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Glutathione is a host-derived cysteine source for Clostridioides difficile

ABSTRACT: Clostridioides difficile is the leading cause of nosocomial diarrhea, afflicting approximately half a million people each year in the USA, burdening both individuals’ quality of life and the healthcare system. In the gastrointestinal (GI) tract, C. difficile must acquire essential nutrients to colonize, establish infection, and persist in a polymicrobial environment. C. difficile is a cysteine auxotroph and the GI tract contains low levels of cysteine, highlighting gaps in our understanding of how C. difficile acquires this amino acid during infection. One possible source of cysteine for C. difficile during infection is glutathione (GSH), a tripeptide thiol found in mammalian cells. Our data indicate that C. difficile encodes two functionally redundant enzymes (UgaA and UgbB) that allow it to use GSH as a source of cysteine. Using murine models of C. difficile infection, we show that C. difficile uses its toxins to increase available GSH in the GI tract during infection. Finally, we show that the ability to utilize GSH gives wild-type C. difficile a fitness advantage over a GSH-deficient mutant in vivo. These findings establish GSH metabolism by C. difficile as a virulence-linked metabolic program and as a possibly impactful target for future therapeutic development.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase

PROVIDER: MTBLS14740 | MetaboLights | 2026-06-10

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14740_LC-MS_negative_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14740_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	s_MTBLS14740.txt	Txt

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Glutathione is a host-derived cysteine source for Clostridioides difficile

Project description:Clostridioides difficile is the leading cause of nosocomial diarrhea, afflicting approximately half a million people each year in the USA, burdening both individuals’ quality of life and the healthcare system. In the gastrointestinal (GI) tract, C. difficile must acquire essential nutrients to colonize, establish infection, and persists in a polymicrobial environment. C. difficile is a cysteine auxotroph and the GI tract contains low levels of cysteine, highlighting gaps in our understanding of how C. difficile acquires this amino acid during infection. One possible source of cysteine for C. difficile during infection is glutathione (GSH), tripeptide thiol in mammalian cells. Our data indicate that C. difficile encodes two redundant enzymes (GecA and GecB) that allow it to use GSH as a source of cysteine. Using murine models of C. difficile infection, we also show that C. difficile uses its toxins to increase available GSH in the GI tract during infection. Finally, we show that the ability to utilize GSH gives wild-type C. difficile a fitness advantage over a GSH-deficient mutant in vivo. These findings establish GSH metabolism as a novel strategy of nutrient acquisition that links C. difficile metabolism and virulence and highlight GSH metabolism as possibly impactful target for future therapeutic development.

2026-06-10 | GSE310543 | GEO

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Project description:Clostridioides difficile can cause severe infections in the gastrointestinal tract and affects almost half a million people in the U.S every year. Upon establishment of infection, a strong immune response is induced. We sought to investigate the dynamics of the mucosal host response during C. difficile infection.

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Clostridium difficile CD630E: growth with 10 mM cysteine in PY vs growth in PY

Project description:Comparison of Clostridium difficile transcriptome of strain CD630E grown for 10 hours in PY (supplemented with mild concentration of cysteine) versus PYC (PY supplemented with 10 mM of cysteine). Experimental procedure was designed to investigate the influence of cysteine on toxins production and the regulatory network involved. two-conditions experiments, excess of cysteine vs mild concentration of cysteine, 4 biological replicates for each condition Description of the supplementary files: Main - Short description of the experiment Result_all - All significative genes Result_Gold* - High quality significative gene Result_Silver** - Medium quality significative gene All_Raw_data - All genes results significative and non significative Design_Genes-OUT - Genes not present in the platform Design_Genes-Oligos - Number of oligos design per gene * Gold : Nbr significative oligos = Nbr oligos designed for this gene ** Silver : Nbr significative oligos = Nbr oligos designed for this gene -1

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Glutathione is a host-derived cysteine source for Clostridioides difficile

Project description:Glutathione is a host-derived cysteine source for Clostridioides difficile

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Enterococci enhance Clostridioides difficile pathogenesis

Project description:Clostridioides difficile is one of the most common nosocomial pathogens and a global public health threat. Upon colonization of the gastrointestinal tract, C. difficile is exposed to a rapidly changing polymicrobial environment and a dynamic metabolic milieu. Despite the link between the gut microbiota and susceptibility to C. difficile, the impact of synergistic interactions between the microbiota and pathogens on the outcome of infection is largely unknown. Here, we show that microbial cooperation between C. difficile and Enterococcus has a profound impact on the growth, metabolism, and pathogenesis of C. difficile.. Through a process of nutrient restriction and metabolite cross-feeding, E. faecalis shapes the metabolic environment in the gut to enhance C. difficile fitness and increase toxin production. These findings demonstrate that members of the microbiota, such as Enterococcus, have a previously unappreciated impact on C. difficile behavior and virulence.

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Project description:The intestines house a diverse microbiota that must compete for nutrients to survive, but the specific limiting nutrients that control pathogen colonization are not clearly defined. Clostridioides difficile colonization typically requires prior disruption of the microbiota, suggesting that outcompeting commensals for resources is key in establishing C. difficile infection (CDI). The immune protein calprotectin (CP) is released into the gut lumen during CDI to chelate zinc (Zn) and other essential nutrient metals. Yet, the impact of Zn limitation on C. difficile colonization is unknown. To define C. difficile responses to Zn limitation, we performed RNA sequencing on C. difficile exposed to CP. In media with CP, C. difficile upregulated genes involved in metal homeostasis and amino acid metabolism.

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