The gut microbiome's role in the development, maintenance, and outcomes of sepsis

Abstract

The gut microbiome regulates a number of homeostatic mechanisms in the healthy host including immune function and gut barrier protection. Loss of normal gut microbial structure and function has been associated with diseases as diverse as Clostridioides difficile infection, asthma, and epilepsy. Recent evidence has also demonstrated a link between the gut microbiome and sepsis. In this review, we focus on three key areas of the interaction between the gut microbiome and sepsis. First, prior to sepsis onset, gut microbiome alteration increases sepsis susceptibility through several mechanisms, including (a) allowing for expansion of pathogenic intestinal bacteria, (b) priming the immune system for a robust pro-inflammatory response, and (c) decreasing production of beneficial microbial products such as short-chain fatty acids. Second, once sepsis is established, gut microbiome disruption worsens and increases susceptibility to end-organ dysfunction. Third, there is limited evidence that microbiome-based therapeutics, including probiotics and selective digestive decontamination, may decrease sepsis risk and improve sepsis outcomes in select patient populations, but concerns about safety have limited uptake. Case reports of a different microbiome-based therapy, fecal microbiota transplantation, have shown correlation with gut microbial structure restoration and decreased inflammatory response, but these results require further validation. While much of the evidence linking the gut microbiome and sepsis has been established in pre-clinical studies, clinical evidence is lacking in many areas. To address this, we outline a potential research agenda for further investigating the interaction between the gut microbiome and sepsis.

Keywords: Sepsis, Gut microbiome, Review, Probiotics, Fecal microbiota transplant.

Fig. 1

Conceptual illustration of the pathway between gut microbiome disruption and sepsis. Gut microbiome alteration predisposes to selection for pathobionts (potentially pathogenic bacteria that can reside in the gut microbiome), immune dysregulation, and decreased production of short-chain fatty acids, beneficial products produced by the gut microbiome. These changes can lower the threshold for sepsis development. Sepsis and treatment with antibiotics can drive worsening microbiome disruption in a vicious cycle, contributing to ongoing end-organ dysfunction. ARDS, acute respiratory distress syndrome; FMT, fecal microbiota transplant; MDRO, multi-drug resistant organism; SCFA, short-chain fatty acid