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 1039. Rapid Restoration of Bile Acid Compositions After Treatment with RBX2660 for Recurrent Clostridioides difficile Infection—Results from the PUNCH CD3 Phase 3 Trial

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S610-S610
Author(s):  
Romeo Papazyan ◽  
Bryan Fuchs ◽  
Ken Blount ◽  
Carlos Gonzalez ◽  
Bill Shannon
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Deoxycholic Acid ◽  
Lithocholic Acid ◽  
Point Group ◽  
Bile Acid Metabolism ◽  
Phase 3 ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Time Point

Abstract Background Microbiota-based treatments are increasingly evaluated as a strategy to reduce recurrence of Clostridioides difficile infection (rCDI), and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid metabolism. RBX2660—a broad-consortium investigational live biotherapeutic—has been evaluated in >600 participants in 6 clinical trials, with consistent reduction of rCDI recurrence. Here we report that fecal bile acid compositions were significantly restored in treatment-responsive participants in PUNCH CD3—a Phase 3 randomized, double-blinded, placebo-controlled trial of RBX2660. Methods PUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 33 bile acids from all participant fecal samples received up to the 8-week time point. Mean bile acid compositions were fit to a Dirichlet multinomial distribution and compared across time points and between RBX2660- and placebo-treated participants. Results Clinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). RBX2660-treated clinical responders’ bile acid compositions shifted significantly from before to after treatment. Specifically, primary bile acids predominated before treatment, whereas secondary bile acids predominated after treatment (Figure 1A). These changes trended higher among RBX2660 responders compared to placebo responders. Importantly, median levels of lithocholic acid (LCA) and deoxycholic acid (DCA) showed large, significant increases after treatment (Figure 1B). A. Bile acid compositions before (BL) and up to 8 weeks after RBX2660 treatment among treatment responders. Compositions are shown as the fraction of total bile acids classified as primary or secondary conjugated or deconjugated bile acids. B. Concentrations of lithocholic acid (LCA) and deoxycholic acid (DCA) among RBX2660 treatment responders, shown with individual samples and time point group median with interquartile ranges. Conclusion Among PUNCH CD3 clinical responders, RBX2660 significantly restored bile acids from less to more healthy compositions. These clinically correlated bile acid shifts are highly consistent with results from a prior trial of RBX2660. Disclosures Romeo Papazyan, PhD, Ferring Research Institute (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)

Mo1928 ARE PATIENTS WITH ALTERED BILE ACID PROFILE AFTER CHOLECYSTECTOMY PROTECTED AGAINST CLOSTRIDIOIDES DIFFICILE INFECTION?

2020 ◽  
Vol 158 (6) ◽  
pp. S-980-S-981
Author(s):  
Mohammad Abureesh ◽  
Motasem Alkhayyat ◽  
Shamsuddin M. Anwar ◽  
Hassan Al Moussawi ◽  
Liliane S. Deeb
Keyword(s):  
Bile Acid ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

scholarly journals Potential for the current National Healthcare Safety Network (NHSN) >3 days after admission definition of laboratory-identified, healthcare-facility–onset, Clostridioides difficile infection (HO-CDI) to overestimate rates

2020 ◽  
Vol 41 (4) ◽  
pp. 467-468
Author(s):  
Shruti Puri ◽  
Heather Y. Hughes ◽  
Monica D. McCrackin ◽  
Robert Williford ◽  
Mulugeta Gebregziabher ◽  
...  
Keyword(s):  
Healthcare Facility ◽  
National Healthcare ◽  
Clostridioides Difficile ◽  
National Healthcare Safety Network ◽  
Positive Stool ◽  
Clostridioides Difficile Infection ◽  
Stool Samples ◽  
Definition Of

AbstractHealthcare-facility–onset C.difficile LabID events are defined as positive stool samples collected >3 days after hospitalization. Using a definition of >72 hours, we found that 84 of 1013 cases (8.3%) identified as C. difficile LabID events were collected between 48 and 72 hours after admission.

scholarly journals The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

2021 ◽  
Vol 14 ◽  
pp. 175628482110177
Author(s):  
Benjamin H. Mullish ◽  
Jessica R. Allegretti
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Acid Metabolism ◽  
Disease Process ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Clostridioides Difficile ◽  
Gut Barrier Function ◽  
Clostridioides Difficile Infection

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites – in particular, bile acid metabolism – being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) – with a resulting alteration of the gut bile acid milieu – contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other ‘next generation’ FMT products) designed to treat CDI may be critical to their success.

scholarly journals 701. An Open-label Phase 2a Study of Ibezapolstat, a Unique Gram-positive Selective Spectrum (GPSS) Antibiotic, for Patients with Clostridioides difficile Infection

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S451-S451
Author(s):  
Kevin W Garey ◽  
Khurshida Begum ◽  
Chenlin Hu ◽  
Weiqun Wang ◽  
Chris Lancaster ◽  
...  
Keyword(s):  
Clinical Cure ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Clinical Development ◽  
Open Label ◽  
Gram Positive ◽  
Clostridioides Difficile ◽  
Open Label Phase ◽  
Clostridioides Difficile Infection ◽  
Stool Samples

Abstract Background Ibezapolstat, a DNA polymerase IIIC inhibitor, currently in Phase 2 clinical development for treatment of C. difficile infection (CDI). Its unique mechanism of action targets low G+C content Gram-positive bacteria primarily Firmicutes including C. difficile. Phase I healthy volunteer results demonstrated a favorable microbiome profile suggestive of an anti-recurrence effect. The purpose of this study was to report clinical outcomes, pharmacokinetics, and microbiome changes from this Phase 2a clinical study and to continue to test for anti-recurrence microbiome properties. Methods Ibezapolstat 450 mg was given twice daily for 10 days to patients with mild-moderate CDI defined as diarrhea plus a positive C. difficile toxin test. Test of cure was evaluated at day 12 and sustained clinical cure at day 38. Stool samples were evaluated for C. difficile cultures and microbiome changes. Results Ten subjects (female: 50%) aged 50 ±15 years were enrolled. All ten subjects experienced a clinical cure by the test of cure visit at day 12 and all 10 subjects experienced a sustained clinical cure at the day 38 visit. Ibezapolstat was well tolerated with 1 adverse event (nausea) probably related to drug. Ibezapolstat systemic exposure was minimal with no plasma level reaching 1 ug/mL any time during therapy. Ibezapolstat colonic concentrations averaged 400 ug/g stool at day 3 and greater than 1,000 ug/g by day 10 of dosing. Six of the seven available baseline stool samples grew toxigenic C. difficile of various ribotypes including RT078-226 and RT014-020 (Ibezapolstat MIC range: 0.25-1 ug/mL). Follow-up cultures were no growth starting from day 3 stool cultures. Microbiome changes included overgrowth of Actinobacteria and/or Firmicute phylum species while on therapy. Conclusion Favorable clinical efficacy and safety results were observed in ibezapolstat patients with CDI including 100% clinical cure and sustained clinical cure. These results begin to validate our approach to ibezapolstat development in that the favorable microbiome effects seen in healthy Phase 1 volunteers may be predictive of beneficial patient outcomes, including low rates of recurrence. These results support the continued clinical development of ibezapolstat. Disclosures Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support) Michael Silverman, MD, Acurx Pharmaceuticals (Consultant)

scholarly journals SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

2020 ◽  
Author(s):  
Barbara H McGovern ◽  
Christopher B Ford ◽  
Matthew R Henn ◽  
Darrell S Pardi ◽  
Sahil Khanna ◽  
...  
Keyword(s):  
Bile Acid ◽  
Statistical Significance ◽  
Standard Of Care ◽  
Lessons Learned ◽  
Metagenomic Sequencing ◽  
Double Blind ◽  
Secondary Bile Acid ◽  
Phase 2 Trial ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Abstract Background Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. Methods In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. Results 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. Conclusions Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. Clinical Trials Registration NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.

scholarly journals 185 Evaluating Dynamics of Bile Acid Metabolism to Predict Recurrence of Clostridioides difficile Infection

2019 ◽  
Vol 114 (1) ◽  
pp. S113-S113
Author(s):  
Jessica R. Allegretti ◽  
Benjamin Mullish ◽  
Lotem Nativ ◽  
Jenna Marcus ◽  
Julian Marchesi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

scholarly journals S138 Bile Acid Profile Changes in Patients Who Develop Recurrent Clostridioides difficile Infection: A Pilot Study

2021 ◽  
Vol 116 (1) ◽  
pp. S60-S61
Author(s):  
Janice Cho ◽  
William Harmsen ◽  
Michael Camilleri ◽  
Darrell Pardi ◽  
Sahil Khanna
Keyword(s):  
Bile Acid ◽  
Pilot Study ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Profile Changes

scholarly journals S139 Bile Acid Profile Changes and Persistent Gastrointestinal Symptoms in Patients Following Clostridioides difficile Infection

2021 ◽  
Vol 116 (1) ◽  
pp. S61-S61
Author(s):  
Janice Cho ◽  
William Harmsen ◽  
Michael Camilleri ◽  
Madhusudan Grover ◽  
Darrell Pardi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gastrointestinal Symptoms ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Profile Changes
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