The Neuropathic Diabetic Foot Ulcer Microbiome Is Associated With Clinical Factors

Abstract

Nonhealing diabetic foot ulcers (DFUs) are a common and costly complication of diabetes. Microbial burden, or “bioburden,” is believed to underlie delayed healing, although little is known of those clinical factors that may influence microbial load, diversity, and/or pathogenicity. We profiled the microbiomes of neuropathic nonischemic DFUs without clinical evidence of infection in 52 individuals using high-throughput sequencing of the bacterial 16S ribosomal RNA gene. Comparatively, wound cultures, the standard diagnostic in the clinic, vastly underrepresent microbial load, microbial diversity, and the presence of potential pathogens. DFU microbiomes were heterogeneous, even in our tightly restricted study population, but partitioned into three clusters distinguished primarily by dominant bacteria and diversity. Ulcer depth was associated with ulcer cluster, positively correlated with abundance of anaerobic bacteria, and negatively correlated with abundance of Staphylococcus. Ulcer duration was positively correlated with bacterial diversity, species richness, and relative abundance of Proteobacteria, but was negatively correlated with relative abundance of Staphylococcus. Finally, poor glycemic control was associated with ulcer cluster, with poorest median glycemic control concentrating to Staphylococcus-rich and Streptococcus-rich ulcer clusters. Analyses of microbial community membership and structure may provide the most useful metrics in prospective studies to delineate problematic bioburden from benign colonization that can then be used to drive clinical treatment.

A systematic literature review of the human skin microbiome as biomarker for dermatological drug development

“…The role of the skin microbiome in UC was explored in 10 different studies, Table 1 37, 38, 39, 40, 41, 42, 43, 44, 45, 46. Current research into UC microbiome, comprises larger, longitudinal studies, compared to those in PV and HS.…”

“…The skin mycobiota of diabetic foot ulcers was longitudinally assessed and was observed to be highly heterogeneous over time and between subjects while the diversity increased upon antibiotic treatment 45. There have been similar efforts to reveal correlations between patient metadata, treatment and/or clinical outcomes and the cutaneous microbiome in studies investigating the microbiota in UC 38, 42, 43, 44, 46. Overall, the most common found genus in these studies was Staphylococcus , with Staphylococcus aureus the most common species.…”

“…Ulcer closing in diabetic patients was found to be positively correlated with higher microbial diversity and relative abundance of Proteobacteria , while a relative abundance of Staphylococcus was correlated negatively in a study by Gardner et al . 42. Although Staphylococcus was consistently reported to be the most common genus, inconsistencies exist regarding other genus that are important in CU.…”

“…For UC inconsistencies in study design, sampling methods and the heterogeneity of the disease group also limit the comparability of study findings. There appears to be a relationship between certain species, types of ulcers and ulcer duration 42, 46. However, longitudinal studies with frequent standard sampling and standard analysis procedures are necessary to make a recommendation.…”

Association Between Microbial Bioburden and Healing Outcomes in Venous Leg Ulcers: A Review of the Evidence

“…Conventional bacterial culture is the most widely available tool for the diagnosis of bacterial infection, but has been shown consistently to underestimate the complexity of wound bacterial burden as revealed by DNA-based molecular methods. [6][7][8][9][10] Bacteria in chronic wounds grow in biofilms, which include many anaerobes and other species not identified by cultivation-based methods. 7,[10][11][12] This complexity of the microbial flora in chronic wounds may explain the lack of improved clinical outcomes observed in many studies of antimicrobial use targeting bacteria identified by cultivation-based methods.…”