Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections

Robinson, John I.; Weir, William H.; Crowley, Jan R.; Hink, Tiffany; Reske, Kimberly A.; Kwon, Jennie H.; Burnham, Carey Ann D.; Dubberke, Erik R.; Mucha, Peter J.; Henderson, Jeffrey P.

doi:10.1172/jci126905

Cited by 77 publications

(85 citation statements)

References 41 publications

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“…Further, in a landmark study, Buffie et al were able to pinpoint the single bacterium, Clostridium scindens, which they showed enhances resistance to C. difficile infection by producing key bile acids that directly inhibit C. difficile outgrowth (27). Finally, a recent study showed differences in bile acid composition between asymptomatic carriers of C. difficile and patients with CDI (28). Taken together, these studies highlight a complex interplay between C. difficile and…”

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confidence: 98%

Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin

Tam

Icho

Utama

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal bile acids are known to modulate the germination and growth ofClostridioides difficile. Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant ofC. difficiledisease. We show that individual primary and secondary bile acids reversibly bind and inhibit TcdB to varying degrees through a mechanism that requires the combined oligopeptide repeats region to which no function has previously been ascribed. We find that bile acids induce TcdB into a compact “balled up” conformation that is no longer able to bind cell surface receptors. Lastly, through a high-throughput screen designed to identify bile acid mimetics we uncovered nonsteroidal small molecule scaffolds that bind and inhibit TcdB through a bile acid-like mechanism. In addition to suggesting a role for bile acids inC. difficilepathogenesis, these findings provide a framework for development of a mechanistic class ofC. difficileantitoxins.

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confidence: 98%

Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin

Tam

Icho

Utama

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…While our study focused solely on the bacterial portion, viruses and fungi have also begun to be implicated in the context of CDIs or FMT treatments for recurrent CDIs (35,(57)(58)(59)(60). Beyond community composition, the metabolic function of the microbiota also has a CDI signature (20,46,61,62) and can vary across mice from different sources (63). For example, microbial metabolites, particularly secondary bile acids and butyrate production, have been implicated as important contributors to C. difficile resistance (33,44).…”

Section: Discussionmentioning

confidence: 99%

The initial gut microbiota and response to antibiotic perturbation influenceClostridioides difficilecolonization in mice

Tomkovich

Stough

Bishop

et al. 2020

Preprint

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The gut microbiota has a key role in determining susceptibility to Clostridioides difficile infections (CDIs). However, much of the mechanistic work examining CDIs in mouse models use animals obtained from a single source. We treated mice from 6 sources (2 University of Michigan colonies and 4 commercial vendors) with clindamycin, followed by a C. difficile challenge and then measured C. difficile colonization levels throughout the infection. The microbiota were profiled via 16S rRNA gene sequencing to examine the variation across sources and alterations due to clindamycin treatment and C. difficile challenge. While all mice were colonized 1-day post-infection, variation emerged from days 3-7 post-infection with animals from some sources colonized with C. difficile for longer and at higher levels. We identified bacteria that varied in relative abundance across sources and throughout the experiment. Some bacteria were consistently impacted by clindamycin treatment in all sources of mice including Lachnospiraceae, Ruminococcaceae, and Enterobacteriaceae. To identify bacteria that were most important to colonization regardless of the source, we created logistic regression models that successfully classified mice based on whether they cleared C. difficile by 7 days post-infection using community composition data at baseline, post-clindamycin, and 1-day post-infection. With these models, we identified 4 bacteria that were predictive of whether C. difficile cleared. They varied across sources (Bacteroides), were altered by clindamycin (Porphyromonadaceae), or both (Enterobacteriaceae and Enterococcus). Allowing for microbiota variation across sources better emulates human inter-individual variation and can help identify bacterial drivers of phenotypic variation in the context of CDIs.ImportanceClostridioides difficile is a leading nosocomial infection. Although perturbation to the gut microbiota is an established risk, there is variation in who becomes asymptomatically colonized, develops an infection, or has adverse infection outcomes. Mouse models of C. difficile infection (CDI) are widely used to answer a variety of C. difficile pathogenesis questions. However, the inter-individual variation between mice from the same breeding facility is less than what is observed in humans. Therefore, we challenged mice from 6 different breeding colonies with C. difficile. We found that the starting microbial community structures and C. difficile persistence varied by the source of mice. Interestingly, a subset of the bacteria that varied across sources were associated with how long C. difficile was able to colonize. By increasing the inter-individual diversity of the starting communities, we were able to better model human diversity. This provided a more nuanced perspective of C. difficile pathogenesis.

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“…Metabolomic studies using antibiotictreated mouse models of infection have strongly implicated the Stickland reaction as an important factor for C. difficile colonization and growth, although proline fermentation is more often highlighted in these studies (18,19). Robinson et al did detect proline and 5-aminovalerate in CDI samples; however, it was not as strong of a with C. difficile (Cx + /EIA -), and patients with non-CDI diarrhea (Cx -/EIA -) (17). The aims of this study were to understand the relationship between the intestinal metabolome and CDI in humans, evaluate if metabolomics could be used to aid in better diagnostic approaches to improve sensitivity, and create a metabolomic model that will aid in the treatment of CDI.…”

Section: Discussionmentioning

confidence: 99%

“…Robinson and colleagues used untargeted and targeted mass spectrometry approaches that spanned multiple platforms, including gas chromatographymass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), to capture a range of metabolites in patient fecal samples (17). They detected 2463 distinct features (metabolites) and applied statistical modeling to define only the key features that were able to differentiate samples between patients with CDI and patients without CDI or with non-CDI diarrhea.…”

Section: Discussionmentioning

confidence: 99%

Human fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatment

Theriot¹,

Fletcher²

2019

Journal of Clinical Investigation

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Antibiotics and the rise of CDI Clostridioides difficile is a spore-forming anaerobic bacterial pathogen. There are approximately 500,000 cases of C. difficile infection (CDI) and 29,000 deaths per year in the United States, making CDI an urgent public health threat (1). Patients with CDI experience a range of clinical disease, from being asymptomatic to experiencing mild to moderate diarrhea, pseudomembranous colitis, more severe colitis, toxin megacolon, and death. Antibiotic use continues to be a major risk factor for acquiring CDI; however, the first line of treatment is the antibiotic vancomycin and/or fidaxomicin, with an average relapse rate of 20% (2, 3). Antibiotics are important for human health but can also cause collateral damage to the indigenous gut microbiota, thereby decreasing colonization resistance and allowing pathogens like C. difficile to colonize the gut (4). Increased precision and resolution of mass spectrometry technology have begun to reveal how antibiot

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Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections

Cited by 77 publications

References 41 publications

Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin

Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin

The initial gut microbiota and response to antibiotic perturbation influenceClostridioides difficilecolonization in mice

Human fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatment

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