High metabolic versatility of different toxigenic and non-toxigenic Clostridioides difficile isolates

Riedel, Thomas; Wetzel, Daniela; Hofmann, Julia; Plorin, Simon Paul Erich Otto; Dannheim, Henning; Berges, Mareike; Zimmermann, Ortrud; Bunk, Boyke; Schober, Isabel; Spröer, Cathrin; Liesegang, Heiko; Jahn, Dieter; Overmann, Jörg; Groß, Uwe; Neumann‐Schaal, Meina

doi:10.1016/j.ijmm.2017.05.007

Cited by 37 publications

(27 citation statements)

References 59 publications

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“…Thus, the σ 54 was predicted to control the ethanol and butanol production in solvent-producing clostridia including C. beijerinckii, C. saccharobutylicum, and C. saccharoperbutylacetonicum. In pathogenic clostridia including C. difficile, C. tetani, and C. botulinum, the σ 54 was proposed to regulate the amino acid catabolism, especially the Stickland reaction, which strongly influences the production of toxins [33,34]. Thus, the σ 54 is probably strongly linked to the virulence of these pathogenic species.…”

Section: Discussionmentioning

confidence: 99%

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Genomic reconstruction of σ54 regulons in Clostridiales

2019

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Background: The σ 54 factor controls unique promoters and interacts with a specialized activator (enhancer binding proteins [EBP]) for transcription initiation. Although σ 54 is present in many Clostridiales species that have great importance in human health and biotechnological applications, the cellular processes controlled by σ 54 remain unknown. Results: For systematic analysis of the regulatory functions of σ 54 , we performed comparative genomic reconstruction of transcriptional regulons of σ 54 in 57 species from the Clostridiales order. The EBP-binding DNA motifs and regulated genes were identified for 263 EBPs that constitute 39 distinct groups. The reconstructed σ 54 regulons contain the genes involved in fermentation and amino acid catabolism. The predicted σ 54 binding sites in the genomes of Clostridiales spp. were verified by in vitro binding assays. To our knowledge, this is the first report about direct regulation of the Stickland reactions and butyrate and alcohols synthesis by σ 54 and the respective EBPs. Considerable variations were demonstrated in the sizes and gene contents of reconstructed σ 54 regulons between different Clostridiales species. It is proposed that σ 54 controls butyrate and alcohols synthesis in solvent-producing species, regulates autotrophic metabolism in acetogenic species, and affects the toxin production in pathogenic species. Conclusions: This study reveals previously unrecognized functions of σ 54 and provides novel insights into the regulation of fermentation and amino acid metabolism in Clostridiales species, which could have potential applications in guiding the treatment and efficient utilization of these species.

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Section: Discussionmentioning

confidence: 99%

“…The Stickland reactions couple the oxidation and reduction of amino acids to their corresponding organic acids, which serves as a primary source of energy generation in Clostridium species [32]. This process strongly influences the production of toxins in pathogenic clostridia [33,34].…”

Section: Regulation Of the Stickland Reactionsmentioning

confidence: 99%

Genomic reconstruction of σ54 regulons in Clostridiales

2019

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“…The second most enriched at day was regulation of peptide secretion, consistent with the role of host-derived antimicrobial peptides being produced as an arm of the innate immune response. Of particular interest was the enrichment of genes involved in the positive regulation of proteolysis, as peptide fragments derived from these processes may serve as nutrient sources for C. difficile, which is well-known for using amino acid fermentation as an energy source in vitro and in vivo 8,9,35,[46][47][48][49][50] . In addition to the upstream regulators of various proteolytic processes, cecal tissue from wild type mice had significant increases in transcripts from genes encoding multiple MMPs including Mmp3, Mmp10, Mmp12, and Mmp13; probes targeting Mmp3 were not included in the NanoString custom panel, so fold change for this transcript is reported based on qRT-PCR results (Fig.…”

Section: Wild Type C Difficile Induces a Robust Inflammatory And Promentioning

confidence: 99%

Clostridioides difficileexploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

Fletcher

Pike

Parsons

et al. 2020

Preprint

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Introductory paragraphClostridioides difficile is a bacterial pathogen that causes a range of clinical disease from mild to moderate diarrhea, pseudomembranous colitis, and toxic megacolon. Typically, C. difficile infections (CDIs) occur after antibiotic treatment, which alters the gut microbiota, decreasing colonization resistance against C. difficile. Disease is mediated by two large toxins and the expression of their genes is induced upon nutrient depletion via the alternative sigma factor TcdR. Using tcdR mutants in two strains of C. difficile, we defined how toxin-induced inflammation alters C. difficile metabolism, tissue gene expression, and the gut microbiota to determine how inflammation by the host may be beneficial to C. difficile. Here we show that C. difficile metabolism is significantly different in the face of inflammation, with changes in many carbohydrate and amino acid uptake and utilization pathways. Host gene expression signatures suggest that degradation of collagen and other components of the extracellular matrix by matrix metalloproteinases is a major source of peptides and amino acids that supports C. difficile growth in vivo. Lastly, the inflammation induced by C. difficile toxin activity alters the gut microbiota, excluding members from the genus Bacteroides that are able to compete against C. difficile for the same essential nutrients released from collagen degradation.

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“…Enterobacteriaceae is thought to be largely responsible for AAA catabolism in the gut (41, 82), and AAA synthesis has been implicated as a metabolic function protective against CDI (83). C. difficile isolates have been shown to have highly variable AAA metabolisms (84), opening the possibility that Enterobacteriaceae interactions with C. difficile are isolate dependent. However, the 22 patients represented in the HEb cluster were reported to have been infected with at least 9 different C. difficile ribotypes.…”

Section: Discussionmentioning

confidence: 99%

Computational Modeling of the Gut Microbiota Predicts Metabolic Mechanisms of RecurrentClostridioides difficileInfection

Henson

2020

Preprint

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Approximately 30% of patients who have a Clostridioides difficile infection (CDI) will suffer at least one incident of reinfection. While the underlying causes of CDI recurrence are poorly understood, interactions between C. difficile and other commensal gut bacteria are thought to play an important role. In this study, an in silico metagenomics pipeline was used to process taxa abundance data from 225 CDI patient stool samples into sample-specific models of bacterial community metabolism. The predicted metabolite production capabilities of each community were shown to provide improved recurrence prediction compared to direct use of taxa abundance data.More specifically, clustered metabolite synthesis rates generated from post-diagnosis samples produced a high Enterobacteriaceae cluster with disproportionate numbers of recurrent samples and patients. This cluster was predicted to have significantly reduced capabilities for secondary bile acid synthesis but elevated capabilities for aromatic amino acid catabolism. When applied to 40 samples from fecal microbiota transplantation (FMT) patients and their donors, community modeling generated a high Enterobacteriaceae cluster with a disproportionate number of pre-FMT samples. This cluster also was predicted to exhibit reduced secondary bile acid synthesis and elevated aromatic amino acid catabolism. Because clustering of CDI and FMT samples did not identify statistical differences in C. difficile abundances, these model predictions support the hypothesis that Enterobacteriaceae may create a gut environment favorable for C. difficile spore germination and toxin synthesis. ImportanceClostridioides difficile is an opportunistic human pathogen responsible for acute and sometimes chronic infections of the colon. Elderly individuals who are immunocompromised, frequently hospitalized and recipients of antibiotics are particular susceptible to infection. Approximately 3 30% of treated patients will suffer at least one episode of reinfection, commonly termed recurrence.The objective of the current study was to utilize computational metabolic modeling to investigate the hypothesis that recurrent infections are related to the composition of the gut bacterial community within each patient. Our model predictions suggest that patients who have high compositions of the bacterial family Enterobacteriaceae during antibiotic treatment are more likely to develop recurrent infections due to a metabolically-disrupted gut environment. Successful treatment of recurrent patients with transplanted fecal matter is predicted to correct this metabolic disruption, suggesting that interactions between C. difficile and Enterobacteriaceae are worthy of additional study.

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High metabolic versatility of different toxigenic and non-toxigenic Clostridioides difficile isolates

Cited by 37 publications

References 59 publications

Genomic reconstruction of σ54 regulons in Clostridiales

Genomic reconstruction of σ54 regulons in Clostridiales

Clostridioides difficileexploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

Computational Modeling of the Gut Microbiota Predicts Metabolic Mechanisms of RecurrentClostridioides difficileInfection

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