Microbial Metabolism Modulates Antibiotic Susceptibility within the Murine Gut Microbiome

Cabral, Damien J.; Penumutchu, Swathi; Reinhart, Elizabeth M.; Zhang, Cheng; Korry, Benjamin J.; Wurster, Jenna I.; Nilson, Rachael; Guang, August; Sano, William H.; Rowan-Nash, Aislinn D.; Li, Hu; Belenky, Peter

doi:10.1016/j.cmet.2019.08.020

Cited by 75 publications

(96 citation statements)

References 238 publications

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“…strict anaerobes), the community is able to resist antibiotic induced changes and reconstitute more quickly once the pressure of antibiotic treatment has been removed. This finding is consistent with a recent study that showed that fiber supplementation in mice lead to a reduced disruption of the gut microbiome to disturbance from amoxicillin, and that this was linked with upregulation of polysaccharide utilization by Bacteroides thetaiotaomicron , an intestinal commensal that individually became less susceptible to amoxicillin in the presence of dietary fiber (29) .…”

Section: Discussionsupporting

confidence: 93%

Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice

Hazleton

Martin

Arnolds

et al. 2019

Preprint

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One Sentence Summary: High dietary fat promoted mortality in a mouse model of antibiotic-17 induced C. difficile infection and low dietary fiber caused higher microbiome disturbance upon 18 broad-spectum antibiotic exposure, suggesting that diets low in fat and high in fiber may protect 19 against C. difficile pathogenesis.Abstract: Clostridoides difficile infection (CDI) is a leading cause of hospital-acquired diarrhea 22 and there has been a steady increase in the number of new infections, emphasizing the 23 importance of novel prevention strategies. Use of broad-spectrum antibiotics and disruption of 24 the intestinal microbiome is one of the most important risk factors of CDI. We used a murine 25 model of antibiotic-induced CDI to investigate the relative contributions of high dietary fat and 26 low dietary fiber on disease pathogenesis. We found that high fat, but not low fiber resulted in 27 increased mortality from CDI (HR 4.95) and increased levels of C. difficile toxin production 28 compared to a regular low-fat/high-fiber mouse diet even though we did not observe a significant 29 change in C. difficile carriage. The high-fat diet also increased levels of primary bile acids 30 known to be germination factors for C. difficile spores. Mice fed low-fat/low-fiber diets did not 31 show increased CDI pathogenesis, but did have a larger antibiotic-induced gut microbiome 32 disturbance compared to mice fed a high-fiber diet, characterized by a greater decrease in alpha 33 diversity. This microbiome disturbance was associated with a loss of secondary bile acids and 34 short chain fatty acids, which are both microbial metabolic products previously shown to protect 35 against CDI. These data suggest that a low-fiber diet contributes to antibiotic-induced dysbiosis, 36 while a high-fat diet promotes CDI pathogenesis. These findings indicate that dietary 37 interventions that increase fiber and decrease fat may be an effective prevention strategy for 38 individuals at high risk of CDI. 39 40 41Clostridoides difficile infection (CDI) is an important cause of morbidity and mortality, 42 with 500,000 cases every year causing 30,000 deaths per year in the US alone (1). Alarmingly, 43 there has been a steady increase in the number of new infections in spite of prevention efforts in 44 hospitals that have focused largely on increased sanitation and antibiotic stewardship (2). These 45 prevention approaches treat CDI as a traditional communicable infection. However, recent data 46 suggests that CDI is often caused by the activation of strains that were already carried in the gut 47 prior to hospital admission and prior to the onset of symptoms rather than by acquisition of a 48 hospital-resident strain (3). Thus, determining strategies to reduce C. difficile carriage and 49 attenuate CDI severity is critical. 50A complex gut microbiome has been shown to be protective against CDI (4). Broad 51 spectrum antibiotic usage, such as clindamycin, beta-lactams, and fluoroquinolones (5, 6) 52 increase risk of CDI as d...

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Section: Discussionsupporting

confidence: 93%

Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice

Hazleton

Martin

Arnolds

et al. 2019

Preprint

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“…In a previous study, we obtained total cecal DNA and RNA from six-week-old female C57BL/6J mice that were treated with amoxicillin (0.1667 mg/mL) for 12 h, or ciprofloxacin (0.0833 mg/mL), or doxycycline hydrochloride (0.067 mg/mL) for 24 h (Cabral et al, 2019). All antibiotic treatments were administered in drinking water, which was provided ad libitum.…”

Section: Mouse Experimentsmentioning

confidence: 99%

“…All reads were deposited in the NCBI Short Read Archive under BioProject numbers PRJNA504846 (metagenomics) and PRJNA515074 (metatranscriptomics). This data set was previously published by Cabral et al (2019). The DNA, RNA, and subsequent libraries and sequencing data were the same as those initially published in Cabral et al (2019).…”

Section: Sequencingmentioning

confidence: 99%

“…This data set was previously published by Cabral et al (2019). The DNA, RNA, and subsequent libraries and sequencing data were the same as those initially published in Cabral et al (2019). Here, we reanalyze this data using a different set of pipelines and with a focus on the detection of ARGs.…”

Section: Sequencingmentioning

confidence: 99%

“…Overall, we found that out of the three antibiotics tested, amoxicillin had the most profound impact on the murine cecal microbiome community in terms of diversity and species relative abundance, while ciprofloxacin and doxycycline exhibit less drastic changes. A more detailed description of the taxonomic shifts is detailed in Cabral et al (2019), while in this study we focus on the ARGs.…”

Section: Microbial Diversitymentioning

confidence: 99%

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Metatranscriptomics Reveals Antibiotic-Induced Resistance Gene Expression in the Murine Gut Microbiota

2020

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Antibiotic resistance is a current and expanding threat to the practice of modern medicine. Antibiotic therapy has been shown to perturb the composition of the host microbiome with significant health consequences. In addition, the gut microbiome is known to be a reservoir of antibiotic resistance genes. Work has demonstrated that antibiotics can alter the collection of antibiotic resistance genes within the microbiome through selection and horizontal gene transfer. While antibiotics also have the potential to impact the expression of resistance genes, metagenomic-based pipelines currently lack the ability to detect these shifts. Here, we utilized a dual sequencing approach combining shotgun metagenomics and metatranscriptomics to profile how three antibiotics, amoxicillin, doxycycline, and ciprofloxacin, impact the murine gut resistome at the DNA and RNA level. We found that each antibiotic induced broad, but untargeted impacts on the gene content of the resistome. In contrast, changes in ARG transcript abundance were more targeted to the antibiotic treatment. Doxycycline and amoxicillin induced the expression of tetracycline and beta-lactamase resistance genes, respectively. Furthermore, the increased beta-lactamase resistance gene transcripts could contribute to an observed bloom of Bacteroides thetaiotaomicron during amoxicillin treatment. Based on these findings, we propose that the utilization of a dual sequencing methodology provides a unique capacity to fully understand the response of the resistome to antibiotic perturbation. In particular, the analysis of transcripts reveals that the expression and utilization of resistance genes is far narrower than their abundance at the genomic level would suggest.

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Synovial fluid NMR‐based metabolomics in septic and aseptic revision total knee arthroplasty: Implications on diagnosis and treatment

de Paula Mozella,

Alexandre de Araujo Barros Cobra,

Monteiro da Palma

et al. 2024

Journal Orthopaedic Research

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Periprosthetic joint infection (PJI) is one of the most challenging complications following total knee arthroplasty. Despite its importance, there is a paucity of reports in the literature regarding its pathogenesis. Recently, cellular metabolic reprogramming has been shown to play an important role in the progression and outcome of infectious diseases. Therefore, the aim of this study was to evaluate the metabolites composition of the synovial fluid from patients with PJI or aseptic failure of total knee arthroplasties. The synovial fluids from 21 patients scheduled for revision total knee arthroplasty (11 with the diagnosis of PJI and 10 with aseptic failures) were analyzed using 1D 1H NMR spectroscopy. Univariate and multivariate statistical analyzes were used to identify metabolites that were differentially abundant between those groups. A total of 28 metabolites were identified and five of them found to be differentially abundant between infected and non‐infected synovial fluids. Lactate, acetate and 3‐hydroxybutyrate were found to be in a higher concentration, and glucose and creatine were found reduced in the synovial fluid from PJI patients. Synovial fluid from patients with PJI exhibit a distinct metabolic profile, possibly reflecting metabolic adaptation that occurs in the infected periprosthetic microenvironment. Further research and studies are warranted to gain a broader insight into the metabolic pathways engaged by both pathogen and immune cells in the context of a PJI.

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Microbial Metabolism Modulates Antibiotic Susceptibility within the Murine Gut Microbiome

Cited by 75 publications

References 238 publications

Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice

Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice

Metatranscriptomics Reveals Antibiotic-Induced Resistance Gene Expression in the Murine Gut Microbiota

Synovial fluid NMR‐based metabolomics in septic and aseptic revision total knee arthroplasty: Implications on diagnosis and treatment

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