In the Journals

Researchers pinpoint microbial strains that delay healing in diabetic foot ulcers

Researchers at the University of Wisconsin-Madison have identified specific strains of microbiota in patients with slow-healing diabetic foot ulcers, indicating the microbiomes of foot ulcers could predict clinical outcomes and responses to therapeutic interventions, according to findings published in Cell Host and Microbe.

Lindsay Kalan

“Our study has shown for the first time that differences at the strain-level within bacterial species can be associated with different outcomes,” Lindsay Kalan, PhD, assistant professor of medical microbiology and immunology at the School of Medicine and Public Health at the University of Wisconsin-Madison, told Endocrine Today. “For example, strain variation in the wound pathogen Staphylococcus aureus is associated with clinical outcome. When we isolated these strains from ulcers with poor outcomes, they also delayed healing in a murine model of diabetic wound healing. Further, when we examined therapeutic intervention, we found that tissue debridement, and not systemic antimicrobial therapy, disrupts the wound microbiota and depletes anaerobic bacteria in patients with favorable outcomes. The use of this metric allows us to predict healing trajectory at the first clinical visit.”

In a longitudinal, prospective study, Kalan and colleagues analyzed data from 46 patients with neuropathic diabetic foot ulcers. Researchers performed metagenomic shotgun sequencing of ulcer microbial samples, taken from wounds immediately before debridement, to identify strain-level diversity and profile the genomic content of the foot ulcer microbiota. New microbial samples were collected every 2 weeks for 26 weeks while researchers tracked outcomes of the ulcers.

Researchers found that strain-level variations of S. aureus and genetic signatures of biofilm formation were associated with poor outcomes in wound healing. In mouse models, cultured wound isolates of S. aureus elicited differential phenotypes that corresponded with patient outcomes, the researchers wrote. Additionally, so-called wound “bystanders,” such as Corynebacterium striatum and Alcaligenes faecalis, also influence wound severity and healing, they wrote.

The researchers also observed that antibiotic resistance genes were “widespread” and found that wound debridement reduced the diversity of bacteria colonizing the wounds in ulcers that went on to heal, whereas treatment with antibiotics did not improve wound outcomes.

The researchers noted that a disrupted microbial community could serve as a sign of successful debridement, helping inform the course of treatment.

“These findings are significant because there are currently no diagnostic tools for these patients, and a lack of biomarkers has been touted as a major impairment to advancing care,” Kalan said. “If we can evaluate the effectiveness of a therapy, such as debridement, within a shorter time period to predict if a wound will heal or not, the clinical team can respond much more rapidly than current standards allow.”

Kalan said the researchers want to further understand the molecular basis of the findings and determine what genes in these specific S. aureus strains make them more virulent or enhance persistence in chronic wounds.

“Further, our study has shown that disruption of anaerobic communities are important for a pro-healing environment,” Kalan said. “Now we want to understand what this means from the host perspective. We hope to learn if successful disruption of the microbiome leads to activation of healing pathways and tissue repair or suppresses the inflammatory response that can become dysregulated in these types of wounds.” – by Regina Schaffer

Lindsay Kalan, PhD, can be reached at the University of Wisconsin-Madison, School of Medicine and Public Health, 1550 Linden Drive, 6155 Microbial Science Building, Madison, WI 53706; email: lkalan@wisc.edu.

Disclosures: The authors report no relevant financial disclosures.

Researchers at the University of Wisconsin-Madison have identified specific strains of microbiota in patients with slow-healing diabetic foot ulcers, indicating the microbiomes of foot ulcers could predict clinical outcomes and responses to therapeutic interventions, according to findings published in Cell Host and Microbe.

Lindsay Kalan

“Our study has shown for the first time that differences at the strain-level within bacterial species can be associated with different outcomes,” Lindsay Kalan, PhD, assistant professor of medical microbiology and immunology at the School of Medicine and Public Health at the University of Wisconsin-Madison, told Endocrine Today. “For example, strain variation in the wound pathogen Staphylococcus aureus is associated with clinical outcome. When we isolated these strains from ulcers with poor outcomes, they also delayed healing in a murine model of diabetic wound healing. Further, when we examined therapeutic intervention, we found that tissue debridement, and not systemic antimicrobial therapy, disrupts the wound microbiota and depletes anaerobic bacteria in patients with favorable outcomes. The use of this metric allows us to predict healing trajectory at the first clinical visit.”

In a longitudinal, prospective study, Kalan and colleagues analyzed data from 46 patients with neuropathic diabetic foot ulcers. Researchers performed metagenomic shotgun sequencing of ulcer microbial samples, taken from wounds immediately before debridement, to identify strain-level diversity and profile the genomic content of the foot ulcer microbiota. New microbial samples were collected every 2 weeks for 26 weeks while researchers tracked outcomes of the ulcers.

Researchers found that strain-level variations of S. aureus and genetic signatures of biofilm formation were associated with poor outcomes in wound healing. In mouse models, cultured wound isolates of S. aureus elicited differential phenotypes that corresponded with patient outcomes, the researchers wrote. Additionally, so-called wound “bystanders,” such as Corynebacterium striatum and Alcaligenes faecalis, also influence wound severity and healing, they wrote.

The researchers also observed that antibiotic resistance genes were “widespread” and found that wound debridement reduced the diversity of bacteria colonizing the wounds in ulcers that went on to heal, whereas treatment with antibiotics did not improve wound outcomes.

The researchers noted that a disrupted microbial community could serve as a sign of successful debridement, helping inform the course of treatment.

“These findings are significant because there are currently no diagnostic tools for these patients, and a lack of biomarkers has been touted as a major impairment to advancing care,” Kalan said. “If we can evaluate the effectiveness of a therapy, such as debridement, within a shorter time period to predict if a wound will heal or not, the clinical team can respond much more rapidly than current standards allow.”

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Kalan said the researchers want to further understand the molecular basis of the findings and determine what genes in these specific S. aureus strains make them more virulent or enhance persistence in chronic wounds.

“Further, our study has shown that disruption of anaerobic communities are important for a pro-healing environment,” Kalan said. “Now we want to understand what this means from the host perspective. We hope to learn if successful disruption of the microbiome leads to activation of healing pathways and tissue repair or suppresses the inflammatory response that can become dysregulated in these types of wounds.” – by Regina Schaffer

Lindsay Kalan, PhD, can be reached at the University of Wisconsin-Madison, School of Medicine and Public Health, 1550 Linden Drive, 6155 Microbial Science Building, Madison, WI 53706; email: lkalan@wisc.edu.

Disclosures: The authors report no relevant financial disclosures.