Nosocomial infection risks in critical illness: the microbiota-immune metasystem connection

An altered metasystem linking the gut microbiota and systemic immune response could lead to impaired host defense and increased vulnerability to hospital-acquired infections in cases of severe illness.
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What is already known
Intensive care unit (ICU) patients who are critically ill undergo significant changes in their gut microbiota, which have been linked to a higher risk of hospital-borne infections and adverse outcomes. The mechanisms behind this connection are not entirely clear. Studies in mice and research on humans imply that the gut microbiota plays a role in maintaining overall immune homeostasis. Additionally, imbalances in the gut microbiota may result in a weakened immune defense against infections.

What this research adds
A recent prospective longitudinal cohort study on severely ill patients, demonstrate that the gut microbiota and systemic immunity work in unison as a metasystem, where disruptions in intestinal microbiota coincide with compromised host defense, and elevated occurrence of nosocomial infections. By using 16s rRNA gene sequencing of rectal swabs and mass cytometry to profile single cells in the blood, researchers determined that the microbiota and immune responses during acute critical illness were closely linked. The findings showed that there was a significant increase in Enterobacteriaceae in the gut microbiota, which corresponded with dysregulated myeloid immune cell responses, systemic inflammation, and reduced adaptive host defense mechanisms. The study also found that the increased presence of Enterobacteriaceae was associated with impaired innate immune responses, including immature and hypofunctional neutrophils. This resulted in a higher risk of infections by various bacterial and fungal pathogens.

This study indicates that an altered metasystem linking the gut microbiota and systemic immune response could lead to impaired host defense and increased vulnerability to hospital-acquired infections in cases of severe illness.

Patients who are critically ill and require life-support interventions in intensive care units have a high risk of developing hospital-acquired infections, which can increase their risk of mortality. This susceptibility to infection in such patients is linked to a breakdown of the immune system’s ability to defend against pathogens, as well as the use of medical devices that compromise physical barriers in the body.

These infections in the ICU are usually caused by pathogens that are not typically associated with invasive disease in healthy individuals, indicating a severely impaired host defense. However, the mechanisms that lead to immune dysfunction in critically ill patients are not well understood.

Gut microbes play a crucial role in maintaining immune equilibrium and protecting the host in the gut and other systemic compartments. However, severely ill patients experience severe gut microbiota imbalances or dysbiosis, as observed in ICU and other hospitalized patients, leading to an increased risk of adverse outcomes, including infections. 

A recent study by Mc Donald and colleagues, published in Nature medicine journal, showed that the intestinal microbiota and systemic immune response of acute critical illness are functionally integrated as a dynamic metasystem, and dysbiosis of this metasystem is associated with progressive Enterobacteriaceae expansion in the gut microbiota, dysregulated innate imunity and increased incidence of bacterial and fungal nosocomial infections.

51 critically ill adults admitted to medical, surgical, trauma and neurological ICUs in Calgary were enrolled in the study. A prospective, longitudinal, integrated multi-omics analysis of the fecal microbiota, as well as of systemic cellular immune and inflammatory responses indicated a shift in the gut microbiota’s composition characterized by progressive enrichment of Enterobacteriaceae triggering disruption of innate immunity, which resulted in impaired host defense and increased vulnerability to bacterial and fungal infections acquired in hospitals.

Pathological gut microbiota is associated with nosocomial infections in critically ill patients

Analysis of fecal microbiota composition from rectal swab samples revealed gut dysbiosis in ill patients compared to healthy volunteers, with reduced taxonomic diversity, richness and significant shifts in microbial community. Progressive alteration of biodiversity, taxonomic richness and compositional shifts, characterized by loss of commensal anaerobic microbes and emergence of Enterococcaceae and Enterobacteriaceae, was observed. Dysbiosis of the fecal bacterial microbiota was established at the time of ICU admission and exhibited dynamic and progressive changes during the acute phase of critical illness. 

Enterobacteriaceae was the most important family associated with the change in microbiota diversity over time in ICU patients and Enterobacteriaceae relative abundance was higher in rectal swab samples of critically ill patients compared to healthy controls, with individual patient variability that was dynamic over the first week of ICU admission. Moreover, progressive Enterobacteriaceae enrichment was linked to a reduction in overall bacterial community stability. Interestingly, patients with progressive Enterobacteriaceae enrichment had significant higher risk of infection or death compared to patients with decreased Enterobacteriaceae. 

Dysbiosis of a microbiota–immune metasystem in critical illness

The authors next conducted a comprehensive analysis of the cellular immune and inflammatory environments in the blood of each patient. Significant changes in innate and adaptive immunity were observed in critically ill patients, that evolved throughout the first week of hospitalization. The cellular immune response in acute critical illness was dominated by an early and sustained elevation of neutrophils, together with depletion of T and B lymphocytes as well as natural killer cells and inflammatory factors. These data revealed dynamic cellular immune and inflammatory responses in critically ill patients characterized by early innate immune dysregulation and systemic inflammation, followed by progressive innate and adaptive immune dysfunction

Significant interactions between microbial taxa and immune components were observed in ICU patients compared to healthy volunteers. Augmented microbiota–immune connectivity was sustained through the early phase of critical illness, and the associations between Enterobacteriaceae and both cellular and inflammatory mediators were unique compared to all other microbial families. Strong correlations were found between Enterobacteriaceae abundance and innate immune responses, with systemic inflammatory mediators; whereas no correlations were found with acute phase reactants. Changes in the magnitude of correlations between Enterobacteriaceae and inflammatory and innate immune landscapes were observed, whereas no significant difference was detected in the circulating inflammatory mediator landscape between patients with and without progressive Enterobacteriaceae enrichment. Collectively, these data demonstrate that microbiota and cellular immune dynamics during acute critical illness function as an integrated metasystem and identify progressive Enterobacteriaceae enrichment as a possible driver of overall metasystem dysbiosis

Metasystem dysbiosis causes innate immune defense breakdown

The authors next found that innate, but not adaptive, immune cell compartment in patients with progressive Enterobacteriaceae enrichment was significantly different in patients with progressive Enterobacteriaceae enrichment in the fecal microbiota compared to those without enrichment. This difference was characterized by large shifts in neutrophil clusters, with more limited impact on monocytes, dendritic cells and innate lymphocytes. Strong correlations were observed in ICU patients between Enterobacteriaceae relative abundance and increased immature neutrophils and decreased mature neutrophils. ICU patients with progressive Enterobacteriaceae enrichment in their fecal microbiota had a notable shift in neutrophils over time. Overall, these findings reveal that increased susceptibility to nosocomial infections in the setting of progressive Enterobacteriaceae enrichment is coupled to dysregulated and hypofunctional neutrophil responses. 

In conclusion, pathological microbiota alterations in critical illness may render the host more susceptible to infections via induction of immune dysfunction, suggesting important therapeutic implications for prevention and treatment of infections in the ICU, a leading cause of adverse outcomes in critical illness including mortality and prolonged hospitalization. Intestinal Enterobacteriaceae expansion can be used as a marker of metasystem dysbiosis in critical illness and targeting intestinal Enterobacteriaceae could be a strategy to reduce infections and adverse outcomes by fortifying systemic immune defenses. Future studies are needed to uncover additional mechanisms of immune dysfunction and microbial alterations of the gut or other sites that contribute to metasystem dysbiosis and impaired host defense in critical illness.