Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis

Abstract

Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. Patients with sepsis have a profoundly distorted composition of the intestinal microbiota, but the impact and therapeutic potential of the microbiome is not well-established in human sepsis. Modulation of the microbiota consists of either resupplying the pool of beneficial microbes by administration of probiotics, improving the intestinal microenvironment to enhance the growth of beneficial species by dietary interventions and prebiotics, or by totally recolonizing the gut with a fecal microbiota transplantation (FMT). We propose that there are three potential opportunities to utilize these treatment modalities over the course of sepsis: to decrease sepsis incidence, to improve sepsis outcome, and to decrease late mortality after sepsis. Exploring these three avenues will provide insight into how disturbances of the microbiota can predispose to, or even perpetuate the dysregulated immune response associated with this syndrome, which in turn could be associated with improved sepsis management.

Keywords: fecal microbiota transplantation; microbiota; pathogenesis; probiotics and synbiotics; sepsis; therapeutics.

Figure 1

Overview of systemic immunomodulatory mechanisms associated with the microbiota. Structural components of gut microbiota, otherwise known as microbe-associated molecular patterns (MAMPs), can elicit a systemic pro-inflammatory response by activating pattern recognition receptors of both the innate and the adaptive immune system. Microbial metabolites, such as short chain fatty acids (SCFAs) modulate epigenetic changes in host leukocytes, which can induce both pro- and anti-inflammatory responses. The presence of the SCFAs butyrate and propionate drives the generation of regulatory T cells (T_reg), which dampen inflammation. In addition, the gut metabolite desaminotyrosine enhances clearance of respiratory viruses by inducing type 1 interferon (IFN) responses. Direct interactions with epithelial cells by segmented filamentous bacteria (SFB) can enhance mucosal immunity by upregulating T helper 17 (Th 17) cells in both in the gut and in the lung. It is important to realize that our knowledge on microbiota-derived host-resistance is fragmented and it remains to be determined how these individual mechanisms fit in an overarching framework of systemic immunity. DC, dendritic cell; ILC3, type 3 innate lymphoid cell; Treg cell, regulatory T cell; IgA, Immunoglobulin A; IgG, Immunoglobulin G; IgM, immunoglobulin M; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MLP, murein lipoprotein.

Figure 2

Timeline of potential microbiota-associated interventions prior to, during and post-sepsis. (A) Hypothetical diagram of the associations between the risk of dysbiosis and sepsis development and outcome. Dysbiosis occurs due to the administration of antibiotics and/or hospitalizations, recover quickly upon hospital discharge or cessation of antibiotic treatment, but it often takes long for the microbiota to recover entirely. These periods of dysbiosis predispose to the development of opportunistic infections, which in turn further worsens the state of dysbiosis and predispose to sepsis development. During sepsis, the microbiota composition is extremely hampered, which has been associated with an increased risk of secondary infections, immunosuppression and potentially even organ dysfunction. Recolonization of a homeostatic microbiota is slow upon hospital discharge and sepsis recovery, which might contribute to prolonged immunosuppression, rehospitalization due to infections and increased mortality. (B) Probiotics and synbiotics have the potential to enhance microbiota colonization in neonates, as well as accelerate the recovery of the microbiota after periods of dysbiosis, which in turn could provide protection against the development of sepsis. During the course of sepsis, microbiota disruption could be ameliorated by the administration of pro- and synbiotics, which potentially reduces the occurrence of secondary infections. In addition, future treatment with fecal microbiota transplantation (FMT) or targeted restoration with microbiota-associated metabolites, such as short-chain fatty acids (SCFAs), could reduce the risk of prolonged immunosuppression and organ dysfunction. Finally, microbiota restoration after sepsis recovery could be accelerated with pro- and synbiotics, or by an autologous FMT. ^*Time depiction is schematic.