Gut Microbial Changes and their Contribution to Post-Burn Pathology

Abstract

Burn injuries are a common form of traumatic injury that leads to significant morbidity and mortality worldwide. Burn injuries are characterized by inflammatory processes and alterations in numerous organ systems and functions. Recently, it has become apparent that the gastrointestinal bacterial microbiome is a key component of regulating the immune response and recovery from burn and can also contribute to significant detrimental sequelae after injury, such as sepsis and multiple organ failure. Microbial dysbiosis has been linked to multiple disease states; however, its role in exacerbating acute traumatic injuries, such as burn, is poorly understood. In this article, we review studies that document changes in the intestinal microbiome after burn injury, assess the implications in post-burn pathogenesis, and the potential for further discovery and research.

Figure 1.. Categorization of burn wound injury.

In addition to wound size, the depth of tissue affected by burn injury contributes to the wound categorization, treatment and patient outcomes. Burn that are restricted to the epidermis are considered superficial and categorized as first-degree burns. Second-degree burns are partial thickness injuries that penetrate varying depths below the epidermis and into the dermis. Once the burn injury penetrates the entire dermal layer and begins to effect the subcutaneous fat layer, the injury is classified as a third-degree burn. These are considered full-thickness burns and result in the destruction of nerve endings which make the wound pain-free. However, burns of this depth require careful management and surgery to support healing and prevent wound infection. A burn that penetrates further and damages the underlying muscle, and even bone, are classified as fourth-degree burn. An injury of this severity often results in permanent damage to the tissue and possible amputation of the injured area.

Figure 2.. Representation of the intestinal barrier and gut microbiome under healthy and burn-injured conditions.

Under healthy conditions, the intestinal barrier is intact and composed of intestinal epithelial cells (IEC) that are tightly bound together by tight junction proteins. Goblet cells that produce mucus (light green) and enteroendocrine cells (yellow) are interspersed between IECs. In the intestinal crypt, there are intestinal stem cells (blue) that continuously replicate and regenerate IECs that are shed in the lumen. Paneth cells (orange) producing anti-microbial peptides (AMPs). M-cells (purple) are continuously testing luminal contents for uptake by any resident antigen presenting cells. Under the IEC barrier is the lamina propria, which contains a variety of immune cells, including dendritic cells, monocytes, and T/B cells (blue). Secretory IgA is continuously passed into the lumen to maintain homeostatic conditions with the microbiome. Under healthy conditions, there is a large diversity of intestinal microbiota with few pathogenic species. With burn injury (right panel), there is a loss of tight junction proteins and the mucus barrier, along with increased IEC apoptosis, leading to a leaky gut. Increased inflammatory cell infiltration by neutrophils and macrophages leads to production of reactive oxygen species (ROS) and further damage of the barrier, allowing for intestinal bacterial and bacterial products to translocate into systemic circulation. Furthermore, there is overgrowth of pathogenic bacterial species and loss of bacterial diversity in the lumen. This image was adapted from Hammer et. al, Alcohol Res. 2015;37(2):209-22.

Figure 3.. Representation of end organ injury and dysfunction following burn injury and microbial dysbiosis.

Both burn and dysbiosis are known to perturb the normal function of the gastrointestinal system. Factors altered in burn injury include barrier dysfunction, gut motility, and bacterial translocation into systemic circulation. This contributes to end organ dysfunction, including hepatic damage, lung injury, and pneumonia. Finally, burn injury and bacterial dysbiosis/translocation is linked to aberrant immune function, including neutrophil infiltration into various tissues, reactive oxygen species (ROS) and inflammatory cytokine production, and lymphocyte dysfunction. Burn injury itself is linked to dysbiosis, however, further work is needed to understand the contribution of microbial dysbiosis and its impact on deleterious outcomes for burn patients, as well as its impact on their recovery.