Distinct bile salt hydrolase substrate preferences dictate <i>C. difficile</i> pathogenesis

Foley, Matthew H.; Walker, Margaret G.; Stewart, Allison K.; O’Flaherty, Sarah; Gentry, Emily C.; Allen, Garrison; Patel, Shakshi; Pan, Meichen; Beaty, Violet V.; Vanhoy, Molly E.; Dougherty, Michael; McGill, Sarah; Gulati, Ajay; Dorrestein, Pieter C.; Baker, Erin; Redinbo, Matthew R.; Barrangou, Rodolphe; Theriot, Casey M.

doi:10.1101/2022.03.24.485529

Cited by 4 publications

(4 citation statements)

References 50 publications

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“…One confounder in interpreting cross-sectional datasets in CDI (particularly primary CDI) is that vancomycin (the major anti-CDI therapy that most participants are initially treated with) has itself been associated with an altered gut microbiota profile, as well as by loss of fecal secondary bile acids and enrichment in primary unconjugated bile acids [36,37]. These data support and extend upon our previous results by demonstrating different dynamics of BSH functionality in recurrers compared to non-recurrers, as does the associated recovery of transition of primary to secondary bile acids and their derivatives (a further nuance in this system relates to the recent demonstration that different BSHs, due to their different substrate specificity, have different degrees of protective ability against CDI [38]). The conventional clinical interpretation of recurrence after an episode of primary CDI is to view this as a pathogen-derived event (e.g.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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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“…41 While these collateral effects of vancomycin on gut microbial BA metabolism may be expected to facilitate C. difficile growth, such effects need to be balanced against the efficacy of the drug in its effect against C. difficile itself, with vancomycin having clear superiority in this regard compared to metronidazole 27 ; a focus for antibiotic discovery within this area has been on molecules with narrow-spectrum activity against C. difficile but which cause minimal perturbation to microbially derived BAs, with ridinilazole being a promising agent with this regard. 42 More broadly, these data support and extend on our previous results by suggesting an increase of BSH functionality in non-recurring patients over time, as does the associated recovery of transition of primary to secondary BAs and their derivatives (a further nuance in this system relates to the recent demonstration that different BSHs, due to their different substrate specificity, have different degrees of protective ability against CDI 43 ).…”

Section: Ta B L Esupporting

confidence: 86%

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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“…Considering the diversity in primary structure of BSH enzymes and the selectivity of BSH enzymes for particular steroidal cores across Bacteroides spp. [23], it is likely that structural differences in the active site or other regions of the conjugating enzyme [25] will determine whether primary amine groups, such as those on GABA and tyramine, form amide bonds with bile acid(s). It is plausible that other bioactive amines present in the gut can be conjugated to bile acids and B. fragilis P207, M. gnavus MSK15.77, B. longum DFI.2.45, and B. ovatus MSK22.29 provide models to begin investigation of this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Microbially-catalyzed conjugation of GABA and tyramine to bile acids

Mullowney,

Fiebig,

Schnizlein

et al. 2023

Preprint

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Bile acids (BAs) are cholesterol-derived molecules in the human gut that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence gut microbiome composition. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate other classes of amines to BAs. We show thatBacteroides fragilisstrain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis (UC) pouchitis, conjugates standard amino acids and the neuroactive amines γ-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended our analysis to other human gut isolates and identified bacterial species that conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and -tyramine amides in human stool. A time-series metabolomic analysis of UC J-pouch contents revealed a lack of secondary bile acids and a shifting BA conjugate profile before, during and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to the neuroactive amines GABA and tyramine, and demonstrates that these molecules are present in the human gut.ImportanceBile acids (BAs) are modified in multiple ways by host enzymes and the microbiota to produce a chemically diverse set of molecules that assist in the digestive process and impact many physiological functions. This study reports the discovery of bacterial species that conjugate the neuroactive molecules, GABA and tyramine, to primary and secondary BAs. We further present evidence that BA-GABA and BA-tyramine conjugates are present in the human gut, and document a shifting BA-GABA profile in a human pouchitis patient before, during and after inflammation and antibiotic treatment. GABA and tyramine are potent neuroactive molecules and common metabolic products of the gut microbiota. GABA- and tyramine-conjugated BAs may influence receptor-mediated regulatory mechanisms within the gastrointestinal tract and absorption of these molecules and their entry into the enterohepatic circulation may impact host physiology at distal tissue sites. This discovery defines new conjugated bile acids in the human gut.

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Distinct bile salt hydrolase substrate preferences dictate C. difficile pathogenesis

Cited by 4 publications

References 50 publications

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

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

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

Microbially-catalyzed conjugation of GABA and tyramine to bile acids

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