Colonization of the live biotherapeutic product VE303 and modulation of the microbiota and metabolites in healthy volunteers

Dsouza, Melissa; Menon, Rajita; Crossette, Emily; Bhattarai, Shakti; Schneider, Jessica; Kim, Yun Gi; Reddy, Shilpa; Caballero, Silvia; Felix, Cintia R.; Cornacchione, Louis P.; Hendrickson, Jared; Watson, Andrea R.; Minot, Samuel S.; Greenfield, Nick; Schopf, Lisa; Szabady, Rose L.; Patarroyo, Juan C.; Smith, William G.; Harrison, Pratibha; Kuijper, Ed J.; Kelly, Ciarán P.; Olle, Bernat; Bobilev, Dmitri; Silber, Jeffrey L.; Bucci, Vanni; Roberts, Bruce; Faith, Jeremiah J.; Norman, Jason

doi:10.1016/j.chom.2022.03.016

Cited by 77 publications

(67 citation statements)

References 117 publications

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“…Interestingly, a previous study showed the capacity of valerate to inhibit C. difficile in an in vitro gut model of the microbiome following antibiotic exposure. 39 However, its effect on gut microbiota recovery was not tested, and future studies are warranted to study its role, as well as other potentially involved metabolites such as bile acids 40 , 41 .…”

Section: Discussionmentioning

confidence: 99%

Improved gut microbiome recovery following drug therapy is linked to abundance and replication of probiotic strains

et al. 2022

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Probiotics have been used for decades to alleviate the negative side-effects of oral antibiotics, but our mechanistic understanding on how they work is so far incomplete. Here, we performed a metagenomic analysis of the fecal microbiota in participants who underwent a 14-d Helicobacter pylori eradication therapy with or without consumption of a multi-strain probiotic intervention ( L. paracasei CNCM I-1518, L. paracasei CNCM I-3689, L. rhamnosus CNCM I-3690, and four yogurt strains) in a randomized, double-blinded, controlled clinical trial. Using a strain-level analysis for detection and metagenomic determination of replication rate, ingested strains were detected and replicated transiently in fecal samples and in the gut during and following antibiotic administration. Consumption of the fermented milk product led to a significant, although modest, improvement in the recovery of microbiota composition. Stratification of participants into two groups based on the degree to which their microbiome recovered showed i) a higher fecal abundance of the probiotic L. paracasei and L. rhamnosus strains and ii) an elevated replication rate of one strain ( L. paracasei CNCMI-1518) in the recovery group. Collectively, our findings show a small but measurable benefit of a fermented milk product on microbiome recovery after antibiotics, which was linked to the detection and replication of specific probiotic strains. Such functional insight can form the basis for the development of probiotic-based intervention aimed to protect gut microbiome from drug treatments.

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Section: Discussionmentioning

confidence: 99%

Improved gut microbiome recovery following drug therapy is linked to abundance and replication of probiotic strains

et al. 2022

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“…Supportive of this view (albeit from the context of recurrent rather than primary CDI) is the finding that a key mechanism underlying the efficacy of faecal microbiota transplant (FMT) in recurrent CDI is through restoration of bacterial BSH functionality, and the associated restoration of a pre‐morbid gut BA profile 18,23,44,45 . Similarly, both a spore‐based ‘microbiome therapeutic’ derived from alcohol‐shocked healthy donor stool and a live biotherapeutic product consisting of eight Clostridia strains were both shown to rapidly and sustainably restore stool secondary BAs 46,47 …”

Section: Discussionmentioning

confidence: 99%

“…18,23,44,45 Similarly, both a spore-based 'microbiome therapeutic' derived from alcohol-shocked healthy donor stool and a live biotherapeutic product consisting of eight Clostridia strains were both shown to rapidly and sustainably restore stool secondary BAs. 46,47 Much research to date on gut microbiome-BA interactions in the context of CDI has focused on the bacterial enzymes BSH and 7α-dehydroxylase, 13 and it was therefore unsurprising to see two…”

Section: Ta B L Ementioning

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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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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“…Supportive of this view, albeit from the context of recurrent rather than primary CDI, is the finding that a key mechanism underlying the efficacy of fecal microbiota transplant (FMT) in recurrent CDI is through restoration of microbial BSH functionality, and the associated restoration of a pre-morbid gut bile acid profile [18,39,40]. Similarly, both a spore-based 'microbiome therapeutic' derived from alcohol-shocked healthy donor stool and a live biotherapeutic product consisting of eight Clostridia strains were both shown to rapidly and sustainably restore stool secondary bile acids [41,42].…”

Section: Discussionmentioning

confidence: 99%

Fecal bile acid profiles predict recurrence in patients with primary Clostridioides difficile infection

Mullish

Martinez‐Gili

Chekmeneva³

et al. 2022

Preprint

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Background: Factors that influence recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools to predict recurrence are lacking. Perturbations in microbial-derived bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis. Aims: To define stool bile acid profiles and microbial bile-metabolising functionality in primary CDI patients, and explore signatures predicting recurrence. Methods: Weekly stool samples were collected from primary CDI patients from the last day of anti-CDI therapy until recurrence, or through eight weeks post-completion otherwise. Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to profile bile acids, and bacterial bile salt hydrolase (BSH) activity was measured to determine primary BA deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in recurrers versus non-recurrers, and assess fecal bile acids as predictive markers for recurrence. Results: Twenty (36%) out of 56 patients (median age 57, 64% male) recurred, with 80% of recurrence occurring within the first nine days post-antibiotic treatment. Principal component analysis (PCA) of stool bile acid profiles demonstrated clustering of samples by recurrence status and post-treatment time point. Longitudinal fecal bile acid trajectories in non-recurrers showed a recovery of secondary bile acids and their derivatives in non-recurring patients that was not observed in recurrers. BSH activity increased over time amongst patients who did not relapse (beta=0.056; likelihood ratio test p=0.018). A joint longitudinal-survival model identified five stool bile acids with AUROC > 0.73 for prediction of recurrence within nine days post-CDI treatment. Conclusions: Gut bile acid metabolism dynamics differ in primary CDI patients between those who develop recurrence versus those who do not. Individual bile acids show promise

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Colonization of the live biotherapeutic product VE303 and modulation of the microbiota and metabolites in healthy volunteers

Cited by 77 publications

References 117 publications

Improved gut microbiome recovery following drug therapy is linked to abundance and replication of probiotic strains

Improved gut microbiome recovery following drug therapy is linked to abundance and replication of probiotic strains

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

Fecal bile acid profiles predict recurrence in patients with primary Clostridioides difficile infection

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