Therapeutic Potential of the Gut Microbiota in the Management of Sepsis

Matteo Bassetti; Alessandra Bandera; Andrea Gori

Disclosures

Crit Care. 2020;24(105) 

In This Article

Mechanisms of Dysbiosis in Sepsis

During recent years, resident gut microbial flora has been identified as a key factor in a broad range of functions, such as food digestion, hormone production, and immune system development. Moreover, it has been demonstrated that a condition of disturbance of the gut microbiota, also termed "dysbiosis," can definitely influence host susceptibility to infections.

In general, the gut microbiota consists of three domains of life: bacteria, archaea, and eukarya. The human gut microbiota has a large variety of bacterial species—around 200 dominant species and 1000 non-dominant species—and they vary across individuals. The diversity within an individual's microbiota is known as alpha diversity, whereas different composition between individuals is called beta diversity. Four phyla represent most of the microbiota members: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria, the former and the latter accounting for more than 90% of the bacterial population of the colon. The bacteroidetes phylum is composed of Gram-negative, rod-shaped bacteria that digest complex polysaccharides with the release of volatile short-chain fatty acids that regulate intestinal epithelial cell growth as well as differentiation and stimulation of the immune system. The Firmicutes phylum is composed mainly of Gram-positive bacteria that can form endospores (Clostridia class). These bacteria release butyrate, promoting intestinal epithelial health and inducing colonic T regulatory cells. However, these phyla contain clinically relevant members such as Bacteroides fragilis, Clostridium perfringens, Clostridium difficile, Enterococcus spp., and Streptococcus spp. that can cause sepsis and fatal outcome during intestinal dysbiosis.[2] As the composition of the gut microbiota is specific for each person, dysbiosis can be interpreted as a relative change in the composition of an individual's commensal microbiota compared with others in the community, which can be loss of beneficial microbiota, increased pathogenic microbiota or decreased microbiota variety. Several mechanisms presenting during gut barrier dysfunction can be considered both a result and a cause of sepsis development: the increased permeability of gut mucosa, tissue edema, reduced perfusion, dysregulation of tissue coagulation, shift in the gut microbiome, apoptotic damage to the mucosal epithelia, and bacterial translocation. Gut mucosal perfusion is reduced during sepsis, which produces destruction of the mucosal barrier and increased permeability.[4] Transmigration of bacteria and endotoxin can induce relevant systemic effects, inducing an immune response in the local gut-associated lymphoid tissue (GALT), which in turn activates Toll-like receptor (TLR)4 and priming neutrophils, causing remote lung injury, explaining the appearance of acute respiratory distress syndrome (ARDS) during sepsis.[5] The dysregulation between diverse resident bacterial populations in the gut can lead to a "pathobiome" that finally dysregulates the immune system[6] (Box 1). Indeed, in critically ill patients, hypoxic injury, disrupted epithelial permeability, altered gut motility, and treatment with vasopressors, parenteral nutrition, and opioids facilitate the expansion of pathobionts, including multidrug-resistant (MDR) bacteria.[8] Commonly, the gut microbiome of septic intensive care unit (ICU) patients demonstrates a loss of microbial richness and diversity, dominance of a single taxon (often a potential pathogen), and loss of site specificity with isolation of the same organism at multiple sites.[9] The duration of ICU dysbiosis, the clinical impact of dysbiosis, and phenotypes of critically ill patients more prone to develop it are all aspects that need to be clarified.

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