Inhibiting Growth of Clostridioides difficile by Restoring Valerate, Produced by the Intestinal Microbiota

McDonald, Julie A. K.; Mullish, Benjamin H.; Liu, Zhigang; Brignardello, Jerusa; Kao, Dina; Holmes, Elaine; Li, Jia V.; Clarke, Tom; Thursz, Mark; Marchesi, Julian R.

doi:10.1053/j.gastro.2018.07.014

Cited by 145 publications

(146 citation statements)

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“…4 inhibited C. difficile at various levels. Several phenotypes, particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol, or succinate, correlated with the C. difficile inhibitor phenotype, in agreement with findings from previous reports indicating that restoration of depleted SCFAs in the gut resolved CDI (42,43) and that competition between C. difficile and commensals for nutrients, and increased availability of mannitol, sorbitol, or succinate, allows C. difficile to invade the gut (27,28). The top inhibiting species in our collection were also depleted in the gut in patients with CDI, thus indicating their role in providing colonization resistance against C. difficile (Fig.…”

Section: Fig 8 Legend (Continued)supporting

confidence: 91%

Identification of Clostridioides difficile-Inhibiting Gut Commensals Using Culturomics, Phenotyping, and Combinatorial Community Assembly

et al. 2020

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A major function of the gut microbiota is to provide colonization resistance, wherein pathogens are inhibited or suppressed below infectious levels. However, the fraction of gut microbiota required for colonization resistance remains unclear. We used culturomics to isolate a gut microbiota culture collection comprising 1,590 isolates belonging to 102 species. This culture collection represents 34.57% of the taxonomic diversity and 70% functional capacity, as estimated by metagenomic sequencing of the fecal samples used for culture. Using whole-genome sequencing, we characterized species representatives from this collection and predicted their phenotypic traits, further characterizing isolates by defining nutrient utilization profiles and short-chain fatty acid production. When screened with a coculture assay, 66 species in our culture collection inhibited Clostridioides difficile. Several phenotypes, particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol, or succinate, correlated with C. difficile inhibition. We used a combinatorial community assembly approach to formulate defined bacterial mixes inhibitory to C. difficile. We tested 256 combinations and found that both species composition and blend size were important in inhibition. Our results show that the interaction of bacteria with one another in a mix and with other members of gut commensals must be investigated to design defined bacterial mixes for inhibiting C. difficile in vivo. IMPORTANCE Antibiotic treatment causes instability of gut microbiota and the loss of colonization resistance, thus allowing pathogens such as Clostridioides difficile to colonize and causing recurrent infection and mortality. Although fecal microbiome transplantation has been shown to be an effective treatment for C. difficile infection (CDI), a more desirable approach would be the use of a defined mix of inhibitory gut bacteria. The C. difficile-inhibiting species and bacterial combinations identified herein improve the understanding of the ecological interactions controlling colonization resistance against C. difficile and could aid in the design of defined bacteriotherapy as a nonantibiotic alternative against CDI.

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Section: Fig 8 Legend (Continued)supporting

confidence: 91%

Identification of Clostridioides difficile-Inhibiting Gut Commensals Using Culturomics, Phenotyping, and Combinatorial Community Assembly

et al. 2020

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“…Many strains in our culture collection shown in Figures 4 inhibit C. difficile at varying levels. Several phenotypes—particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol or succinate—correlated with the C. difficile -inhibitor phenotype, consistent with previous reports that restoration of depleted SCFAs in the gut resolved CDI [42, 43] and competition between C. difficile and commensals for nutrients and increased availability of mannitol, sorbitol or succinate allowed C. difficile invasion of the gut [27, 28]. Top inhibiting species in our collection were also depleted in the CDI patient gut, indicating their role in providing colonization resistance against C. difficile (Figure 7).…”

Section: Discussionsupporting

confidence: 89%

IdentifyingClostridioides difficile-inhibiting gut commensals using culturomics, phenotyping, and combinatorial community assembly

Ghimire

Roy

Wongkuna

et al. 2019

Preprint

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A major function of the gut microbiota is to provide colonization resistance, wherein pathogens are inhibited or suppressed below infectious level. However, the fraction of gut microbiota required for colonization resistance remains unclear. We used culturomics to isolate a gut microbiota culture collection comprising 1590 isolates belonging to 102 species. Estimated by metagenomic sequencing of fecal samples used for culture, this culture collection represents 50.73% of taxonomic diversity and 70% functional capacity. Using whole genome sequencing we characterized species representatives from this collection, and predicted their phenotypic traits, further characterizing isolates by defining nutrient utilization profile and short chain fatty acid (SCFA) production. When screened using a co-culture assay, 66 species in our culture collection inhibited C. difficile. Several phenotypes, particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol or succinate correlated with C. difficile inhibition. We used a combinatorial community assembly approach to formulate defined bacterial mixes inhibitory to C. difficile. When 256 combinations were tested, we found both species composition and blend size to be important in inhibition. Our results show that the interaction of bacteria with each other in a mix and with other members of gut commensals must be investigated for designing defined bacterial mixes for inhibiting C. difficile in vivo. IMPORTANCEAntibiotic treatment causes instability of gut microbiota and the loss of colonization resistance, allowing pathogens such as C. difficile to colonize, causing recurrent infection and mortality.Although fecal microbiome transplantation has shown to be an effective treatment for C. difficile infection (CDI), a more desirable approach would be the use of a defined mix of inhibitory gut bacteria. C. difficile-inhibiting species and bacterial combinations we identify herein improve our understanding of the ecological interactions controlling colonization resistance against C. difficile, and could aid the design of defined bacteriotherapy as a non-antibiotic alternative against CDI.

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“…Short chain fatty acids (SCFAs) are end metabolites produced by microbial fermentation of undigested carbohydrates and dietary fibers. Butyrate, acetate, and propionate are the main SCFAs, but others, such as lactate and valerate, are also produced by microbiota [1][2][3]. SCFAs have important roles in human gut homeostasis by exerting several effects on the host and its own microbiota.…”

Section: Introductionmentioning

confidence: 99%

Short Chain Fatty Acids Commonly Produced by Gut Microbiota Influence Salmonella enterica Motility, Biofilm Formation, and Gene Expression

et al. 2019

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Short chain fatty acids (SCFAs) are commonly produced by healthy gut microbiota and they have a protective role against enteric pathogens. SCFAs also have direct antimicrobial activity against bacterial pathogens by diffusion across the bacterial membrane and reduction of intracellular pH. Due to this antimicrobial activity, SCFAs have promising applications in human health and food safety. In this study, the minimum inhibitory concentrations (MICs) of four SCFAs (acetic acid, butyric acid, propionic acid, and valeric acid) in Salmonella strains isolated from poultry were determined. The effect of subinhibitory concentrations of SCFAs in Salmonella biofilm formation, motility, and gene expression was also evaluated. Butyric acid, propionic acid, and valeric acid showed a MIC of 3750 µg/mL in all strains tested, while the MIC of acetic acid was between 1875 and 3750 µg/mL. Subinhibitory concentrations of SCFAs significantly (p < 0.05) reduced the motility of all Salmonella strains, especially in the presence of acetic acid. Biofilm formation was also significantly (p < 0.05) lower in the presence of SCFAs in some of the Salmonella strains. Salmonella strain. Salmonella Typhimurium T7 showed significant (p < 0.05) upregulation of important virulence genes, such as invA and hilA, especially in the presence of butyric acid. Therefore, SCFAs are promising substances for the inhibition of the growth of foodborne pathogens. However, it is important to avoid the use of subinhibitory concentrations that could increase the virulence of foodborne pathogen Salmonella.

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Inhibiting Growth of Clostridioides difficile by Restoring Valerate, Produced by the Intestinal Microbiota

Abstract: We identified valerate as a metabolite that is depleted with clindamycin and only recovered with FMT. Valerate is a target for a rationally designed recurrent CDI therapy.

Cited by 145 publications

References 62 publications

Identification of Clostridioides difficile-Inhibiting Gut Commensals Using Culturomics, Phenotyping, and Combinatorial Community Assembly

Identification of Clostridioides difficile-Inhibiting Gut Commensals Using Culturomics, Phenotyping, and Combinatorial Community Assembly

IdentifyingClostridioides difficile-inhibiting gut commensals using culturomics, phenotyping, and combinatorial community assembly

Short Chain Fatty Acids Commonly Produced by Gut Microbiota Influence Salmonella enterica Motility, Biofilm Formation, and Gene Expression

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