Strain- and Species-Level Variation in the Microbiome of Diabetic Wounds Is Associated with Clinical Outcomes and Therapeutic Efficacy

Kalan, Lindsay; Meisel, Jacquelyn S.; Loesche, Michael A.; Horwinski, Joseph; Soaita, Ioana; Chen, Xiaoxuan; Uberoi, Aayushi; Gardner, Sue E.; Grice, Elizabeth A.

doi:10.1016/j.chom.2019.03.006

Cited by 253 publications

(287 citation statements)

References 58 publications

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“…Alcaligenes faecalis is an aerobic Gram-negative nosocomial pathogen (20,21) that is generally regarded as a colonizer rather than a causative pathogen (22). However, recent research has explored its role in wound exacerbation (23). We hypothesize that the presence of Alcaligenes might interfere with the growth of other readily culturable microbes, providing the illusion of culture-negative results.…”

Section: Discussionmentioning

confidence: 99%

Microbial Community Distribution and Core Microbiome in Successive Wound Grades of Individuals with Diabetic Foot Ulcers

Jnana

Muthuraman

Varghese

et al. 2020

Appl Environ Microbiol

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Diabetic foot ulcer (DFU) is a major complication of diabetes with high morbidity and mortality rates. The pathogenesis of DFUs is governed by a complex milieu of environmental and host factors. The empirical treatment is initially based on wound severity since culturing and profiling the antibiotic sensitivity of wound-associated microbes is time-consuming. Hence, a thorough and rapid analysis of the microbial landscape is a major requirement toward devising evidence-based interventions. Toward this, 122 wound (100 diabetic and 22 nondiabetic) samples were sampled for their bacterial community structure using both culture-based and next-generation 16S rRNA-based metagenomics approach. Both the approaches showed that the Gram-negative microbes were more abundant in the wound microbiome. The core microbiome consisted of bacterial genera, including Alcaligenes, Pseudomonas, Burkholderia, and Corynebacterium in decreasing order of average relative abundance. Despite the heterogenous nature and extensive sharing of microbes, an inherent community structure was apparent, as revealed by a cluster analysis based on Euclidean distances. Facultative anaerobes (26.5%) were predominant in Wagner grade 5, while strict anaerobes were abundant in Wagner grade 1 (26%). A nonmetric dimensional scaling analysis could not clearly discriminate samples based on HbA1c levels. Sequencing approach revealed the presence of major culturable species even in samples with no bacterial growth in culture-based approach. Our study indicates that (i) the composition of core microbial community varies with wound severity, (ii) polymicrobial species distribution is individual specific, and (iii) antibiotic susceptibility varies with individuals. Our study suggests the need to evolve better-personalized care for better wound management therapies. IMPORTANCE Chronic nonhealing diabetic foot ulcers (DFUs) are a serious complication of diabetes and are further exacerbated by bacterial colonization. The microbial burden in the wound of each individual displays diverse morphological and physiological characteristics with unique patterns of host-pathogen interactions, antibiotic resistance, and virulence. Treatment involves empirical decisions until definitive results on the causative wound pathogens and their antibiotic susceptibility profiles are available. Hence, there is a need for rapid and accurate detection of these polymicrobial communities for effective wound management. Deciphering microbial communities will aid clinicians to tailor their treatment specifically to the microbes prevalent in the DFU at the time of assessment. This may reduce DFUs associated morbidity and mortality while impeding the rise of multidrug-resistant microbes.

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Section: Discussionmentioning

confidence: 99%

Microbial Community Distribution and Core Microbiome in Successive Wound Grades of Individuals with Diabetic Foot Ulcers

Jnana

Muthuraman

Varghese

et al. 2020

Appl Environ Microbiol

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“…While the role of eosinophils and their cross-talk with mast cells during wound healing are poorly understood, our data demonstrate that the presence of eosinophils specific for DFUs may have a role in contributing to the wound chronicity. Furthermore, Staphylococcus aureus the most prevalent pathogen in both DFU 62 and atopic dermatitis 63 has shown to be responsible for increased recruitment of mast cells and eosinophils in animal models of atopic dermatitis 64 , suggesting similar traits in DFUs.…”

Section: Discussionmentioning

confidence: 99%

Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

et al. 2020

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Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of “ideal” adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.

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“…However, neither patient demographics nor wound type influenced the bacterial composition of the chronic wound microbiome [ 17 ]. Different studies have described this DFU microbiota [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Although they have produced interesting results and confirmed that the microbiota is a highly dynamic microbial community that maintains a relationship with the host, understanding the complex competitive or synergistic interaction between commensal and pathogenic microorganisms is necessary as it could play an important role in the severity and evolution of the wound.…”

Section: Pathophysiology Of Diabetic Foot Ulcersmentioning

confidence: 99%

Biofilms in Diabetic Foot Ulcers: Significance and Clinical Relevance

et al. 2020

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Foot infections are the main disabling complication in patients with diabetes mellitus. These infections can lead to lower-limb amputation, increasing mortality and decreasing the quality of life. Biofilm formation is an important pathophysiology step in diabetic foot ulcers (DFU)—it plays a main role in the disease progression and chronicity of the lesion, the development of antibiotic resistance, and makes wound healing difficult to treat. The main problem is the difficulty in distinguishing between infection and colonization in DFU. The bacteria present in DFU are organized into functionally equivalent pathogroups that allow for close interactions between the bacteria within the biofilm. Consequently, some bacterial species that alone would be considered non-pathogenic, or incapable of maintaining a chronic infection, could co-aggregate symbiotically in a pathogenic biofilm and act synergistically to cause a chronic infection. In this review, we discuss current knowledge on biofilm formation, its presence in DFU, how the diabetic environment affects biofilm formation and its regulation, and the clinical implications.

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Strain- and Species-Level Variation in the Microbiome of Diabetic Wounds Is Associated with Clinical Outcomes and Therapeutic Efficacy

Cited by 253 publications

References 58 publications

Microbial Community Distribution and Core Microbiome in Successive Wound Grades of Individuals with Diabetic Foot Ulcers

Microbial Community Distribution and Core Microbiome in Successive Wound Grades of Individuals with Diabetic Foot Ulcers

Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

Biofilms in Diabetic Foot Ulcers: Significance and Clinical Relevance

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