Bacteroides fragilis Prevents Clostridium difficile Infection in a Mouse Model by Restoring Gut Barrier and Microbiome Regulation

Deng, Huimin; Yang, Siqi; Zhang, Yucheng; Qian, Kai; Zhang, Zhaohui; Liu, Yangyang; Wang, Ye; Bai, Yang; Fan, Huiying; Zhao, Xinmei; Zhi, Fachao

doi:10.3389/fmicb.2018.02976

Cited by 98 publications

(65 citation statements)

References 33 publications

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“…suggesting that the inflammation induced by wild type C. difficile in our mouse model selects against a Bacteroidaceae population expansion. In support of this, negative associations between C. difficile and members of the Bacteroidaceae have been reported in human studies, as well as in vitro, and in mouse models of CDI[59][60][61][62][63] . Further work is necessary to identify which mediator(s) of host inflammation are responsible for the restriction of the Bacteroidaceae in our model of CDI.…”

supporting

confidence: 53%

Clostridioides difficileexploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

Fletcher

Pike

Parsons

et al. 2020

Preprint

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Introductory paragraphClostridioides difficile is a bacterial pathogen that causes a range of clinical disease from mild to moderate diarrhea, pseudomembranous colitis, and toxic megacolon. Typically, C. difficile infections (CDIs) occur after antibiotic treatment, which alters the gut microbiota, decreasing colonization resistance against C. difficile. Disease is mediated by two large toxins and the expression of their genes is induced upon nutrient depletion via the alternative sigma factor TcdR. Using tcdR mutants in two strains of C. difficile, we defined how toxin-induced inflammation alters C. difficile metabolism, tissue gene expression, and the gut microbiota to determine how inflammation by the host may be beneficial to C. difficile. Here we show that C. difficile metabolism is significantly different in the face of inflammation, with changes in many carbohydrate and amino acid uptake and utilization pathways. Host gene expression signatures suggest that degradation of collagen and other components of the extracellular matrix by matrix metalloproteinases is a major source of peptides and amino acids that supports C. difficile growth in vivo. Lastly, the inflammation induced by C. difficile toxin activity alters the gut microbiota, excluding members from the genus Bacteroides that are able to compete against C. difficile for the same essential nutrients released from collagen degradation.

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supporting

confidence: 53%

Clostridioides difficileexploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

Fletcher

Pike

Parsons

et al. 2020

Preprint

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“…We also recently reported that C. difficile growth on epithelial cells in an in vitro gut model was reduced in the presence of B. doreP 8 . B. fragilis has been recently reported to prevent C. difficile infection in a murine infection model by potentially impacting the integrity of the epithelial barrier 64 . While these data support a role for Bacteroides spp in preventing C. difficile infection, patients infected with C. difficile generally have a reduction in the abundance and diversity of Bacteroidetes 61 .…”

Section: Discussionmentioning

confidence: 99%

Dissecting individual pathogen-commensal interactions within a complex gut microbiota community

Hassall

Unnikrishnan

2020

Preprint

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14Interactions of commensal bacteria within the gut microbiota and with invading pathogens 15 are critical in determining the outcome of an infection. While murine studies have been 16 valuable, we lack in vitro tools to monitor community responses to pathogens at a single-17 species level. We have developed a multi-species community of nine representative gut 18 species cultured together as a mixed biofilm and tracked numbers of individual species over 19 time using a qPCR-based approach. Introduction of the major nosocomial gut pathogen, 20Clostridiodes difficile, to this community resulted in increased adhesion of commensals and 21 inhibition of C. difficile multiplication. Interestingly, we observed an increase in individual 22Bacteroides species accompanying the inhibition of C. difficile. Furthermore, Bacteroides 23 dorei reduced C. difficile growth within biofilms, suggesting a role for Bacteroides spp in 24 prevention of C. difficile colonisation. We report here an in vitro tool with excellent 25 applications for investigating bacterial interactions within a complex community. 26 27 28 Disturbed microbiota and the loss of colonisation resistance are associated with several 49 pathogen infections including Clostridioides difficile 8 , Enterohemorrhagic E. coli 15 , and 50 Campylobacter jejuni 16 . 51 In the case of C. difficile, a leading cause of healthcare-associated diarrhoea worldwide, 52 colonisation occurs only when the microbiota is altered, usually due to treatment with 53 antibiotics such as fluoroquinolones 17 . The increased susceptibility of C. difficile infection (CDI) 54 after antibiotic-induced dysbiosis of the gut microbiota is well documented 18,19 . While most 55 4 studies demonstrating the link between CDI and antibiotic therapy are based on changes in 56 microbial populations by microbiota sequencing, recent studies have reported mechanisms by 57 which the microbiota can prevent C. difficile infections 20 . The microbiota in a healthy state 58 consumes or converts primary bile acid into secondary bile acids, reducing the ability of C. 59 difficile to germinate 21 . Secondary bile acids such as deoxycholic acid (DCA) and lithocholic 60 acid (LCA), are toxic to vegetative C. difficile 22,23 . Additionally, gut bacteria like Clostridium 61 scindens which encode secondary bile acid synthesis enzymes have been associated to 62 resistance to C. difficile infection 24 . The microbiota not only competes for resources but 63 actively inhibits C. difficile through production of bacteriocins such as the thuricin CD, 64 produced by Bacteroides thuringiensis 25 . 65While the microbiota is clearly important in preventing infections, current knowledge is mainly 66 based on microbiota profiles from faeces. The gut microbiota is composed of bacteria within 67 the lumen, which are usually detected in faeces and bacteria associated with the gut mucosa. 68Few studies have profiled the adherent microbiota population of healthy human guts as they 69 require invasive biopsies 26 . While not much is known abou...

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“…"+++" indicates the metabolite with the strongest growth-promoting capability, while the "+" means that the metabolite induced a mild growth promotion results in significant perturbation of the gut microbiome, it is conceivable that this model would demonstrate increased susceptibility to infections by other enteric pathogens such as Salmonella enterica serovar Typhimurium, Citrobacter rodentium, and Clostridium difficile. However, for the aforementioned enteric pathogens, there already exists a wellestablished adult mouse model [50,51]. Here, we suggest a simple and convenient animal model to study V. cholerae infection.…”

Section: Discussionmentioning

confidence: 99%

Commensal-derived metabolites govern Vibrio cholerae pathogenesis in host intestine

et al. 2019

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Background Recent evidence suggests that the commensal microbes act as a barrier against invading pathogens and enteric infections are the consequences of multi-layered interactions among commensals, pathogens, and the host intestinal tissue. However, it remains unclear how perturbations of the gut microbiota compromise host infection resistance, especially through changes at species and metabolite levels. Results Here, we illustrate how Bacteroides vulgatus, a dominant species of the Bacteroidetes phylum in mouse intestine, suppresses infection by Vibrio cholerae, an important human pathogen. Clindamycin (CL) is an antibiotic that selectively kills anaerobic bacteria, and accordingly Bacteroidetes are completely eradicated from CL-treated mouse intestines. The Bacteroidetes-depleted adult mice developed severe cholera-like symptoms, when infected with V. cholerae. Germ-free mice mono-associated with B. vulgatus became resistant to V. cholerae infection. Levels of V. cholerae growth-inhibitory metabolites including short-chain fatty acids plummeted upon CL treatment, while levels of compounds that enhance V. cholerae proliferation were elevated. Furthermore, the intestinal colonization process of V. cholerae was well-simulated in CL-treated adult mice. Conclusions Overall, we provide insights into how a symbiotic microbe and a pathogenic intruder interact inside host intestine. We identified B. vulgatus as an indigenous microbial species that can suppress intestinal infection. Our results also demonstrate that commensal-derived metabolites are a critical determinant for host resistance against V. cholerae infection, and that CL pretreatment of adult mice generates a simple yet useful model of cholera infection.

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Bacteroides fragilis Prevents Clostridium difficile Infection in a Mouse Model by Restoring Gut Barrier and Microbiome Regulation

Cited by 98 publications

References 33 publications

Clostridioides difficileexploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

Clostridioides difficileexploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

Dissecting individual pathogen-commensal interactions within a complex gut microbiota community

Commensal-derived metabolites govern Vibrio cholerae pathogenesis in host intestine

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