The Gut-Skin Microbiota Axis and Its Role in Diabetic Wound Healing-A Review Based on Current Literature

Abstract

Diabetic foot ulcers (DFU) are a growing concern worldwide as they pose complications in routine clinical practices such as diagnosis and management. Bacterial interactions on the skin surface are vital to the pathophysiology of DFU and may control delayed wound healing. The microbiota from our skin directly regulates cutaneous health and disease by interacting with the numerous cells involved in the wound healing mechanism. Commensal microbiota, in particular, interact with wound-repairing skin cells to enhance barrier regeneration. The observed microbes in DFU include Staphylococcus, Streptococcus, Corynebacterium, Pseudomonas, and several anaerobes. Skin commensal microbes, namely S. epidermidis, can regulate the gamma delta T cells and induce Perforin-2 expression. The increased expression of Perforin-2 by skin cells destroyed S. aureus within the cells, facilitating wound healing. Possible crosstalk between the human commensal microbiome and different cell types involved in cutaneous wound healing promotes the immune response and helps to maintain the barrier function in humans. Wound healing is a highly well-coordinated, complex mechanism; it can be devastating if interrupted. Skin microbiomes are being studied in relation to the gut-skin axis along with their effects on dermatologic conditions. The gut-skin axis illustrates the connection wherein the gut can impact skin health due to its immunological and metabolic properties. The precise mechanism underlying gut-skin microbial interactions is still unidentified, but the immune and endocrine systems are likely to be involved. Next-generation sequencing and the development of bioinformatics pipelines may considerably improve the understanding of the microbiome-skin axis involved in diabetic wound healing in a much more sophisticated way. We endeavor to shed light on the importance of these pathways in the pathomechanisms of the most prevalent inflammatory conditions including the diabetes wound healing, as well as how probiotics may intervene in the gut-skin axis.

Keywords: diabetes; dysbiosis; microbiota; probiotics; wound healing.

Figure 1

This figure depicts the differences between the normal and diabetic wound healing phases. When an injury occurs, the formation of various growth factors and cytokines such as transforming growth factor (TGF-) and monocyte chemoattractant protein 1 (MCP-1) from aggregated platelets begins. This is required for the formation of new tissue in the first stage. As a result, growth factors, keratinocytes, and activated fibroblasts start to form a new extracellular matrix and new blood vessels. Reduced levels of all growth factors and cytokines (such as TGF-), MCP-1, and growth and angiogenic factors (VEGF and PDGF) are major contributors to diabetic foot ulcer refractoriness. In short, wound closure is severely impaired in diabetic foot ulcer patients; additionally, reduced angiogenesis is observed due to the hyperglycemic phase, decreased migration of keratinocytes and fibroblasts, resulting in a deficient re-epithelialization; similarly, poor production of the extracellular matrix by fibroblasts contributes to the problem of deficient wound closure.

Figure 2

This figure explains the altered microbiota in diabetic wound healing. In general, diabetic foot wounds are complicated by various factors contributing to impaired tissue regeneration. Several factors impairing wound healing and associated factors are hyperglycaemia, peripheral neuropathy, vascular disease, and a complex microbiome. It is challenging to identify microbial communities that assemble in wound tissue and have not necessarily been associated with cardinal signs of infection. A debridement elicited reduced diversity of bacteria, governed by decreased anaerobic bacterial abundance in the overall community. One subset of wounds achieved complete re-epithelialization within 12 weeks. Kalan et al. [111] investigated the role of colonizing microbiota in wound healing, clinical outcomes, and a response to therapy in patients with chronic diabetic wounds. Strains of the wound pathogen S. aureus were associated with poor outcomes, and sharp debridement therapy depleted anaerobic bacteria in wounds with favorable outcomes.

Figure 3

This Venn diagram depicts all the microbes (commensal, genera as well as spp.) present in gut, skin, wound and DFU.