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

The Gut Microbiota as a Predictor of Clinical Outcome in Sepsis

The transition of a microbiome into a pathobiome has also been hypothesized to be a driver of severe outcome and mortality from sepsis, at least in part by the ability of invading bacteria to act as antigens and thus modulate the host immune response.

In animal models, the effect of the gut microbiome on sepsis outcome has been clearly demonstrated by different studies. In a well-designed recent study, sepsis evolution was analyzed in genetically identical, age- and sex-matched mice obtained from different vendors and subjected to cecal ligation and puncture (CLP), the most frequently used model of sepsis.[17] Beta diversity of the microbiome measured from feces of mice coming from two different laboratories demonstrated significant differences and, more importantly, mice from the first lab had significantly higher mortality following CLP, as compared to mice from the second lab (90% vs. 53%). Differences were also found in immune phenotypes in splenic or Peyer's patch lymphocytes. To verify if the differences in the microbiome were responsible for the different outcomes, mice were co-housed for 3 weeks, after which they assumed a similar microbiota composition. Interestingly, co-housed mice had similar survival regardless of their vendor of origin and differences in immune phenotype disappeared. This elegant experiment clearly shows that the microbiome plays a crucial role in survival from and in the host immune response to sepsis, representing a potential target for therapeutic intervention.

Clinical studies also confirmed the observation that outcome of sepsis could be influenced by gut microbiota disruption. In the ICU setting, Shimizu et al. quantitatively measured changes in gut microbiota in patients with systemic inflammatory response syndrome (SIRS). These patients had 100–10,000 times fewer total anaerobes, including Bifidobacterium and Lactobacillus, and 100 times more Staphylococcus bacteria compared with healthy volunteers. An important finding of this study was that the dominant factors associated with mortality and septic complications were the numbers of total obligate anaerobes.[6] To evaluate the effect of dynamics of the gut microbiome, a single-center study prospectively analyzed 12 ICU patients and showed that changes in the gut microbiota can be associated with patient prognosis.[18] Indeed, the proportions of Bacteroidetes and Firmicutes significantly changed during the stay in the ICU, and "extreme changes" in the Bacteroides/Firmicutes ratio were observed in almost all the patients with a poor prognosis, suggesting a correlation between alteration in gut microbiota composition and sepsis outcome.[18]

The gut has been also hypothesized to be "the motor" of multiple organ dysfunction syndrome (MODS), as reviewed by Klingensmith and Coopersmith.[19] Indeed, evidence from models of murine sepsis and from human patients with ARDS has shown that the lung microbiota is enriched by bacteria translocating from the gut. Importantly, the presence of these bacteria, such as Bacteroides spp, is associated with the grade of systemic and local inflammation.[20] Moreover, preliminary studies performed in mice and in patients dying from sepsis suggest that microbial translocation from the gut can be related to neuro-inflammation in sepsis.[21] All these observations provide evidence that dysbiosis observed during sepsis could potentially contribute to worsening inflammation and consequently severe clinical outcome. However, well-designed human clinical studies are still needed as our current knowledge of the consequences of ICU-related dysbiosis in clinical practice is limited.

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