scholarly journals Development and Validation of a Novel Microbiome-Based Biomarker of Post-antibiotic Dysbiosis and Subsequent Restoration

2022 ◽  
Vol 12 ◽  
Author(s):  
Ken Blount ◽  
Courtney Jones ◽  
Dana Walsh ◽  
Carlos Gonzalez ◽  
William D. Shannon
Keyword(s):  
Clinical Response ◽  
Gastrointestinal Disease ◽  
Antibiotic Administration ◽  
Strongly Correlated ◽  
Health And Wellness ◽  
A Algorithm ◽  
Disease States ◽  
Clostridioides Difficile ◽  
Development And Validation ◽  
Microbiome Data

Background: The human gut microbiota are important to health and wellness, and disrupted microbiota homeostasis, or “dysbiosis,” can cause or contribute to many gastrointestinal disease states. Dysbiosis can be caused by many factors, most notably antibiotic treatment. To correct dysbiosis and restore healthier microbiota, several investigational microbiota-based live biotherapeutic products (LBPs) are in formal clinical development. To better guide and refine LBP development and to better understand and manage the risks of antibiotic administration, biomarkers that distinguish post-antibiotic dysbiosis from healthy microbiota are needed. Here we report the development of a prototype Microbiome Health Index for post-Antibiotic dysbiosis (MHI-A).Methods: MHI-A was developed and validated using longitudinal gut microbiome data from participants in clinical trials of RBX2660 and RBX7455 – investigational LBPs in development for reducing recurrent Clostridioides difficile infections (rCDI). The MHI-A algorithm relates the relative abundances of microbiome taxonomic classes that changed the most after RBX2660 or RBX7455 treatment, that strongly correlated with clinical response, and that reflect biological mechanisms believed important to rCDI. The diagnostic utility of MHI-A was reinforced using publicly available microbiome data from healthy or antibiotic-treated populations.Results: MHI-A has high accuracy to distinguish post-antibiotic dysbiosis from healthy microbiota. MHI-A values were consistent across multiple healthy populations and were significantly shifted by antibiotic treatments known to alter microbiota compositions, shifted less by microbiota-sparing antibiotics. Clinical response to RBX2660 and RBX7455 correlated with a shift of MHI-A from dysbiotic to healthy values.Conclusion: MHI-A is a promising biomarker of post-antibiotic dysbiosis and subsequent restoration. MHI-A may be useful for rank-ordering the microbiota-disrupting effects of antibiotics and as a pharmacodynamic measure of microbiota restoration.

scholarly journals Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease

2020 ◽  
Vol 13 ◽  
pp. 175628482094690 ◽  
Author(s):  
Jonathan P. Segal ◽  
Benjamin H. Mullish ◽  
Mohammed N. Quraishi ◽  
Tariq Iqbal ◽  
Julian R. Marchesi ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Gastrointestinal Disease ◽  
Full Potential ◽  
Faecal Microbiota ◽  
Therapeutic Tool ◽  
Faecal Microbiota Transplantation ◽  
Disease States ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Recommended Therapy

Faecal microbiota transplantation (FMT) is currently a recommended therapy for recurrent/refractory Clostridioides difficile infection (CDI). The success of FMT for CDI has led to interest in its therapeutic potential in many other disorders. The mechanisms that underpin the efficacy of FMT are not fully understood. Importantly, FMT remains a crucial treatment in managing CDI and understanding the mechanisms that underpin its success will be critical to improve its clinical efficacy, safety and usability. Furthermore, a deeper understanding of this may allow us to expose FMT’s full potential as a therapeutic tool for other disease states. This review will explore the current understanding of the mechanisms underlying the efficacy of FMT across a variety of diseases.

scholarly journals Client Satisfaction and Experience With Telepsychiatry: Development and Validation of a Survey Using Clinical Quality Domains (Preprint)

2020 ◽  
Author(s):  
Eva Serhal ◽  
Anne Kirvan ◽  
Marcos Sanches ◽  
Allison Crawford
Keyword(s):  
Mental Health ◽  
Patient Satisfaction ◽  
Quality Of Care ◽  
Quality Care ◽  
Clinical Intervention ◽  
Strongly Correlated ◽  
Clinical Quality ◽  
Survey Tool ◽  
Development And Validation

BACKGROUND Telepsychiatry is an increasingly used model of mental health care that connects patients with psychiatrists at a distance via videoconference. Telepsychiatry is an effective clinical intervention that improves access to quality care in regions with limited resources or in clinical situations where in-person care is unavailable. OBJECTIVE This study aims to develop a validated survey tool to measure patient experience and satisfaction with telepsychiatry based on the quality of care domains. This study also seeks to understand which health service outcomes were most strongly correlated with overall satisfaction in the context of telepsychiatry. METHODS The survey created in this study was developed and validated with a panel of subject matter and process experts and was piloted with 274 patients who received clinical consultations through the TeleMental Health Program at the Centre for Addiction and Mental Health. Factor analysis was used to determine correlations between questions and quality of care domains and was also used to assess model fit. RESULTS The study provides a validated survey to measure patient satisfaction and experience with telepsychiatry across 4 domains: access and timeliness, appropriateness, effectiveness, and safety. Both safety and access and timeliness were found to be statistically significant predictors of satisfaction in our sample. CONCLUSIONS By situating patient satisfaction and experience within this framework, the survey facilitates patient data collection and interpretation through a clinical quality lens.

scholarly journals A Bayesian zero-inflated negative binomial regression model for the integrative analysis of microbiome data

Biostatistics ◽  
2019 ◽  
Author(s):  
Shuang Jiang ◽  
Guanghua Xiao ◽  
Andrew Y Koh ◽  
Jiwoong Kim ◽  
Qiwei Li ◽  
...  
Keyword(s):  
Regression Model ◽  
Negative Binomial ◽  
Human Microbiome ◽  
Simulated Data ◽  
Negative Binomial Regression ◽  
Bayesian Regression ◽  
Negative Binomial Regression Model ◽  
Disease States ◽  
Binomial Regression ◽  
Microbiome Data

Summary Microbiome omics approaches can reveal intriguing relationships between the human microbiome and certain disease states. Along with identification of specific bacteria taxa associated with diseases, recent scientific advancements provide mounting evidence that metabolism, genetics, and environmental factors can all modulate these microbial effects. However, the current methods for integrating microbiome data and other covariates are severely lacking. Hence, we present an integrative Bayesian zero-inflated negative binomial regression model that can both distinguish differentially abundant taxa with distinct phenotypes and quantify covariate-taxa effects. Our model demonstrates good performance using simulated data. Furthermore, we successfully integrated microbiome taxonomies and metabolomics in two real microbiome datasets to provide biologically interpretable findings. In all, we proposed a novel integrative Bayesian regression model that features bacterial differential abundance analysis and microbiome-covariate effects quantifications, which makes it suitable for general microbiome studies.

scholarly journals Bile Acid Profile and its Changes in Response to Cefoperazone Treatment in MR1 Deficient Mice

Metabolites ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 127 ◽  
Author(s):  
Jinchun Sun ◽  
Zhijun Cao ◽  
Ashley D. Smith ◽  
Paul E. Carlson Jr ◽  
Michael Coryell ◽  
...  
Keyword(s):  
Bile Acid ◽  
Intestinal Content ◽  
Knock Out ◽  
Mait Cells ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Infection Resistance ◽  
Stool Samples ◽  
Cecum Content ◽  
Microbiome Data

Mucosal associated invariant T-cells (MAIT cells) are activated following recognition of bacterial antigens (riboflavin intermediates) presented on major histocompatibility complex class I-related molecule (MR1). Our previous study showed that MR1−/− knock-out (KO) mice (lacking MAIT cells) harbor a unique microbiota that is resistant to antibiotic disruption and Clostridioides difficile colonization. While we have characterized the microbiota of this mouse strain, changes in global metabolic activity in these KO mice have not been assessed. Here, LC/MS-based untargeted metabolomics was applied to investigate the differences in the metabolome, specifically in the bile acid (BA) profile of wild-type (WT) and MR1−/− KO mice, as well as how antibiotics change these profiles. BA changes were evaluated in the intestinal content, cecum content, and stool samples from MR1−/− mice and WT mice treated with cefoperazone (Cef). Fecal pellets were collected daily and both intestinal and cecal contents were harvested at predetermined endpoints on day 0 (D0), day 1 (D1), day 3 (D3), and day 5 (D5). KO mice exhibited no changes in 6-hydroxymethyl-8-D-ribityllumazine (rRL-6-CH2OH; an MR1-restricted riboflavin derivative) in the stool samples at either time point vs. D0, while WT mice showed significant decreases in rRL-6-CH2OH in the stool samples on all treatment days vs. D0. Metabolomics analysis from cecal and stool samples showed that KO mice had more total BA intensity (KO/WT = ~1.7 and ~3.3 fold higher) than that from WT mice prior to Cef treatment, while the fold change difference (KO/WT = ~4.5 and ~4.4 fold) increased after five days of Cef treatment. Both KO and WT mice showed decreases in total BA intensity in response to Cef treatment, however, less dramatic decreases were present in KO vs. WT mice. Increases in taurocholic acid (TCA) intensity and decreases in deoxycholic acid (DCA) intensity in the stool samples from WT mice were associated with the depletion of certain gut bacteria, which was consistent with the previously reported microbiome data. Furthermore, the non-detected TCA and relatively higher DCA intensity in the KO mice might be related to Clostridioides difficile infection resistance, although this needs further investigation.

scholarly journals Predictive Factors for the First Recurrence of Clostridioides difficile Infection in the Elderly from Western Romania

Medicina ◽  
2020 ◽  
Vol 56 (9) ◽  
pp. 439
Author(s):  
Iosif Marincu ◽  
Felix Bratosin ◽  
Iulia Vidican ◽  
Bianca Cerbu ◽  
Mirela Turaiche ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Predictive Factors ◽  
Gastrointestinal Disease ◽  
National Health System ◽  
Public Health Problem ◽  
The Elderly ◽  
Control Group ◽  
The European Union ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Background and objectives: At present, Romania and parts of the European Union are facing an increasingly challenging public health problem consisting of nosocomial Clostridioides difficile infection (CDI), mostly in the elderly. Relapse cases have become more frequent, which present higher morbidity and mortality rates than the initial CDI infection. The aim of this study is to determine the predictive factors for recurrence, with the purpose of reducing the exposure of patients diagnosed with CDI, as well as aiming to initiate early treatment. Materials and Methods: In this retrospective descriptive study, we analyze a database from the First Department of Infectious Diseases at the Dr. Victor Babes Clinical Hospital for Infectious Diseases and Pulmonology in Timisoara, looking for patient history of CDI recurrences. We analyzed CDI recurrence in patients aged ≥65 years from 1 January 2016 to 31 December 2019, identifying 77 cases of CDI recurrence. The determination of predictive factors for recurrence involved the formation of a randomized control group, consisting of 74 patients aged ≥65 years who were diagnosed with C. difficile enterocolitis, but did not suffer a recurrence and survived ≥2 weeks after symptom onset. Results: Immunocompromised status, pre-existing gastrointestinal disease, and fever on initial hospitalization for CDI were all found to be significant independent positive predictive factors for the condition recurring in elderly Romanian patients. Conclusions: As the geriatric population in Romania grows, the national health system becomes increasingly overburdened, both from a financial standpoint and a human resources perspective. The analysis of factors predictive for CDI recurrence is, thus, of the utmost importance, particularly for the early identification of patients most at risk of CDI recurrence. Our findings could help physicians to identify recurrence early, consequently benefitting patients by a rapid intervention with a potential decrease in the associated complications and mortality.

scholarly journals Development and Application of Mass Spectroscopy Assays for Nε-(1-Carboxymethyl)-L-Lysine and Pentosidine in Renal Failure and Diabetes

2020 ◽  
Vol 5 (3) ◽  
pp. 558-568
Author(s):  
Katherine L O’Grady ◽  
Sundeep Khosla ◽  
Joshua N Farr ◽  
Olga P Bondar ◽  
Elizabeth J Atkinson ◽  
...  
Keyword(s):  
Renal Failure ◽  
Mass Spectroscopy ◽  
Disease States ◽  
Glycation End Products ◽  
Control Versus ◽  
Development And Validation ◽  
Lower Limits ◽  
Circulating Levels ◽  
Separate Cohort

Abstract Background Advanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging. Methods We describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine. Results Serum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P < 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P < 0.001). Conclusions These mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.

scholarly journals Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

2015 ◽  
Vol 309 (12) ◽  
pp. G927-G941 ◽  
Author(s):  
Calvin S. Pohl ◽  
Julia E. Medland ◽  
Adam J. Moeser
Keyword(s):  
Animal Models ◽  
Life Stress ◽  
Early Life ◽  
Disease Susceptibility ◽  
Gastrointestinal Disease ◽  
Adult Life ◽  
Early Life Stress ◽  
Early Postnatal Development ◽  
Disease States ◽  
Fundamental Understanding

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted.

scholarly journals Biofilm regulation in Clostridioides difficile: Novel systems linked to hypervirulence

2021 ◽  
Vol 17 (9) ◽  
pp. e1009817
Author(s):  
Megan G. Taggart ◽  
William J. Snelling ◽  
Patrick J. Naughton ◽  
Roberto M. La Ragione ◽  
James S. G. Dooley ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Gastrointestinal Disease ◽  
Regulatory System ◽  
Disease Recurrence ◽  
The United States ◽  
Extracellular Dna ◽  
Published Data ◽  
Bacterial Cells ◽  
Healthcare Associated Infection ◽  
Clostridioides Difficile

Clostridiodes difficile (C. difficile) was ranked an “urgent threat” by the Centers for Disease Control and Prevention (CDC) in 2019. C. difficile infection (CDI) is the most common healthcare-associated infection (HAI) in the United States of America as well as the leading cause of antibiotic-associated gastrointestinal disease. C. difficile is a gram-positive, rod-shaped, spore-forming, anaerobic bacterium that causes infection of the epithelial lining of the gut. CDI occurs most commonly after disruption of the human gut microflora following the prolonged use of broad-spectrum antibiotics. However, the recurrent nature of this disease has led to the hypothesis that biofilm formation may play a role in its pathogenesis. Biofilms are sessile communities of bacteria protected from extracellular stresses by a matrix of self-produced proteins, polysaccharides, and extracellular DNA. Biofilm regulation in C. difficile is still incompletely understood, and its role in disease recurrence has yet to be fully elucidated. However, many factors have been found to influence biofilm formation in C. difficile, including motility, adhesion, and hydrophobicity of the bacterial cells. Small changes in one of these systems can greatly influence biofilm formation. Therefore, the biofilm regulatory system would need to coordinate all these systems to create optimal biofilm-forming physiology under appropriate environmental conditions. The coordination of these systems is complex and multifactorial, and any analysis must take into consideration the influences of the stress response, quorum sensing (QS), and gene regulation by second messenger molecule cyclic diguanosine monophosphate (c-di-GMP). However, the differences in biofilm-forming ability between C. difficile strains such as 630 and the “hypervirulent” strain, R20291, make it difficult to assign a “one size fits all” mechanism to biofilm regulation in C. difficile. This review seeks to consolidate published data regarding the regulation of C. difficile biofilms in order to identify gaps in knowledge and propose directions for future study.

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