Protection from Lethal Clostridioides difficile Infection via Intraspecies Competition for Cogerminant

Leslie, Jhansi L.; Jenior, Matthew L.; Vendrov, Kimberly C.; Standke, Alexandra; Barron, Madeline R.; O’Brien, Tricia J.; Unverdorben, Lavinia V.; Thaprawat, Pariyamon; Bergin, Ingrid L.; Schloss, Patrick D.; Young, Vincent B.

doi:10.1128/mbio.00522-21

Cited by 26 publications

(26 citation statements)

References 54 publications

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“…This step is potentiated, in vitro, by cholic acid class bile acids and amino acids. In a recent study, Leslie and colleagues demonstrated that consumption of the glycine cogerminant can block the colonization of C. difficile by reducing spore germination [20]. Though we find that C. scindens, C. hiranonis and C. leptum reduce the abundance of glycine, proline and prolylglycine in monoassociated mice (S7 Fig) , we do observe C. difficile colonization but lack of disease (S3 Table ).…”

Section: Discussioncontrasting

confidence: 41%

“…Bile acid germinants are recognized by the CspC pseudoprotease germinant receptor [8] and the cogerminants (e.g., glycine) are recognized by the CspA pseudoprotease germinant receptor [19]. Recent work has shown that glycine is an important in vivo spore cogerminant and consumption of glycine by one C. difficile strain prevents spore germination (and colonization) by an invading strain [20].…”

Section: Introductionmentioning

confidence: 99%

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Bile acid-independent protection against Clostridioides difficile infection

Aguirre

Yalçınkaya

et al. 2021

PLoS Pathog

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Clostridioides difficile infections occur upon ecological / metabolic disruptions to the normal colonic microbiota, commonly due to broad-spectrum antibiotic use. Metabolism of bile acids through a 7α-dehydroxylation pathway found in select members of the healthy microbiota is regarded to be the protective mechanism by which C. difficile is excluded. These 7α-dehydroxylated secondary bile acids are highly toxic to C. difficile vegetative growth, and antibiotic treatment abolishes the bacteria that perform this metabolism. However, the data that supports the hypothesis that secondary bile acids protect against C. difficile infection is supported only by in vitro data and correlative studies. Here we show that bacteria that 7α-dehydroxylate primary bile acids protect against C. difficile infection in a bile acid-independent manner. We monoassociated germ-free, wildtype or Cyp8b1-/- (cholic acid-deficient) mutant mice and infected them with C. difficile spores. We show that 7α-dehydroxylation (i.e., secondary bile acid generation) is dispensable for protection against C. difficile infection and provide evidence that Stickland metabolism by these organisms consumes nutrients essential for C. difficile growth. Our findings indicate secondary bile acid production by the microbiome is a useful biomarker for a C. difficile-resistant environment but the microbiome protects against C. difficile infection in bile acid-independent mechanisms.

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Section: Discussioncontrasting

confidence: 41%

Section: Introductionmentioning

confidence: 99%

Bile acid-independent protection against Clostridioides difficile infection

Aguirre

Yalçınkaya

et al. 2021

PLoS Pathog

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“…Bile acids metabolized by the gut bacteria can inhibit C. difficile growth and affect toxin production (9,10). Bacteria in the gut also can compete more directly with C. difficile through antibiotic production or nutrient consumption (11)(12)(13). While the relationship between the gut bacteria and C. difficile has been established, the effect the gut bacteria can have on CDI disease severity is unclear.…”

Section: Introductionmentioning

confidence: 99%

The gut bacterial community potentiates Clostridioides difficile infection severity

Lesniak

Schubert

Flynn

et al. 2022

Preprint

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The severity of Clostridioides difficile infections (CDI) has increased over the last few decades. Patient age, white blood cell count, creatinine levels as well as C. difficile ribotype and toxin genes have been associated with disease severity. However, it is unclear whether there is an association between members of the gut microbiota and disease severity. The gut microbiota is known to interact with C. difficile during infection. Perturbations to the gut microbiota are necessary for C. difficile to colonize the gut. The gut microbiota can inhibit C. difficile colonization through bile acid metabolism, nutrient consumption and bacteriocin production. Here we sought to demonstrate that members of the gut bacterial communities can also contribute to disease severity. We derived diverse gut communities by colonizing germ-free mice with different human fecal communities. The mice were then infected with a single C. difficile ribotype 027 clinical isolate which resulted in moribundity and histopathologic differences. The variation in severity was associated with the human fecal community that the mice received. Generally, bacterial populations with pathogenic potential, such as Escherichia, Helicobacter, and Klebsiella, were associated with more severe outcomes. Bacterial groups associated with fiber degradation, bile acid metabolism and lantibiotic production, such as Anaerostipes and Coprobacillus, were associated with less severe outcomes. These data indicate that, in addition to the host and C. difficile, populations of gut bacteria can influence CDI disease severity.

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“…Furthermore, the protection was lost when the colonizing NTCD was removed using vancomycin before the challenge (Borriello and Barclay, 1985). Since then, a variety of animal models have shown that non-toxigenic strains can colonize the GIT and protect against TCD -mediated disease (Borriello and Barclay, 1985;Sambol et al, 2003;Nagaro et al, 2013;de Oliveira Júnior et al, 2016;Oliveira Júnior et al, 2019;Leslie et al, 2021). The first human clinical trial was performed in 1980s where two patients suffering from rCDI were treated with NTCD-M1 strain after vancomycin administration with a 50% clinical success rate (Seal et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

et al. 2021

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Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

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Protection from Lethal Clostridioides difficile Infection via Intraspecies Competition for Cogerminant

Cited by 26 publications

References 54 publications

Bile acid-independent protection against Clostridioides difficile infection

Bile acid-independent protection against Clostridioides difficile infection

The gut bacterial community potentiates Clostridioides difficile infection severity

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

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