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

Dysbiosis as a Potential Risk Factor for Sepsis

It is generally assumed that sepsis mortality is due to an immunologic disorder, where the causative pathogen is considered irrelevant once the deregulated immune response has begun.[10] As a healthy gut microbiota has been demonstrated to have protective effects on the host and to prevent colonization with MDR bacteria, several researchers have hypothesized that shifts in microbiota composition potentially predispose patients to a state of immunosuppression and thus increase the risk of sepsis.

In an animal model of mice fed with an obesogenic Western diet, a diet high in fat and sucrose and low in fiber, it has been recently demonstrated that they become susceptible to lethal sepsis with multiple organ damage after exposure to antibiotics and an otherwise-recoverable sterile surgical injury. Analysis of the gut microbiota in this model demonstrated that the Western diet alone led to loss of Bacteroidetes, increased Proteobacteria, and had evidence of antibiotic resistance development even before antibiotics were administered. In this elegant work, it was clearly shown how the selective pressures of diet, antibiotic exposure, and surgical injury can converge on the microbiome, resulting in lethal sepsis and organ damage without the introduction of an exogenous pathogen.[11]

A similar recent study conducted by Napier and colleagues, while confirming the effect of Western diet on disease state and outcomes of a lipopolysaccharide (LPS)-driven sepsis model, found that this relationship was independent of the microbiome. Indeed, they demonstrated that Western diet-fed mice had higher baseline inflammation and signs of sepsis-associated immunoparalysis compared with mice fed with standard fiber-rich chow. Western diet mice also had an increased frequency of neutrophils, some with an "aged" phenotype, in the blood during sepsis compared with standard fiber-rich mice. Importantly, they found that the Western diet-dependent increase in sepsis severity and higher mortality was independent of the microbiome, suggesting that the diet may be directly regulating the innate immune system through an unknown mechanism.[12]

This preclinical observation has been confirmed by some limited clinical studies in which patients who developed sepsis showed an altered microbiota pattern at baseline. In a recent study, differences in the gut microbiota and plasma LPS level were evaluated in 32 patients who underwent splenectomy and 42 healthy individuals. The splenectomy group was divided into three subgroups according to the length of their postoperative time. Significant differences were observed in gut microbiota composition measured by 16s rRNA gene sequencing with regard to the relative bacterial abundances of 2 phyla, 7 families, and 15 genera. The LPS level was significantly higher in the splenectomy group than in healthy controls and was negatively associated with five bacterial families with low abundance in the splenectomy group. Interestingly, the degree of gut microbiota alteration increased with the length of the postoperative time.[13] Similarly, a seminal study showed that patients undergoing allogeneic bone marrow transplantation who developed antibiotic-induced dysbiosis had a five- to ninefold increased risk of bloodstream infection and sepsis.[14] These observations were confirmed by a retrospective cohort study including over 10,000 elderly patients in the United States and showing that dysbiosis was associated with a more than threefold increased incidence of a subsequent hospitalization for sepsis.[15] Expanding on these findings, Baggs et al. recently showed that exposure to longer durations of antibiotics, additional classes of antibiotics and broader-spectrum antibiotics during hospitalization were each associated with dose-dependent increases in the risk of subsequent sepsis. This association was not found for other causes of hospital readmissions, suggesting that the association between antibiotic exposure and subsequent sepsis is related to microbiome depletion, not to severity of illness.[16]

Accumulating evidences thus indicate that gut microbiota disruption may increase the risk of sepsis; future innovations focused on restoring or protecting the gut microbiota from disruption might become a possible approach for preventing sepsis, especially in fragile populations.

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