The Experts below are selected from a list of 52716 Experts worldwide ranked by ideXlab platform
Casey M Theriot - One of the best experts on this subject based on the ideXlab platform.
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strain dependent inhibition of clostridioides difficile by Commensal clostridia carrying the bile acid inducible bai operon
Journal of Bacteriology, 2020Co-Authors: A D Reed, Matthew A Nethery, Allison K Stewart, Rodolphe Barrangou, Casey M TheriotAbstract:ABSTRACT Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and Commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that Commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four Commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these Commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by Commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four Commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four Commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by Commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the Commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
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strain dependent inhibition of clostridioides difficile by Commensal clostridia encoding the bile acid inducible bai operon
Journal of Bacteriology, 2020Co-Authors: A D Reed, Matthew A Nethery, Allison K Stewart, Rodolphe Barrangou, Casey M TheriotAbstract:ABSTRACT Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and Commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that Commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four Commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these Commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by Commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four Commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four Commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by Commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the Commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
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strain dependent inhibition of clostridioides difficile by Commensal clostridia encoding the bile acid inducible bai operon
bioRxiv, 2020Co-Authors: A D Reed, Matthew A Nethery, Allison K Stewart, Rodolphe Barrangou, Casey M TheriotAbstract:Abstract Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and Commensal Clostridia that encode the bile acid inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study we hypothesized that Commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the ability of four Commensal Clostridia encoding the bai operon (C. scindens VPI 12708, C. scindens ATCC 35704, C. hiranonis, and C. hylemonae) to convert CA to DCA in vitro, and if the amount of DCA produced was sufficient to inhibit growth of a clinically relevant C. difficile strain. We also investigated the competitive relationship between these Commensals and C. difficile using an in vitro co-culture system. We found that inhibition of C. difficile growth by Commensal Clostridia supplemented with CA was strain-dependent, correlated with the production of ∼2 mM DCA, and increased expression of bai operon genes. We also found that C. difficile was able to outcompete all four Commensal Clostridia in an in vitro co-culture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. Importance Commensal Clostridia encoding the bai operon such as C. scindens have been associated with protection against CDI, however the mechanism for this protection is unknown. Herein, we show four Commensal Clostridia that encode the bai operon effect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by Commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the Commensals in an in vitro co-culture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
Barbel Stecher - One of the best experts on this subject based on the ideXlab platform.
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the roles of inflammation nutrient availability and the Commensal microbiota in enteric pathogen infection
Microbiology spectrum, 2015Co-Authors: Barbel StecherAbstract:Genetic susceptibility, the mucosal immune system, and environmental factors such as the microbiota, stress, and diet, contribute to the pathogenesis of inflammatory bowel disease (IBD) ( 15 ). Involvement of the microbiota has been proposed early on, as microbiota manipulation by antibiotics or probiotics can treat or alleviate IBD symptoms in humans. In experimental animal models, the gut luminal microbiota is required for the induction of chronic inflammation ( 16 ). Different theories about how the microbiota is involved in the pathogenesis of IBD have been proposed. (1) Mutations that lead to a defective mucosal barrier function (e.g., mucus layer, innate killing, antimicrobial peptides) involve excessive translocation of Commensal bacteria and triggering of proinflammatory signalling cascades. (2) Abnormal host immune regulation induces an overshooting immune response against intrinsic Commensal bacteria. (3) The presence of an unidentified pathogen leads to induction of the disease or (4), a dysbiotic microbiota, characterized by an imbalance between “beneficial” and “potentially harmful” Commensal bacteria, acts as a trigger or driver of the disease. The latter theory has been challenged by studies conducted in experimental rodent models: inflammatory disease conditions in the course of chronic colitis or enteropathogen infection can disrupt normal microbiota composition, induce dysbiosis, and favor overgrowth of pathogens and Commensals with an increased virulence potential ( 10 , 14 , 17 ). Therefore, dysbiosis may not only be considered as a cause but also a consequence of gut inflammation.
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gut inflammation can boost horizontal gene transfer between pathogenic and Commensal enterobacteriaceae
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Barbel Stecher, Remy Denzler, Lisa A Maier, Florian Bernet, Mandy Sanders, Derek Pickard, Manja Barthel, Astrid M Westendorf, Karen A Krogfelt, A WalkerAbstract:The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident Commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ∼100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the Commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and Commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.
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gut inflammation can boost horizontal gene transfer between pathogenic and Commensal enterobacteriaceae
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Barbel Stecher, Remy Denzler, Lisa A Maier, Florian Bernet, Mandy Sanders, Derek Pickard, Manja Barthel, Astrid M Westendorf, Karen A Krogfelt, A WalkerAbstract:The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident Commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ∼100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the Commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and Commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.
A Walker - One of the best experts on this subject based on the ideXlab platform.
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gut inflammation can boost horizontal gene transfer between pathogenic and Commensal enterobacteriaceae
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Barbel Stecher, Remy Denzler, Lisa A Maier, Florian Bernet, Mandy Sanders, Derek Pickard, Manja Barthel, Astrid M Westendorf, Karen A Krogfelt, A WalkerAbstract:The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident Commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ∼100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the Commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and Commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.
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gut inflammation can boost horizontal gene transfer between pathogenic and Commensal enterobacteriaceae
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Barbel Stecher, Remy Denzler, Lisa A Maier, Florian Bernet, Mandy Sanders, Derek Pickard, Manja Barthel, Astrid M Westendorf, Karen A Krogfelt, A WalkerAbstract:The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident Commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ∼100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the Commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and Commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.
Shruti Naik - One of the best experts on this subject based on the ideXlab platform.
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Commensal dendritic cell interaction specifies a unique protective skin immune signature
Nature, 2015Co-Authors: Shruti Naik, Clayton Deming, Christoph Wilhelm, Nicolas Bouladoux, Sean Conlan, Jonathan L Linehan, Oliver J Harrison, Sarah Himmelfarb, Allyson L Byrd, Mariam QuiñonesAbstract:Defined skin Commensal bacteria elicit a dermal dendritic-cell-dependent, long-lasting, Commensal-specific CD8+ T-cell response that promotes protection against pathogens while preserving tissue homeostasis. The importance of our gut microbiota in health and disease is well established. Less clear is the role of the Commensal microbes on the skin, where they interact with a tissue that, unlike the gut, is not designed for absorption. Here Yasmine Belkaid and colleagues examine the nature of the antigen presenting cells involved in the dialogue between the immune system and skin Commensals. They find that defined skin Commensal bacteria elicit a dermal dendritic-cell-dependent, long-lasting and Commensal-specific CD8+ T-cell response, while preserving tissue homeostasis. The CD8+ T cells are shown to enhance innate protection against a fungal pathogen. The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity1,2,3,4. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges5,6,7. How, in the context of this complexity, individual Commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined Commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A+ CD8+ T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating Commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined Commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.
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Commensal dendritic cell interaction specifies a unique protective skin immune signature
Nature, 2015Co-Authors: Shruti Naik, Christoph Wilhelm, Nicolas Bouladoux, Sean Conlan, Jonathan L Linehan, Seongji Han, Oliver J Harrison, Sarah Himmelfarb, Allyson L Byrd, Clayton DemingAbstract:The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual Commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined Commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating Commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined Commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.
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Compartmentalized and systemic control of tissue immunity by Commensals
Nature Immunology, 2013Co-Authors: Yasmine Belkaid, Shruti NaikAbstract:The body is composed of various tissue microenvironments with finely tuned local immunosurveillance systems, many of which are in close apposition with distinct Commensal niches. Mammals have formed an evolutionary partnership with the microbiota that is critical for metabolism, tissue development and host defense. Despite our growing understanding of the impact of this host-microbe alliance on immunity in the gastrointestinal tract, the extent to which individual microenvironments are controlled by resident microbiota remains unclear. In this Perspective, we discuss how resident Commensals outside the gastrointestinal tract can control unique physiological niches and the potential implications of the dialog between these Commensals and the host for the establishment of immune homeostasis, protective responses and tissue pathology.
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Compartmentalized Control of Skin Immunity by Resident Commensals
Science, 2012Co-Authors: Shruti Naik, Michael J Molloy, Nicolas Bouladoux, Mariam Quiñones, Sean Conlan, Julia A. Segre, Jason A Hall, Daniel J. Campbell, Heidi H Kong, Clayton Deming, Wolfgang Kastenmuller, Rosalba Salcedo, Giorgio Trinchieri, Amiran Dzutsev, Christoph Wilhelm, Sean Spencer, Lily Koo, Yasmine BelkaidAbstract:Intestinal Commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident Commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin Commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident Commensal niches in health and disease.
A D Reed - One of the best experts on this subject based on the ideXlab platform.
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strain dependent inhibition of clostridioides difficile by Commensal clostridia carrying the bile acid inducible bai operon
Journal of Bacteriology, 2020Co-Authors: A D Reed, Matthew A Nethery, Allison K Stewart, Rodolphe Barrangou, Casey M TheriotAbstract:ABSTRACT Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and Commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that Commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four Commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these Commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by Commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four Commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four Commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by Commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the Commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
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strain dependent inhibition of clostridioides difficile by Commensal clostridia encoding the bile acid inducible bai operon
Journal of Bacteriology, 2020Co-Authors: A D Reed, Matthew A Nethery, Allison K Stewart, Rodolphe Barrangou, Casey M TheriotAbstract:ABSTRACT Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and Commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that Commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four Commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these Commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by Commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four Commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four Commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by Commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the Commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
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strain dependent inhibition of clostridioides difficile by Commensal clostridia encoding the bile acid inducible bai operon
bioRxiv, 2020Co-Authors: A D Reed, Matthew A Nethery, Allison K Stewart, Rodolphe Barrangou, Casey M TheriotAbstract:Abstract Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and Commensal Clostridia that encode the bile acid inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study we hypothesized that Commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the ability of four Commensal Clostridia encoding the bai operon (C. scindens VPI 12708, C. scindens ATCC 35704, C. hiranonis, and C. hylemonae) to convert CA to DCA in vitro, and if the amount of DCA produced was sufficient to inhibit growth of a clinically relevant C. difficile strain. We also investigated the competitive relationship between these Commensals and C. difficile using an in vitro co-culture system. We found that inhibition of C. difficile growth by Commensal Clostridia supplemented with CA was strain-dependent, correlated with the production of ∼2 mM DCA, and increased expression of bai operon genes. We also found that C. difficile was able to outcompete all four Commensal Clostridia in an in vitro co-culture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. Importance Commensal Clostridia encoding the bai operon such as C. scindens have been associated with protection against CDI, however the mechanism for this protection is unknown. Herein, we show four Commensal Clostridia that encode the bai operon effect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by Commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the Commensals in an in vitro co-culture system. These studies are instrumental in understanding the relationship between Commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.