25 - Microbiome and Metabolic Markers of Clostridium Difficile Recurrance

Allegretti, Jessica R.; Mullish, Benjamin H.; Bogart, Eli; Shu, Edina; Dong, Xiaoxi; McDonald, Julie A. K.; Pechlivanis, Alexandros; Marchesi, Julian; Gerber, Georg K.; Bry, Lynn

doi:10.1016/s0016-5085(18)30514-6

Cited by 4 publications

(4 citation statements)

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“…Patients who were excluded were as follows: patients with inflammatory bowel disease; patients with inherited or acquired immunodeficiencies; severe or fulminant CDI, as diagnosed by Infectious Diseases Society of America and/or American College of Gastroenterology guidelines 9,10 ; or the need for ongoing non‐CDI antibiotic use that continued past the CDI antibiotic course. Initial powering of the study was derived focused on the expected clinical outcomes, 27 and suggested 20 patients with recurrence would be required to reach these primary outcomes; however, an interim analysis of BA profiles from samples from this study demonstrated that at least 10 patients experiencing recurrence would be sufficient for intended BA‐related analyses 28 …”

Section: Methodsmentioning

confidence: 99%

“…Initial powering of the study was derived focused on the expected clinical outcomes, 27 and suggested 20 patients with recurrence would be required to reach these primary outcomes; however, an interim analysis of BA profiles from samples from this study demonstrated that at least 10 patients experiencing recurrence would be sufficient for intended BA-related analyses. 28 Participating patients were recruited at the time of CDI diagnosis and samples collected through up to 8 weeks post-completion of their anti-CDI therapy to assess for recurrence, with clinical assessments regarding the presence or absence of diarrhoea occurring at each timepoint. Active stool collection began 1 day after completing anti-CDI antibiotics; stool was collected up to twice a week for the first 2 weeks post-therapy completion, and weekly through to week 8 (in the case of no recurrence), or until the point of recurrence.…”

Section: Patient Cohortmentioning

confidence: 99%

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Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection

Mullish

Martinez‐Gili

Chekmeneva

et al. 2022

Aliment Pharmacol Ther

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Summary Background Factors influencing recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools predicting recurrence are lacking. Perturbations in bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis. Aims To define stool BA dynamics in patients with primary CDI and to explore signatures predicting recurrence Methods Weekly stool samples were collected from patients with primary CDI from the last day of anti‐CDI therapy until recurrence or, otherwise, through 8 weeks post‐completion. Ultra‐high performance liquid chromatography‐mass spectrometry was used to profile BAs. Stool bile salt hydrolase (BSH) activity was measured to determine primary BA bacterial deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in patients with recurrence versus those without, and to assess faecal BAs as predictive markers for recurrence. Results Twenty (36%) of 56 patients (median age: 57, 64% male) had recurrence; 80% of recurrences occurred within the first 9 days post‐antibiotic treatment. Principal component analysis of stool BA profiles demonstrated clustering by recurrence status and post‐treatment timepoint. Longitudinal faecal BA trajectories showed recovery of secondary BAs and their derivatives only in patients without recurrence. BSH activity increased over time only among non‐relapsing patients (β = 0.056; likelihood ratio test p = 0.018). A joint longitudinal‐survival model identified five stool BAs with area under the receiver operating characteristic curve >0.73 for predicting recurrence within 9 days post‐CDI treatment. Conclusions Gut BA metabolism dynamics differ in primary CDI patients between those developing recurrence and those who do not. Individual BAs show promise as potential novel biomarkers to predict CDI recurrence.

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Section: Methodsmentioning

confidence: 99%

Section: Patient Cohortmentioning

confidence: 99%

Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection

Mullish

Martinez‐Gili

Chekmeneva

et al. 2022

Aliment Pharmacol Ther

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“…Whilst recent antibiotic exposure, immunosuppression and older age are established risk factors for CDI, the underlying mechanistic pathways contributing to its pathogenesis have only become more apparent in recent years. A variety of experimental approaches have revealed that perturbations to the gut microbiome resulting in loss of gut microbial species containing BSH and 7a-dehydroxylation enzymes, and subsequent increases in conjugated PBAs (in particular taurocholic acid) and reductions in SBAs, promote Clostridium difficile spore germination and growth in the gut (37)(38)(39). Furthermore, faecal microbiota transplantation (FMT) which is a highly efficacious therapy for recurrent or refractory CDI (rCDI), is also dependent on BA metabolism.…”

Section: Changes In Bile Acid Composition In Ibd Patientsmentioning

confidence: 99%

The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease

et al. 2022

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Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that arises due to complex interactions between host genetic risk factors, environmental factors, and a dysbiotic gut microbiota. Although metagenomic approaches have attempted to characterise the dysbiosis occurring in IBD, the precise mechanistic pathways interlinking the gut microbiota and the intestinal mucosa are still yet to be unravelled. To deconvolute these complex interactions, a more reductionist approach involving microbial metabolites has been suggested. Bile acids have emerged as a key class of microbiota-associated metabolites that are perturbed in IBD patients. In recent years, metabolomics studies have revealed a consistent defect in bile acid metabolism with an increase in primary bile acids and a reduction in secondary bile acids in IBD patients. This review explores the evolving evidence that specific bile acid metabolites interact with intestinal epithelial and immune cells to contribute to the inflammatory milieu seen in IBD. Furthermore, we summarise evidence linking bile acids with intracellular pathways that are known to be relevant in IBD including autophagy, apoptosis, and the inflammasome pathway. Finally, we discuss how novel experimental and bioinformatics approaches could further advance our understanding of the role of bile acids and inform novel therapeutic strategies in IBD.

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“…In a study currently reported in abstract form only, 29 patients with primary CDI were monitored prospectively, and stool samples were collected once to twice weekly from diagnosis up until approximately 6 weeks if no recurrence occurred ( n = 19) or until the point of recurrence ( n = 10). 36 Stool 16S rRNA gene sequencing was performed for each sample, and analysed using a machine-learning based approach; this demonstrated a greatly reduced rate of CDI recurrence occurring among patients whose gut microbiome contained C. scindens or Clostridium hylemonae , both 7-α-dehydroxylase-producing organisms. Further analysis demonstrated that, whereas levels of stool TCA significantly reduced over time (and levels of BSH activity restored) compared with baseline among patients who did not experience recurrence, neither changed significantly from baseline level in patients who went on to develop CDI recurrence.…”

Section: Experimental Data Regarding Altered Gut Microbiome–bile Acid Interactions In CDImentioning

confidence: 99%

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

Mullish

Allegretti

2021

Therap Adv Gastroenterol

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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.

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25 - Microbiome and Metabolic Markers of Clostridium Difficile Recurrance

Cited by 4 publications

References 0 publications

Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection

Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection

The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease

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

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