by University of Calgary

Intestinal dysbiosis with progressive Enterobacteriaceae enrichment in critical illness is associated with nosocomial infections. a, Taxonomic composition by relative abundance of bacterial families. b, Three-dimensional principal-coordinates analysis (Bray–Curtis dissimilarity distances, genus level) analyzed by PERMANOVA. c, Shannon index. d, Chao1 index in rectal swabs from critically ill patients on day 1 (n = 51) and again from survivors who remained in ICU on day 3 (n = 44) and day 7 (n = 15), compared to healthy volunteers (n = 15). Dots represent individual patients, central line indicates median, box shows interquartile range (IQR) and whiskers show range; analyzed by two-sided Kruskal–Wallis test (healthy versus ICU days) with pairwise comparisons of repeated measures across days using a mixed linear regression model with a post hoc Tukey’s test. e, MOFA of microbiota composition between healthy volunteers and ICU patients showing top ten taxonomic factors (families) and their relative contributions to explained microbiota variance (factor weight). f, Enterobacteriaceae relative abundance on days 1, 3 and 7 of ICU admission compared to healthy controls. Dots represent individual patients, central line shows median, box shows IQR and whiskers show range, analysis as per c and d. g, Correlation between Enterobacteriaceae relative abundance and Shannon index, analyzed using Spearman correlation test. Dots show individual patient samples, regression (line) and 95% confidence intervals (shaded area) are shown. h, Penalized ridge regression of the 15 most abundant bacterial families and their importance toward change in Shannon diversity from days 1–3 of ICU admission. i,j, Mean relative abundance († indicates P_adj < 0.1 by ANCOM-II differential abundance) (i) and correlation matrices (j) of the 15 most abundant bacterial families on ICU day 3. k, Longitudinal microbiota community stability index between patients with progressive Enterobacteriaceae enrichment (n = 18) or no enrichment (n = 26). Dots represent individual patients, central line shows the median, box shows IQR and whiskers show range; analyzed by two-sided Mann–Whitney U-test. l–n, The 30-d nosocomial infection-free survival analyzed by log-rank test (l), odds ratio of nosocomial infection caused by any pathogen or Enterobacteriaceae pathogen determined by two-sided Fisher’s exact test (m) and pathogens identified in nosocomial infections (n) (n = 30 infections in 28 patients). P values as shown in b; *P < 0.05, **P < 0.01. Credit: Nature Medicine (2023). DOI: 10.1038/s41591-023-02243-5

A University of Calgary study indicates a healthy microbiome may prevent deadly infections in critically ill people. The study looked at the interaction between the human gut and the immune system. Findings showed that the gut microbiota and systemic immunity work together as a dynamic "metasystem," in which problems with gut microbes and immune system dysfunction are associated with significantly increased rates of hospital-acquired infections.

The findings suggest that if we want to fight infection, we can't just target these bad bacteria in isolation and the immune system in isolation. The researchers say what's needed is a more holistic view of how things are functioning.

Twenty to 50 percent of all critically ill patients contract potentially deadly infections during their stay in the intensive care unit or in hospital after being in the ICU—markedly increasing the risk of death.

"Despite the use of antibiotics, hospital-acquired infections are a major clinical problem that persists to be a huge issue for which we don't have good solutions," says Dr. Braedon McDonald, MD, Ph.D., an intensive care physician at the Foothills Medical Centre (FMC) and assistant professor at the Cumming School of Medicine (CSM). "We tackled this issue from a different angle. We looked at the body's natural defense to infection to better understand why some people are more susceptible to these deadly infections."

The study involved 51 patients newly admitted to the intensive care unit (ICU) at FMC. Patients were studied over the first week of acute critical illness. The research showed that the gut microbiota and systemic immunity work together as a dynamic "metasystem," in which problems with gut microbes and immune system dysfunction are associated with significantly increased rates of hospital-acquired infections.

"The signal that we've seen in our research is that a family of bacteria, that naturally live in the gut, seems to be important for directing the immune system," says Jared Schlechte, Ph.D. candidate in McDonald's lab and first author of the study. "However, during critical illness the microbiome becomes injured allowing these bacteria to start taking over."

The study, published in Nature Medicine, found that patients who experienced an abnormal increase in the growth of this common bacteria, called a bloom, were at the highest risk of severe infections.

"This information is important because it gives us a whole new avenue to start thinking about not just ways to treat infections, but a potential treatment to prevent them," says McDonald. "The findings suggest that if we want to fight infection, we can't just target these bad bacteria in isolation and the immune system in isolation. We really need to have a more holistic view of how things are functioning."

As a next step, McDonald and the team plan to launch a randomized, controlled clinical trial—based on a precision medicine approach that borrows from probiotics therapy, and utilizes multiple different bacteria engineered to specifically target the bacteria identified in the study. People who agree to participate will be given engineered microbiomes.

"What we're trying to do is restore the normal mechanism that work when we're healthy, and take advantage of that to help protect people from infections," McDonald says.

More information: Jared Schlechte et al, Dysbiosis of a microbiota–immune metasystem in critical illness is associated with nosocomial infections, Nature Medicine (2023). DOI: 10.1038/s41591-023-02243-5

Provided by University of Calgary