Influence of L-lactate and low glucose concentrations on the metabolism and the toxin formation of Clostridioides difficile

Hofmann, Julia; Biedendieck, Rebekka; Michel, Annika-Marisa; Schomburg, Dietmar; Jahn, Dieter; Neumann‐Schaal, Meina

doi:10.1371/journal.pone.0244988

Cited by 16 publications

(24 citation statements)

References 42 publications

(94 reference statements)

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“…The unique energy metabolism of C. difficile preferentially utilizes amino acids through a process called Stickland fermentation which firstly produces ATP via substrate level phosphorylation ( Stickland, 1934 ; Neumann-Schaal et al, 2015 ). Secondly, various carbohydrates are the basis for a complex mixed acid fermentation ( Riedel et al, 2017 ; Hofmann et al, 2021 ). Some of the involved processes are coupled via the membrane associated Rnf complex to the formation of an ion gradient which in turn drives ATP formation via a classical F O F 1 -ATPase ( Müller et al, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

“…Some of the involved processes are coupled via the membrane associated Rnf complex to the formation of an ion gradient which in turn drives ATP formation via a classical F O F 1 -ATPase ( Müller et al, 2008 ). Alternative carbon sources like ethanolamine are used additionally ( Nawrocki et al, 2018 ; Hofmann et al, 2021 ). When preferred amino acids and glucose are depleted from the medium, C. difficile is able to generate energy from lactate fermentation and to fix CO 2 via the Wood-Ljungdahl pathway ( Köpke et al, 2013 ; Hofmann et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Alternative carbon sources like ethanolamine are used additionally ( Nawrocki et al, 2018 ; Hofmann et al, 2021 ). When preferred amino acids and glucose are depleted from the medium, C. difficile is able to generate energy from lactate fermentation and to fix CO 2 via the Wood-Ljungdahl pathway ( Köpke et al, 2013 ; Hofmann et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

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What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile

et al. 2021

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The anaerobic pathogen Clostridioides difficile is perfectly equipped to survive and persist inside the mammalian intestine. When facing unfavorable conditions C. difficile is able to form highly resistant endospores. Likewise, biofilms are currently discussed as form of persistence. Here a comprehensive proteomics approach was applied to investigate the molecular processes of C. difficile strain 630Δerm underlying biofilm formation. The comparison of the proteome from two different forms of biofilm-like growth, namely aggregate biofilms and colonies on agar plates, revealed major differences in the formation of cell surface proteins, as well as enzymes of its energy and stress metabolism. For instance, while the obtained data suggest that aggregate biofilm cells express both flagella, type IV pili and enzymes required for biosynthesis of cell-surface polysaccharides, the S-layer protein SlpA and most cell wall proteins (CWPs) encoded adjacent to SlpA were detected in significantly lower amounts in aggregate biofilm cells than in colony biofilms. Moreover, the obtained data suggested that aggregate biofilm cells are rather actively growing cells while colony biofilm cells most likely severely suffer from a lack of reductive equivalents what requires induction of the Wood-Ljungdahl pathway and C. difficile’s V-type ATPase to maintain cell homeostasis. In agreement with this, aggregate biofilm cells, in contrast to colony biofilm cells, neither induced toxin nor spore production. Finally, the data revealed that the sigma factor SigL/RpoN and its dependent regulators are noticeably induced in aggregate biofilms suggesting an important role of SigL/RpoN in aggregate biofilm formation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile

et al. 2021

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“…The metabolome of mice treated with the broad-spectrum antibiotic cefoperazone contains a higher abundance of sugar alcohols relative to the metabolome of mock treated animals, similar to what we observed after streptomycin treatment, and this treatment renders mice susceptible to C. difficile infection [ 38 ]. Additionally, the sugar alcohols sorbitol and mannitol are sufficient for C. difficile growth in NCDM in vitro [ 38 ] and increase toxin production [ 39 ]. Furthermore, depletion of alcoholic sugars by the gut microbiota contributes to colonization resistance against C. difficile [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

The metabolic footprint of Clostridia and Erysipelotrichia reveals their role in depleting sugar alcohols in the cecum

et al. 2021

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Background The catabolic activity of the microbiota contributes to health by aiding in nutrition, immune education, and niche protection against pathogens. However, the nutrients consumed by common taxa within the gut microbiota remain incompletely understood. Methods Here we combined microbiota profiling with an un-targeted metabolomics approach to determine whether depletion of small metabolites in the cecum of mice correlated with the presence of specific bacterial taxa. Causality was investigated by engrafting germ-free or antibiotic-treated mice with complex or defined microbial communities. Results We noted that a depletion of Clostridia and Erysipelotrichia from the gut microbiota triggered by antibiotic treatment was associated with an increase in the cecal concentration of sugar acids and sugar alcohols (polyols). Notably, when we inoculated germ-free mice with a defined microbial community of 14 Clostridia and 3 Erysipelotrichia isolates, we observed the inverse, with a marked decrease in the concentrations of sugar acids and polyols in cecal contents. The carbohydrate footprint produced by the defined microbial community was similar to that observed in gnotobiotic mice receiving a cecal microbiota transplant from conventional mice. Supplementation with sorbitol, a polyol used as artificial sweetener, increased cecal sorbitol concentrations in antibiotic-treated mice, which was abrogated after inoculation with a Clostridia isolate able to grow on sorbitol in vitro. Conclusions We conclude that consumption of sugar alcohols by Clostridia and Erysipelotrichia species depletes these metabolites from the intestinal lumen during homeostasis.

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“…Catabolite control protein A is a pleiotropic regulator involved in controlling in carbon metabolism in many bacteria species in response to changes in overall energy levels and amount of carbohydrate ( Abranches et al, 2008 ; Willenborg et al, 2014 ; Hofmann et al, 2021 ). For example, >80% of the genes are controlled by CcpA in response to glucose in Bacillus subtilis ( Moreno et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis Reveals Catabolite Control Protein A Regulatory Mechanisms Underlying Glucose-Excess or -Limited Conditions in a Ruminal Bacterium, Streptococcus bovis

et al. 2021

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Ruminants may suffer from rumen acidosis when fed with high-concentrate diets due to the higher proliferation and overproduction of lactate by Streptococcus bovis. The catabolite control protein A (CcpA) regulates the transcription of lactate dehydrogenase (ldh) and pyruvate formate-lyase (pfl) in S. bovis, but its role in response to different carbon concentrations remains unclear. To characterize the regulatory mechanisms of CcpA in S. bovis S1 at different levels of carbon, herein, we analyzed the transcriptomic and physiological characteristics of S. bovis S1 and its ccpA mutant strain grown in glucose-excess and glucose-limited conditions. A reduced growth rate and a shift in fermentation pattern from homofermentation to heterofermentation were observed under glucose-limited condition as compared to glucose-excess condition, in S. bovis S1. Additionally, the inactivation of ccpA significantly affected the growth and end metabolites in both conditions. For the glycolytic intermediate, fructose 1,6-bisphosphate (FBP), the concentration significantly reduced at lower glucose conditions; its concentration decreased significantly in the ccpA mutant strain. Transcriptomic results showed that about 46% of the total genes were differentially transcribed between the wild-type strain and ccpA mutant strain grown in glucose-excess conditions; while only 12% genes were differentially transcribed in glucose-limited conditions. Different glucose concentrations led to the differential expression of 38% genes in the wild-type strain, while only half of these were differentially expressed in the ccpA-knockout strain. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the substrate glucose concentration significantly affected the gene expression in histidine metabolism, nitrogen metabolism, and some carbohydrate metabolism pathways. The deletion of ccpA affected several genes involved in carbohydrate metabolism, such as glycolysis, pyruvate metabolism, fructose and mannose metabolism, as well as in fatty acid biosynthesis pathways in bacteria grown in glucose-excess conditions; this effect was attenuated under glucose-limited conditions. Overall, these findings provide new information on gene transcription and metabolic mechanisms associated with substrate glucose concentration and validate the important role of CcpA in the regulation of carbon metabolism in S. bovis S1 at differential glucose availability.

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Influence of L-lactate and low glucose concentrations on the metabolism and the toxin formation of Clostridioides difficile

Cited by 16 publications

References 42 publications

What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile

What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile

The metabolic footprint of Clostridia and Erysipelotrichia reveals their role in depleting sugar alcohols in the cecum

Transcriptome Analysis Reveals Catabolite Control Protein A Regulatory Mechanisms Underlying Glucose-Excess or -Limited Conditions in a Ruminal Bacterium, Streptococcus bovis

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