-host interactions is diZcult due to limited access to immature human tissue. Here, we demonstrate that the epithelium of human pluripotent stem cell-derived human intestinal organoids is globally similar to the immature human epithelium and we utilize HIOs to investigate complex host-microbe interactions in this naive epithelium. Our findings demonstrate that the immature epithelium is intrinsically capable of establishing a stable host-microbe symbiosis. Microbial colonization leads to complex contact and hypoxia driven responses resulting in increased antimicrobial peptide production, maturation of the mucus layer, and improved barrier function. These studies lay the groundwork for an improved mechanistic understanding of how colonization influences development of the immature human intestine.

developmental biology↗

bioRxiv2017

Inter-individual Recovery Of The Microbiota And Metabolome Over Time Following Fecal Microbiota Transplantation In Patients With Recurrent Clostridium difficile Infection

A significant proportion of individuals develop recurrent Clostridium difficile infection (CDI) following initial disease. Fecal microbiota transplantation (FMT), a highly effective treatment method for recurrent CDI, has been demonstrated to induce microbiota recovery, a critical component of disease recovery. However, identification of the specific microbes and their functions that directly impact recovery from CDI remains difficult. We assessed for associations among microbial community members and metabolites in patients with recurrent CDI following treatment with FMT over time to identify groups of bacteria with potential restorative functions. Using 16S rRNA gene-based sequencing, we observed marked similarity of the microbiota between recipients following FMT (n = 6, sampling up to 6 months post-FMT) and their respective donors. Increased levels of the secondary bile acid deoxycholic acid and the short chain fatty acids (SCFAs) butyrate, acetate, and propionate were observed post-FMT. To take into account longitudinal sampling and intra-individual differences, we applied a generalized estimating equation approach to model metabolite concentrations with the presence of specific members of the microbiota. Microbial metabolites that were increased following FMT associated with members classified within the Lachnospiraceae, Ruminococcaceae, and unclassified Clostridiales families. In contrast, members of these taxa were inversely associated with primary bile acids. The longitudinal aspect of this study allowed us to characterize individualized patterns of recovery, revealing variability between and within patients following FMT.\n\nIMPORTANCEClostridium difficile infection (CDI) is an urgent and serious healthcare-associated problem. In recent years, fecal microbiota transplantation (FMT) has been successfully used to treat recurrent CDI, a frequent outcome of disease. While it is apparent that FMT promotes recovery of the microbiota, it is unclear how microbes and their functions promote recovery from disease. This study aimed to identify associations among microbes and metabolites following FMT and to identify critical microbial functions following FMT treatment for recurrent CDI. Overall, recovery of the metabolome was highly dynamic and individualized in all patients, who were all successfully treated. Our results suggest that microbial changes following FMT may be highly specific to the donor-recipient relationship. Further understanding of the host-microbe environments necessary to enable successful transplantation of microbes during FMT could aid development of specific microbial therapeutics for recurrent CDI and other gastrointestinal diseases.

microbiology↗

bioRxiv2016

Clostridium difficile colonizes alternative nutrient niches during infection across distinct murine gut environments

Clostridium difficile is the largest single cause of hospital-acquired infection in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they disrupt the gut bacterial community which protects from C. difficile colonization. Multiple antibiotic classes have been associated with CDI susceptibility; many leading to distinct community structures stemming from variation in bacterial targets of action. These community structures present separate metabolic challenges to C. difficile. Therefore we hypothesized that the pathogen adapts its physiology to the nutrients within different gut environments. Utilizing an in vivo CDI model, we demonstrated C. difficile highly colonized ceca of mice pretreated with any of three antibiotics from distinct classes. Levels of C. difficile spore formation and toxin activity varied between animals based on the antibiotic pretreatment. These physiologic processes in C. difficile are partially regulated by environmental nutrient concentrations. To investigate metabolic responses of the bacterium in vivo, we performed transcriptomic analysis of C. difficile from ceca of infected mice across pretreatments. This revealed heterogeneous expression in numerous catabolic pathways for diverse growth substrates. To assess which resources C. difficile exploited, we developed a genome-scale metabolic model with a transcriptome-enabled metabolite scoring algorithm integrating network architecture. This platform identified nutrients C. difficile used preferentially between pretreatments, which were validated through untargeted mass spectrometry of each microbiome. Our results supported the hypothesis that C. difficile inhabits alternative nutrient niches across cecal microbiomes with increased preference for nitrogen-containing carbon sources, particularly Stickland fermentation substrates and host-derived glycans.\n\nImportanceInfection by the bacterium Clostridium difficile causes an inflammatory diarrheal disease which can become life-threatening, and has grown to be the most prevalent nosocomial infection. Susceptibility to C. difficile infection is strongly associated with previous antibiotic treatment, which disrupts the gut microbiota and reduces its ability to prevent colonization. In this study we demonstrated that C. difficile altered pathogenesis between hosts pretreated with antibiotics from separate classes, and exploited different nutrient sources across these environments. Our metabolite score calculation also provides a platform to study nutrient requirements of pathogens during an infection. Our results suggest that C. difficile colonization resistance is mediated by multiple groups of bacteria competing for several subsets of nutrients and could explain why total reintroduction of competitors through fecal microbial transplant currently is the most effective treatment for recurrent CDI. This work could ultimately contribute to the identification of targeted, context-dependent measures that prevent or reduce C. difficile colonization including pre- and probiotic therapies.

microbiology↗